Protein degraders and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for the targeted degradation of proteins, and the treatment of target protein-mediated disorders.

Description

PROTEIN DEGRADERS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Appl. No.63 / 380,922, filed October 25, 2022, the entirety of which, is herein incorporated by reference. TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods useful for the modulation of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degraded and / or otherwise inhibited by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION

[0003] Ubiquitin-Proteasome Pathway (UPP) or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity.

[0004] Cullin RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases. In the CRL ligase complexes, cullin serves as a scaffold to bind small RING finger protein ROC1 or ROC2 (RBX1 or RBX2) through a C-terminal domain and a linker-substrate receptor dimer or a substrate receptor directly through an N-terminal domain. Mammalian cells express nine distinct cullins, including two cullin 4 (CUL4) proteins: CUL4A and CUL4B, which use DNA damage-binding protein 1 (DDB1) as the linker. DDB1 bridges the interaction between CUL4 and a subset of DDB1 binding WD40 repeat proteins (DWD or DCAFs for DDB1 cullin associated factors). These DCAF proteins function as substrate receptors to target specific substrates to the CRL4 E3 complexes. One of the most abundant DCAF proteins is DDB1-and CUL4-associated factor 1 or DCAF1 (also known as VprBP).

[0005] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome- dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer thepossibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).

[0006] An ongoing need exists in the art for effective treatments for disease, especially cancer. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage or potentiate DCAF1 substrate specificity and, at the same time, are “tunable” such that a wide range of protein classes can be targeted and modulated with specificity would be very useful as a therapeutic. Accordingly, there remains a need to find bifunctional compounds that are DCAF1-based protein degraders useful as therapeutic agents. SUMMARY OF THE INVENTION

[0007] The present application relates novel compounds which modulate DCAF1 and / or function to recruit targeted proteins to DCAF1 for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation / inhibition of targeted polypeptides from virtually any protein class or family. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer.

[0008] The present application further relates to targeted degradation of proteins through the use of bifunctional molecules, including bifunctional molecules that link a DCAF1 binding moiety to a ligand that binds the targeted protein. Such compounds have the general formula I:or a pharmaceutically acceptable salt thereof, wherein: TBM is target binding moiety capable of binding to a targeted protein(s); L is a bivalent moiety that connects TBM to DBM; and DBM is a DCAF binding moiety capable of binding to DCAF1 protein.

[0009] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions. Such diseases, disorders, or conditions include those described herein.

[0010] Compounds provided by this invention are also useful for the study of DCAF1 and targeted proteins in biological and pathological phenomena; the study of DCAF1 and targeted proteins occurring in bodily tissues; and the comparative evaluation of new DCAF1 or targeted protein ligands or other regulators of DCAF1 or targeted proteins in vitro or in vivo. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention:

[0011] Compounds of the present invention, and compositions thereof, are useful for the modulation DCAF1 and targeted ubiquitination. As defined herein, the terms “binder,” “modulator,” and “ligand” are used interchangeably and describe a compound that binds to, modulates or is a ligand for DCAF1 or a targeted protein.

[0012] In certain embodiments, the present invention provides a compound of formula I as a compound of any one of the following formulae:I-b’ or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. 2. Compounds and Definitions:

[0013] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0014] 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 completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0015] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads,where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include: HN

[0016] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0017] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0018] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H- pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0019] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0020] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0021] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0022] The term “alkenylene” refers to a bivalent 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 a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0023] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[0024] The term “halogen” means F, Cl, Br, or I.

[0025] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein 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 present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0026] The terms “heteroaryl” and “heteroar–,” 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 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. 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, without limitation, 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 “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, 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. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 9–membered monocyclic or 7– to 11–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, 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 a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0029] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0030] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are 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 substituent may be either the same or different at every position. Combinations of substituents envisioned by this 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 not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OR ^)2; –(CH2)0–4SR ^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; – (CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R ^)2; – (CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH2)0–4N(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)0–4C(O)R ^; –C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)0–4C(O)OSiR ^3; –(CH2)0–4OC(O)R ^; –OC(O)(CH2)0–4SR ^; -SC(S)SR°; –(CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; -(CH2)0–4OC(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)0–4S(O)2R ^; – (CH2)0–4S(O)2OR ^; –(CH2)0–4OS(O)2R ^; –S(O)2NR ^2; -(CH2)0–4S(O)R ^; -N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; –C(NH)NR ^2; –-(CH2)0–4P(O)2R ^; –-(CH2)0–4P(O)R ^2; – (CH2)0–4OP(O)R ^2; –(CH2)0–4OP(O)(OR ^)2; –SiR ^3; –(C1–4 straight or branched alkylene)O–N(R ^)2; or – (C1–4straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3–12–memberedsaturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0032] Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, – (haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, – (CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, – (CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^,–(C1–4straight or branched alkylene)C(O)OR^, or – SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S.

[0033] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on the aliphatic group of R†are independently halogen, –R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, 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 and the like, and are 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, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, 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, valerate salts, and the like.

[0039] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0040] 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; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, and Ra(or M) and Sa(or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds 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. Additionally, 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, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a provided compound may be substituted with one or more deuterium atoms.

[0041] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0042] As used herein, the term “binder” or “inhibitor” is defined as a compound that binds to DCAF1 and binds to or inhibits a targeted protein with measurable affinity. In certain embodiments, an inhibitor has an IC50and / or binding constant of less than about 50 ^M, less than about 1 ^M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0043] As used herein, the term “degrader” is defined as a heterobifunctional compound that binds to and / or inhibits both a target protein and an E3 ligase with measurable affinity resulting in the ubiqitination and subsequent degradation of the target protein. In certain embodiments, a degrader has an DC50 of less than about 50 ^M, less than about 1 ^M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0044] A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attachedvia a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of 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.

[0045] As used herein, the term “detectable moiety” is used interchangeably with the term "label" and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium,32P,33P,35S, or14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.

[0046] The term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.

[0047] The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 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, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), 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, Texas Red-X.

[0048] The term “mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass- tags include electrophore release tags such as N-[3-[4’-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3- methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and5,650,270. Other examples of mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.

[0049] The terms “measurable affinity” and “measurably modulate,” as used herein, means a measurable change in a DCAF1 activity between a sample comprising a compound of the present invention, or composition thereof, and DCAF1, and an equivalent sample comprising DCAF1, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments:

[0050] The compounds of the present application include DCAF1 binding compounds and bifunctional molecules that link a DCAF1 binding moiety to a ligand that bind target proteins, bifunctional compounds having the general formula I:or a pharmaceutically acceptable salt thereof, wherein: TBM is target binding moiety capable of binding to a targeted protein(s); L is a bivalent moiety that connects TBM to DBM; and DBM is a DCAF binding moiety capable of binding to DCAF1 protein. DCAF1 Binding Moiety (DBM)

[0051] As described above and in certain embodiments, the present invention provides a compound of formula I-a:I-a or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined and described herein, and wherein:Ring E is phenyl, a 4-7 membered partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring F is phenylenyl, a 4-10 membered partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Y1is a C1-3 hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, - C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-; Rais an optionally substituted C1-6aliphatic orRing G is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rbis hydrogen, an optionally substituted C1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Raand Rbare optionally taken together with their intervening atoms to form an optionally substituted 9-10 membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: when Y1is -C(NR)-, Rbis optionally taken together with R of -C(NR)- with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 nitrogen atoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur; Rcis -CR2CONR2, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rdis hydrogen, or: when Rcis -CR2CONR2, Rdis optionally taken together with a single R of -CR2CONR2with their intervening atoms to form a 5-7 membered saturated or partially unsaturated heterocyclyl with 0-3 heteroatoms, in addition to the nitrogen atom to which Rdis attached, independently selected from nitrogen, oxygen, and sulfur; Re, Rf, and Rgare each independently selected from hydrogen, oxo, RA, 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; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; each of s’ and s’’ are independently 0 or 1; and each of e, f, and g are independently 0, 1, 2, 3, or 4; wherein said compound of formula I-a is optionally substituted withis a warhead group.

[0052] As described above and in certain embodiments, the present invention provides a compound of formula I as a compound of formula I-a’:or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined and described herein, and wherein: Ring E is phenyl, naphthyl, a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring F is phenyl, a 4-11 membered partially unsaturated monocyclic or bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Y2is a C1-4hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, - C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, -S(O)2-, -C(OR)=N-, -N(Rd)-, or -O-; Rais hydrogen, an optionally substituted C1-6aliphatic, orRing G is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rbis hydrogen, an optionally substituted C1-6aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Raand Rbare taken together with their intervening atoms to form an optionally substituted 9-10 membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: when Y1is -C(NR)-, Rbis taken together with R of -C(NR)- with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur; Rcis halogen, -CN, -CFR2, -CF2R, -CF3, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)(NR)R, -S(O)R, -C(O)R, -CR=NOR, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -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, -P(O)(NR2)2, -CR2CN, -CR2CFR2, - CR2CF2R, -CR2CF3, -CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, - CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, - CR2C(O)NR2, -CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2OP(O)R2, - CR2OP(O)(OR)2, -CR2OP(O)(OR)NR2, -CR2OP(O)(NR2)2, -CR2NRC(O)OR, -CR2NRC(O)R, - CR2NRC(O)N(R)2, -CR2NRS(O)2R, -CR2NP(O)R2, -CR2NRP(O)(OR)2, -CR2NRP(O)(OR)NR2, - CR2NRP(O)(NR2)2, -CR2P(O)R2, -CR2P(O)(OR)2, -CR2P(O)(OR)NR2, -CR2P(O)(NR2)2, - CR2CR2CN, -CR2CR2CFR2, -CR2CR2CF2R, -CR2CR2CF3, -CR2CR2NO2, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, - CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, -CR2CR2CR=NOR, -CR2CR2C(O)OR, - CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2OP(O)R2, -CR2CR2OP(O)(OR)2, -CR2CR2OP(O)(OR)NR2, - CR2CR2OP(O)(NR2)2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, - CR2CR2NRS(O)2R, -CR2CR2NP(O)R2, -CR2CR2NRP(O)(OR)2, -CR2CR2NRP(O)(OR)NR2, - CR2CR2NRP(O)(NR2)2, -CR2CR2P(O)R2, -CR2CR2P(O)(OR)2, -CR2CR2P(O)(OR)NR2, - CR2CR2P(O)(NR2)2, -CR2CR(OR)CR2OR, or an optionally substituted group selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: -(CR2)0-2C(O)Rccor -(CR2)0-2S(O)0-2Rcc; or: Rband Rcare taken together with their intervening atoms to form an optionally substituted 4-6 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: Rais absent and Rband Rcare taken together with their intervening atoms to form an optionally substituted phenyl; Rdis hydrogen or an optionally substituted C1-6 aliphatic, or: when Rcis -CR2CONR2, Rdis taken together with a single R of -CR2CONR2with their intervening atoms to form a 5-7 membered saturated or partially unsaturated heterocyclyl with 0-3 heteroatoms, in addition to the nitrogen atom to which Rdis attached, independently selected from nitrogen, oxygen, and sulfur; Re, Rf, and Rgare each independently selected from hydrogen, RA, 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, -C(NOR)R, -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; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rccis RA, halogen, -CN, -OR, -SR, -NR2, -NROR, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -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; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, naphthyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, or on different atoms, are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom, or different atoms, to which they are attached, independently selected from nitrogen, oxygen, and sulfur; s” is 0 or 1; each of e, f, and g are independently 0, 1, 2, 3, or 4; wherein said compound of formula I-a’ is optionally substituted with ,nrhead group.

[0053] As described above and in certain embodiments, the present invention provides a compound of formula I-b:I-b or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined and described herein, and wherein: Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, orspirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring I is phenylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring K is phenyl, naphthyl, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroarylenyl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rh, Ri, Rj, and Rkare each independently selected from hydrogen, oxo, RA, 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: an Rigroup on Ring I and an Rjgroup or Ring J are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur;each of X1and X2is independently a covalent bond, spiro-fusion between the two rings that X1or X2connect, -CR2-, -CR(OR)-, -CRF-, -CF2-, -NR-, -O-, -S-, or -S(O)2-; each of s’ and s’’ are independently 0 or 1; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4; wherein said compound of formula I-b is optionally substituted withis a warhead group.

[0054] As described above and in certain embodiments, the present invention provides a compound of formula I as a compound of formula I-b’:I-b’ or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined and described herein, and wherein: Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring I is phenylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring J is phenylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring K is phenyl, naphthyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroarylenyl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rh, Ri, Rj, and Rkare each independently selected from hydrogen, RA, 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: an Rigroup on Ring I and an Rjgroup or Ring J are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: an Rjgroup on Ring J and an Rkgroup or Ring K are optionally taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, naphthyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, or on different atoms, are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom, or different atoms, to which they are attached, independently selected from nitrogen, oxygen, and sulfur; each of X1and X2are independently a covalent bond, spiro-fusion between the two rings that X1or X2connect, or a bivalent, saturated or unsaturated, straight or branched C1-6 hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, - CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-; s” is 0 or 1; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4; wherein said compound of formula I-b’ is optionally substituted with ,nhead group. [ in and described below, wherein a formula is depicted using square brackets, eLis attached to a modifiable carbon, oxygen, or nitrogen atom within the referenced DCAF1 binder genus including substitution on or replacement of a defined variable within the referenced DCAF1 binder genus.

[0056] As described above and defined herein, Ring E is phenyl, naphthyl, a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0057] In some embodiments, Ring E is phenyl. In some embodiments, Ring E is naphthyl. In some embodiments, Ring E is a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl. In some embodiments, Ring E is a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0058] In some embodiments, Ring E is phenyl, naphthyl, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0059] In some embodiments, Ring E is phenyl or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0060] In some embodiments, Ring E is phenyl or a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0061] In some embodiments, Ring E is phenyl or a 5-6-membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0062] In some embodiments, Ring E is cyclobutyl, azetinyl, cyclohexyl, cyclohexenyl, tetrahydro- 2H-pyranyl, 3,6-dihydro-2H-pyranyl, pyrrolidinyl, imidazolyl, 4,5-dihydro-1H-pyrazolyl, piperidinyl, phenyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 2,3-dihydro-1H-indenyl, indolyl, benzoimidazolyl, pyrazolo[1,5-a]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, bicyclo[2.2.2]octane, or naphthyl.

[0063] In some embodiments, Ring E is as depicted in the compounds of Table 1A or 1B, below.

[0064] As described above and defined herein, Ring F is phenylenyl, a 4-11 membered partiallyunsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;.

[0065] In some embodiments, Ring F is phenylenyl. In some embodiments, Ring F is a 4-11 membered partially unsaturated monocyclic or bicyclic carbocyclylenyl. In some embodiments, Ring F is a 4-11 membered partially unsaturated monocyclic or bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring F is a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0066] In some embodiments, Ring F is phenyl or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0067] In some embodiments, F is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0068] In some embodiments, Ring F is a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0069] In some embodiments, Ring F is a 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0070] In some embodiments, Ring F is a 5-membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0071] In some embodiments, Ring F is a 5-membered heteroaryl with 1-2 nitrogen heteroatoms.

[0072] In some embodiments, Ring F is cyclobutylenyl, azetinylenyl, cyclopentylenyl cyclohexylenyl, phenylenyl, pyrrolylenyl, imidazolylenyl, pyrazolylenyl, isoxazolylenyl, thiophenylenyl, 2,5-dihydro-1H-pyrrolylenyl, 1,2,3-triazolylenyl, 1,2,4-triazolylenyl, 1,2-dihydro-3H-pyrazol-3-onylenyl, thiazolylenyl, pyridylenyl, indazolylenyl, 1,2,3,6-tetrahydropyridinylenyl, benzoimidazolylenyl, 3,4- dihydroquinolinylenyl, 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridylenyl, 2,3,4,5- tetrahydrobenzo[f][1,4]oxazepanylenyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinylenyl, 1,3,4,5- tetrahydro-2H-benzo[b][1,4]diazepin-2-onylenyl, or 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridylenyl.

[0073] In some embodiments, Ring F is as depicted in the compounds of Table 1A or 1B, below.

[0074] As described above and defined herein, Ring G is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0075] In some embodiments, Ring G is phenyl. In some embodiments, Ring G is a 5-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring G is a 5-7 memberedsaturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0076] In some embodiments, Ring G is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0077] In some embodiments, Ring G is phenyl or a 6-membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0078] In some embodiments, Ring G is cyclohexyl, cyclohexenyl, isothiazolyl, phenyl, or pyridyl.

[0079] In some embodiments, Ring G is as depicted in the compounds of Table 1A or 1B, below.

[0080] As described above and defined herein, Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0081] In some embodiments, Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl. In some embodiments, Ring H is a 3- 11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments, Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, Ring H is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0084] In some embodiments, Ring H is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, Ring H is a 6-membered saturated monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen and oxygen.

[0086] In some embodiments, Ring H is cyclopropyl, cyclobutyl, azetinyl, cyclopentyl, pyrrolidinyl, cyclohexyl, piperidinyl, piperazinyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, morpholinyl, piperzinyl, isoindolinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 6- azabicyclo[3.1.1]heptanyl, azepanyl, 2-3-azabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, 5- azaspiro[2.5]octanyl, 2,7-diazaspiro[3.5]nonanyl, 3-azaspiro[5.5]undecanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, octahydrocyclopenta[c]pyrrolyl, 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.

[0087] In some embodiments, Ring H is as depicted in the compounds of Table 1A or 1B, below.

[0088] As described above and defined herein, Ring I is phenylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- 10 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0089] In some embodiments, Ring I is phenylenyl. In some embodiments, Ring I is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl. In some embodiments, Ring I is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring I is a 5-10 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0090] In some embodiments, Ring I is phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0091] In some embodiments, Ring I is phenyl or a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0092] In some embodiments, Ring I is phenyl or a 6-membered monocyclic heteroaryl with 1-2 nitrogen heteroatoms.

[0093] In some embodiments, Ring I is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, Ring I is a 3-11 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, Ring I is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl with 1-2 nitrogen heteroatoms.

[0096] In some embodiments, Ring I is cyclohexylenyl, phenylenyl, imidazolylenyl, pyrazolylenyl, oxazolylenyl, thiazolylenyl, 1,2-thiazinanylenyl, pyridylenyl, pyridazinylenyl, pyrimidinylenyl, indolinylenyl, 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, 7H-pyrrolo[2,3-d]pyrimidinylenyl, 1H- imidazo[4,5-b]pyridinylenyl, 3H-imidazo[4,5-b]pyridylenyl, 9H-purinylenyl, octahydro-1H-pyrrolo[3,2- b]pyridinylenyl, decahydroisoquinolinylenyl, quinolinylenyl, isoquinolinylenyl, 3,4-dihydroquinoxalin- 2(1H)-onylenyl, 1,2,3,4-tetrahydroquinoxalinylenyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinylenyl, 1,2,3,4-tetrahydro-1,8-naphthyridinylenyl, or 1,2,3,4-tetrahydro-1,6-naphthyridinylenyl.

[0097] In some embodiments, Ring I is as depicted in the compounds of Table 1A or 1B, below.

[0098] As described above and defined herein, phenylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, Ring J is phenylenyl. In some embodiments, Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl. In some embodiments, Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring J is a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, Ring J is a 6-9 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, Ring J is a 6-membered saturated monocyclic carbocyclyl or heterocyclyl with 1 nitrogen heteroatom.

[0103] In some embodiments, Ring J is a 9-membered saturated monocyclic heterocyclyl with 1-2 nitrogen heteroatoms.

[0104] In some embodiments, Ring J is a 10-membered bicyclic heteroaryl ring having 1-2 nitrogen heteroatoms.

[0105] In some embodiments, Ring J is cyclohexylenyl, azetidinylenyl, pyrrolidinylenyl, imidazolylenyl, thiazolylenyl, piperidinylenyl, piperzinylenyl, azepanylenyl, phenylenyl, pyridinylenyl, isoindolinyl, quinazolinylenyl, octahydro-1H-indolylenyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridylenyl, 8- azabicyclo[3.2.1]octanylenyl, 2-azabicyclo[3.2.1]octanylenyl, 2,7-diazaspiro[4.4]nonanylenyl, octahydropyrrolo[3,2-b]pyrrolylenyl, 2-azabicyclo[3.2.2]nonanylenyl, octahydro-1H-pyrrolo[3,2- b]pyridylenyl, octahydro-1H-pyrrolo[3,4-b]pyridinylenyl, 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.

[0106] In some embodiments, Ring J is as depicted in the compounds of Table 1A or 1B, below.

[0107] As described above and defined herein, Ring K is phenyl, naphthyl, a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroaryl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0108] In some embodiments, Ring K is phenyl. In some embodiments, Ring K is naphthyl. In some embodiments, Ring K is a 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring K is a 3-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring K is a 9-10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring K is a 5-13 membered monocyclic, bicyclic, or tricyclic heteroaryl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0109] In some embodiments, Ring K is phenyl, a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0110] In some embodiments, Ring K is phenyl or a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0111] In some embodiments, Ring K is phenyl or a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, Ring K is phenyl or a 6-membered saturated carbocyclyl or heterocyclyl with 1-2 nitrogen heteroatoms.

[0113] In some embodiments, Ring K is 1,2,3-triazolyl, thiazolyl, pyrazolyl, cyclohexyl, piperdinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, 2,3-dihydro-1H-indenyl, purinyl, indazolyl, benzo[d]imidazoyl, benzo[d][1,3]dioxolyl, benzo[b]thiophenyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[d]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, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, naphthyl, 5,6,7,8-tetrahydropyrido[3,4- d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, quinolinyl, isoquinolinyl, isoquinolin-3(2H)- onyl, 1,6-naphthyridinyl, phthalazinyl, quinazolinyl, 2,7-naphthyridinyl, or tetrazolo[1,5-a]quinoxalinyl.

[0114] In some embodiments, Ring K is as depicted in the compounds of Table 1A or 1B, below.

[0115] As described above and defined herein, Rais hydrogen, an optionally substituted C1-6aliphatic or

[0116] In some embodiments, Rais hydrogen. In some embodiments, Rais an optionally substituted C1-6aliphatic. In some embodiments, Rais.

[0117] In some embodiments, Ring Rais methyl, -CH(Me)OH, benzyl, -CH2tolyl, or -CH2indolyl.

[0118] In some embodiments, Ring Rais as depicted in the compounds of Table 1A or 1B, below.

[0119] As described above and defined herein, Rbis hydrogen, an optionally substituted C1-6aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or Raand Rbare optionally taken together with their intervening atoms to form an optionally substituted 9-10 membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or when Y is -C(NR)-, Rbis optionally taken together with R of -C(NR)- with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 nitrogen atoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur.

[0120] In some embodiments, Rbis hydrogen. In some embodiments, Rbis hydrogen is an optionally substituted C1-6aliphatic. In some embodiments, Rbis hydrogen is an optionally substituted C1-6alkyl. In some embodiments, Rbis hydrogen is phenyl. In some embodiments, Rbis hydrogen is a 5- 6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Raand Rbare optionally taken together with their intervening atoms to form an optionally substituted 9-10 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)-, Rbis optionally taken together with R of -C(NR)- with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 nitrogen atoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiment, Rbis methyl, -CH(Me)OH, cyclopropyl, phenyl, -CO2H, - CH2cyclopropyl, -CH2OH, -CH2OMe, or -CH2CO2H.

[0122] In some embodiments, Ring Rbis as depicted in the compounds of Table 1A or 1B, below.

[0123] As described above and defined herein, Rcis -CO2R, -CONR2, -CR2CF2R, -CR2CONR2, - CR2C(O)R, -CR2CO2R, -CR2NR2, -CR2OR, -CR2SO2NR2, -CR2S(O)R, -CR2SO2R, -CR2S(O)(NR)R, - CR2CN, -CR2CR2NR2, -CR2CR2OR, -CR2CR=NOR, -CR2CR(OR)CR2OR, or an optionally substituted group selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: Rband Rcare taken together with their intervening atoms to form an optionally substituted 4-6 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: Rais absent and Rband Rcare taken together with their intervening atoms to form an optionally substituted phenyl; or: when Y1is -C(OR)=, Rcis taken together with R of - C(OR)= with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur.

[0124] As described above and defined herein, Rcis halogen, -CN, -CFR2, -CF2R, -CF3, -NO2, -OR, - SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)(NR)R, -S(O)R, -C(O)R, -CR=NOR, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -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, -P(O)(NR2)2, -CR2CN, - CR2CFR2, -CR2CF2R, -CR2CF3, -CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, - CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, -CR2C(O)NR2, - CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2OP(O)R2, -CR2OP(O)(OR)2, - CR2OP(O)(OR)NR2, -CR2OP(O)(NR2)2, -CR2NRC(O)OR, -CR2NRC(O)R, -CR2NRC(O)N(R)2, - CR2NRS(O)2R, -CR2NP(O)R2, -CR2NRP(O)(OR)2, -CR2NRP(O)(OR)NR2, -CR2NRP(O)(NR2)2, - CR2P(O)R2, -CR2P(O)(OR)2, -CR2P(O)(OR)NR2, -CR2P(O)(NR2)2, -CR2CR2CN, -CR2CR2CFR2, - CR2CR2CF2R, -CR2CR2CF3, -CR2CR2NO2, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, - CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2OP(O)R2, -CR2CR2OP(O)(OR)2, - CR2CR2OP(O)(OR)NR2, -CR2CR2OP(O)(NR2)2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, -CR2CR2NRS(O)2R, -CR2CR2NP(O)R2, -CR2CR2NRP(O)(OR)2, -CR2CR2NRP(O)(OR)NR2, -CR2CR2NRP(O)(NR2)2, -CR2CR2P(O)R2, -CR2CR2P(O)(OR)2, - CR2CR2P(O)(OR)NR2, -CR2CR2P(O)(NR2)2, -CR2CR(OR)CR2OR, or an optionally substituted group selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or – (CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or -(CR2)0-2C(O)Rccor -(CR2)0- 2S(O)0-2Rcc; or: Rband Rcare taken together with their intervening atoms to form an optionally substituted 4-6 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Rais absent and Rband Rcare taken together with their intervening atoms to form an optionally substituted phenyl.

[0125] As described above and defined herein, Rcis halogen, -CN, -CFR2, -CF2R, -CF3, -NO2, -OR, - SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)(NR)R, -S(O)R, -C(O)R, -CR=NOR, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -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, -P(O)(NR2)2, -CR2CN, - CR2CFR2, -CR2CF2R, -CR2CF3, -CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, - CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, -CR2C(O)NR2, - CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2OP(O)R2, -CR2OP(O)(OR)2, - CR2OP(O)(OR)NR2, -CR2OP(O)(NR2)2, -CR2NRC(O)OR, -CR2NRC(O)R, -CR2NRC(O)N(R)2, - CR2NRS(O)2R, -CR2NP(O)R2, -CR2NRP(O)(OR)2, -CR2NRP(O)(OR)NR2, -CR2NRP(O)(NR2)2, - CR2P(O)R2, -CR2P(O)(OR)2, -CR2P(O)(OR)NR2, -CR2P(O)(NR2)2, -CR2CR2CN, -CR2CR2CFR2, - CR2CR2CF2R, -CR2CR2CF3, -CR2CR2NO2, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, - CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2OP(O)R2, -CR2CR2OP(O)(OR)2, - CR2CR2OP(O)(OR)NR2, -CR2CR2OP(O)(NR2)2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, -CR2CR2NRS(O)2R, -CR2CR2NP(O)R2, -CR2CR2NRP(O)(OR)2, - CR2CR2NRP(O)(OR)NR2, -CR2CR2NRP(O)(NR2)2, -CR2CR2P(O)R2, -CR2CR2P(O)(OR)2, - CR2CR2P(O)(OR)NR2, -CR2CR2P(O)(NR2)2, -CR2CR(OR)CR2OR, , or an optionally substituted group selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclicor bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0126] In some embodiments, Rcis -CO2R, -CONR2, -CR2CN, -CR2CFR2, -CR2CF2R, -CR2CF3, - CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, -CR2S(O)2NR2, -CR2S(O)(NR)R, - CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, -CR2C(O)NR2, -CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2NRC(O)OR, -CR2NRC(O)R, -CR2NRC(O)N(R)2, -CR2NRS(O)2R, - CR2CR2CN, -CR2CR2CFR2, -CR2CR2CF2R, -CR2CR2CF3, -CR2CR2NO2, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, -CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, -CR2CR2NRS(O)2R, -CR2CR(OR)CR2OR; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0127] In some embodiments, Rcis -CO2R, -CONR2, -CR2CN, -CR2CF2R, -CR2OR, -CR2SR, - CR2NR2, -CR2S(O)2R, -CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, - CR2C(O)OR, -CR2C(O)NR2, -CR2CR2CN, -CR2CR2CF2R, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, - CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, - CR2CR(OR)CR2OR; or: –(CR2)1-2-Xa, wherein Xais an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0128] In some embodiments, Rcis -CO2R, -CONR2, -CR2CN, -CR2CF2R, -CR2CONR2, - CR2C(O)R, -CR2CO2R, -CR2NR2, -CR2OR, -CR2S(O)NR2, -CR2SO2NR2, -CR2S(O)R, -CR2SO2R, - CR2S(O)(NR)R, -CR2CN, -CR2CR2NR2, -CR2CR2OR, -CR2CR=NOR, -CR2CR(OR)CR2OR.

[0129] In some embodiments, Rcis -CR2CN, -CR2CF2R, -CR2CONR2, -CR2C(O)R, -CR2CO2R, - CR2NR2, -CR2OR, -CR2SONR2, -CR2SO2NR2, -CR2S(O)R, -CR2SO2R, -CR2S(O)(NR)R, or -CR2CN.

[0130] In some embodiments, Rcis -CR2CN, -CR2CONR2, -CR2C(O)R, -CR2CO2R, -CR2S(O)NR2, - CR2SO2NR2, -CR2S(O)R, -CR2SO2R, or -CR2CR2NR2.

[0131] In some embodiments, Rcis -CO2R. In some embodiments, Rcis -CONR2. In some embodiments, Rcis -CR2CF2R. In some embodiments, Rcis -CR2CONR2. In some embodiments, Rcis - CR2C(O)R. In some embodiments, Rcis -CR2CO2R. In some embodiments, Rcis -CR2NR2. In some embodiments, Rcis -CR2OH. In some embodiments, Rcis -CR2SO2NR2. In some embodiments, Rcis - CR2S(O)R. In some embodiments, Rcis -CR2SO2R. In some embodiments, Rcis -CR2S(O)(NR)R. In some embodiments, Rcis -CR2CN. In some embodiments, Rcis -CR2CR2NR2. In some embodiments, Rcis -CR2CR2OR. In some embodiments, Rcis -CR2CR=NOR. In some embodiments, Rcis - CR2CR(OR)CR2OR. In some embodiments, Rcis an optionally substituted phenyl. In some embodiments, Rcis an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Rcis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rcis an optionally substituted 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0132] In some embodiments, Rcis -CH2CONH2, -CH2CONHMe, -CH2CONHEt, - CH2CON(Me)CH2CH2NH2, -CH2CONHCONH2, -CH2CONHCH2Ph, -CH2CONHcyclopropyl, - CH2SO2Me, -CH2SO2Et, -CH2SO2iPr, -CH2CH2NH2, or -CH2CH2NMe2.

[0133] In some embodiments, Rcis -CH2CONH2, -CH2SO2Me, or -CH2CH2NH2.

[0134] In some embodiments, Rcis -CH2CONH2. In some embodiments, Rcis -CH2SO2Me. In some embodiments, is -CH2CH2NH2.

[0135] In some embodiments, Rcis –(CR2)1-2-Xa, wherein Xais halogen. In some embodiments, Rcis –(CR2)1-2-Xa, wherein Xais an optionally substituted phenyl. In some embodiments, Rcis –(CR2)1-2-Xa, wherein Xais an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Rcis –(CR2)1-2-Xa, wherein Xais an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rcis –(CR2)1-2-Xa, wherein Xais an optionally substituted 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0136] In some embodiments, Rband Rcare taken together with their intervening atoms to form an optionally substituted 4-6 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rband Rcare taken together with their intervening atoms to form an optionally substituted pyrrolyl. In some embodiments, Rband Rcare taken together with their intervening atoms to form oxetanyl,

[0137] In some embodiments, Rais absent and Rband Rcare taken together with their intervening atoms to form an optionally substituted phenyl. In some embodiments, Rais absent and Rband Rcare taken together with their intervening atoms to form

[0138] In some embodiments, when Y1is -C(OR)=, Rcis taken together with R of -C(OR)= with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Y1is -C(OR)=, Rcis taken together with R of -C(OR)= with their intervening atoms to formor .

[0139] In some embodiments, Rcis -CO2Bn, -CONHPh, -CR2CF2Me, -CH2CONH2, - CH(Me)CONH2, -CH2CONHMe, -CH2CONHEt, -CH2COMe, -CH2CON(Me)CH2CH2NH2, - CH2CONHCONH2, -CH2CONHCH2Ph, -CH2CONHcyclopropyl, -CH2OH, -CH2Cl, -CH2NMe2, - CH2CO2H, -CH2CO2Me, -CH2COCH2CH2OMe, -CH2COCH2CH2CH2OMe, -CH(Ph)OH, -CH(PhF)OH, - CH(Ph)NH2, -CH(PhMe)NH2, -CH2SOMe, -CH2SO2NHEt, -CH2SO2NHMe, -CH2SO2Me, -CH2SO2Et, - CH2SO2iPr, -CH2S(O)(NH)Me, -CH2S(O)(NMe)Me, -CH2C(Me)=NOH, -CH2C(Me)=NOMe, oxetanyl, thietanyl, theitanyl dioxide, pyrrolidin-2-onyl, piperidin-2-onyl, isoxazolyl, imidazolyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl dioxide, pyridine-2-onyl, phenyl, tolyl, indolyl, -CH2CN, - CH(Me)CN, -CH2CH2Cl, -CH2CH2NH2, -CH2CH2NMe2, -CH2CH2OH, -CH2CH2OMe, -CH2pyrrolyl, - CH2pyridyl, -CH2indolyl,, , , , ,

[0140] In some embodiments, Ring Rcis as depicted in the compounds of Table 1A or 1B, below.

[0141] As described above and defined herein, Rdis hydrogen or an optionally substituted C1-6aliphatic, or when Rcis -CR2CONR2, Rdis optionally taken together with a single R of -CR2CONR2with their intervening atoms to form a 5-7 membered saturated or partially unsaturated heterocyclyl with 0-3 heteroatoms, in addition to the nitrogen atom to which Rdis attached, independently selected from nitrogen, oxygen, and sulfur.

[0142] In some embodiments, Rdis hydrogen. In some embodiments, Rdis an optionally substituted C1-6 aliphatic. In some embodiments, Rdis a C1-6 alkyl. In some embodiments, Rdis benzyl. In some embodiments, Rdis methyl.

[0143] In some embodiments, Rdis absent.

[0144] In some embodiments, Ring Rdis as depicted in the compounds of Table 1A or 1B, below.

[0145] As described above and defined herein, Rcc, Re, Rr, Rg, Rh, Ri, Rj, and Rkare each independently selected from hydrogen, oxo, RA, 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, -C(NOR)R, -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 an Rigroup on Ring I and an Rjgroup or Ring J are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an Rjgroup on Ring J and an Rkgroup or Ring K are optionally taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, Rccis is RA. In some embodiments, Rccis halogen. In some embodiments, Rccis -CN. In some embodiments, Rccis -NO2. In some embodiments, Rccis -OR. In some embodiments, Rccis -SR. In some embodiments, Rccis -NR2. In some embodiments, Rccis -SiR3.In some embodiments, Rccis -S(O)2R. In some embodiments, Rccis -S(O)2NR2. In some embodiments, Rccis -S(O)R. In some embodiments, Rccis -C(O)R. In some embodiments, Rccis -C(O)OR. In some embodiments, Rccis -C(O)NR2. In some embodiments, Rccis -C(O)NROR. In some embodiments, Rccis -C(NOR)R. In some embodiments, Rccis -OC(O)R. In some embodiments, Rccis -OC(O)NR2. In some embodiments, Rccis -OP(O)R2. In some embodiments, Rccis -OP(O)(OR)2. In some embodiments, Rccis -OP(O)(OR)NR2. In some embodiments, Rccis -OP(O)(NR2)2. In some embodiments, Rccis - NRC(O)OR. In some embodiments, Rccis -NRC(O)R. In some embodiments, Rccis -NRC(O)N(R)2. In some embodiments, Rccis -NRS(O)2R. In some embodiments, Rccis -NP(O)R2. In some embodiments, Rccis -NRP(O)(OR)2. In some embodiments, Rccis -NRP(O)(OR)NR2. In some embodiments, Rccis - NRP(O)(NR2)2. In some embodiments, Rccis -P(O)R2. In some embodiments, Rccis -P(O)(OR)2. In some embodiments, Rccis -P(O)(OR)NR2. In some embodiments, Rccis -P(O)(NR2)2.

[0147] In some embodiments, Reis hydrogen. In some embodiments, Reis oxo. In some embodiments, Reis is RA. In some embodiments, Reis halogen. In some embodiments, Reis -CN. In some embodiments, Reis -NO2. In some embodiments, Reis -OR. In some embodiments, Reis -SR. In some embodiments, Reis -NR2. In some embodiments, Reis -SiR3. In some embodiments, Reis -S(O)2R. In some embodiments, Reis -S(O)2NR2. In some embodiments, Reis -S(O)R. In some embodiments, Reis -C(O)R. In some embodiments, Reis -C(O)OR. In some embodiments, Reis -C(O)NR2. In some embodiments, Reis -C(O)NROR. In some embodiments, Reis -C(NOR)R. In some embodiments, Reis -OC(O)R. In some embodiments, Reis -OC(O)NR2. In some embodiments, Reis -OP(O)R2. In some embodiments, Reis -OP(O)(OR)2. In some embodiments, Reis -OP(O)(OR)NR2. In some embodiments, Reis -OP(O)(NR2)2. In some embodiments, Reis -NRC(O)OR. In some embodiments, Reis -NRC(O)R. In some embodiments, Reis -NRC(O)N(R)2. In some embodiments, Reis -NRS(O)2R. In some embodiments, Reis -NP(O)R2. In some embodiments, Reis -NRP(O)(OR)2. In some embodiments, Reis -NRP(O)(OR)NR2. In some embodiments, Reis -NRP(O)(NR2)2. In some embodiments, Reis -P(O)R2. In some embodiments, Reis -P(O)(OR)2. In some embodiments, Reis -P(O)(OR)NR2. In some embodiments, Reis -P(O)(NR2)2.

[0148] In some embodiments, Reis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0149] In some embodiments, Reis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0150] In some embodiments, Reis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0151] In some embodiments, Reis hydrogen, oxo, fluoro, chloro, -CN, methyl, -CF3, isopropyl, cyclopropyl, ethynyl, -CO2H, -CO2Me, -CONH2, -C(O)CHCH2, -OH, -OMe, -CH2CHF2, -CH2OMe, - CH2CO2H, -CH2CONH2, -CH2SO2Me, -CH2CH2CO2H, -CH2CH2CONH2, -CH2CH2SO2Me, - CH2CH2OMe, -NHC(O)CHCH2, tetrazolyl, or N-methyltetrazolyl.

[0152] In some embodiments, Rfis hydrogen. In some embodiments, Rfis oxo. In some embodiments, Rfis is RA. In some embodiments, Rfis halogen. In some embodiments, Rfis -CN. In some embodiments, Rfis -NO2. In some embodiments, Rfis -OR. In some embodiments, Rfis -SR. In some embodiments, Reis -NR2. In some embodiments, Rfis -SiR3. In some embodiments, Rfis -S(O)2R. In some embodiments, Rfis -S(O)2NR2. In some embodiments, Rfis -S(O)R. In some embodiments, Rfis -C(O)R. In some embodiments, Rfis -C(O)OR. In some embodiments, Rfis -C(O)NR2. In some embodiments, Rfis -C(O)NROR. In some embodiments, Rfis -C(NOR)R. In some embodiments, Rfis -OC(O)R. In some embodiments, Rfis -OC(O)NR2. In some embodiments, Rfis -OP(O)R2. In some embodiments, Rfis -OP(O)(OR)2. In some embodiments, Rfis -OP(O)(OR)NR2. In some embodiments, Rfis -OP(O)(NR2)2. In some embodiments, Rfis -NRC(O)OR. In some embodiments, Rfis -NRC(O)R. In some embodiments, Rfis -NRC(O)N(R)2. In some embodiments, Rfis -NRS(O)2R. In some embodiments, Rfis -NP(O)R2. In some embodiments, Rfis -NRP(O)(OR)2. In some embodiments, Rfis -NRP(O)(OR)NR2. In some embodiments, Rfis -NRP(O)(NR2)2. In some embodiments, Rfis -P(O)R2. In some embodiments, Rfis -P(O)(OR)2. In some embodiments, Rfis -P(O)(OR)NR2. In some embodiments, Rfis -P(O)(NR2)2.

[0153] In some embodiments, Rfis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0154] In some embodiments, Rfis optionally substituted C1-6 aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0155] In some embodiments, Rfis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0156] In some embodiments, Rfis hydrogen, oxo, -CN, methyl, ethyl, isopropyl, -CF3, phenyl, pyrrolyl, pyridinyl, -CONH2, -COcyclohexyl, -CH2cyclopropyl, -CH2cyclopentyl, -CH2cyclohexyl, - CH2morpholinyl, -CH2Ph, -CH2thiazolyl, -CH2pyrimidinyl, -CH2CH2OMe, -CH2CH2Ph, -C(O)Me, - C(O)CHCH2, -C(O)CH2CH2OMe, -C(O)CH2OCH2CH2OMe, -CH2CH2OCH2CH2OMe, -C(O)Ph, - C(O)pyridinyl, -C(O)naphthyl, -C(O)CH2Ph, -C(O)pyrimidinyl, -NH2, -NHC(O)CHCH2, - CH2NHC(O)CHCH2, -CCNHC(O)CHCH2, -NHcyclohexyl, -NHphenyl, -NHpyrimidinyl, -SO2Me, tosyl,[.

[0158] In some embodiments, Rfis attached to L, e.g.

[0159] In some embodiments, Rhis hydrogen. In some embodiments, Rhis oxo. In some embodiments, Rhis is RA. In some embodiments, Rhis halogen. In some embodiments, Rhis -CN. In some embodiments, Rhis -NO2. In some embodiments, Rhis -OR. In some embodiments, Rhis -SR. In some embodiments, Rhis -NR2. In some embodiments, Rhis -SiR3. In some embodiments, Rhis -S(O)2R. In some embodiments, Rhis -S(O)2NR2. In some embodiments, Rhis -S(O)R. In some embodiments, Rhis -C(O)R. In some embodiments, Rhis -C(O)OR. In some embodiments, Rhis - C(O)NR2. In some embodiments, Rhis -C(O)NROR. In some embodiments, Rhis -C(NOR)R. In some embodiments, Rhis -OC(O)R. In some embodiments, Rhis -OC(O)NR2. In some embodiments, Rhis - OP(O)R2. In some embodiments, Rhis -OP(O)(OR)2. In some embodiments, Rhis -OP(O)(OR)NR2. In some embodiments, Rhis -OP(O)(NR2)2. In some embodiments, Rhis -NRC(O)OR. In some embodiments, Rhis -NRC(O)R. In some embodiments, Rhis -NRC(O)N(R)2. In some embodiments, Rhis -NRS(O)2R. In some embodiments, Rhis -NP(O)R2. In some embodiments, Rhis -NRP(O)(OR)2. In some embodiments, Rhis -NRP(O)(OR)NR2. In some embodiments, Rhis -NRP(O)(NR2)2. In some embodiments, Rhis -P(O)R2. In some embodiments, Rhis -P(O)(OR)2. In some embodiments, Rhis - P(O)(OR)NR2. In some embodiments, Rhis -P(O)(NR2)2.

[0160] In some embodiments, Rhis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0161] In some embodiments, Rhis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0162] In some embodiments, Rhis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0163] In some embodiments, Rhis hydrogen, oxo, fluoro, methyl, ethyl, n-propyl, n-butyl, - CH2N(Me)CH2CH2OMe, -CH2CH2OMe, -CH2CH2OCH2CH2OMe, -C(O)Me, -C(O)CHCH2, -OH, - N -

[0164] In some embodiments, Rgis hydrogen. In some embodiments, Rgis oxo. In some embodiments, Rgis is RA. In some embodiments, Rgis halogen. In some embodiments, Rgis -CN. In some embodiments, Rgis -NO2. In some embodiments, Rgis -OR. In some embodiments, Rgis -SR. In some embodiments, Rgis -NR2. In some embodiments, Rgis -SiR3. In some embodiments, Rgis -S(O)2R. In some embodiments, Rgis -S(O)2NR2. In some embodiments, Rgis -S(O)R. In some embodiments, Rgis -C(O)R. In some embodiments, Rgis -C(O)OR. In some embodiments, Rgis - C(O)NR2. In some embodiments, Rgis -C(O)NROR. In some embodiments, Rgis -C(NOR)R. In some embodiments, Rgis -OC(O)R. In some embodiments, Rgis -OC(O)NR2. In some embodiments, Rgis - OP(O)R2. In some embodiments, Rgis -OP(O)(OR)2. In some embodiments, Rgis -OP(O)(OR)NR2. In some embodiments, Rgis -OP(O)(NR2)2. In some embodiments, Rgis -NRC(O)OR. In some embodiments, Rgis -NRC(O)R. In some embodiments, Rgis -NRC(O)N(R)2. In some embodiments, Rgis -NRS(O)2R. In some embodiments, Rgis -NP(O)R2. In some embodiments, Rgis -NRP(O)(OR)2. In some embodiments, Rgis -NRP(O)(OR)NR2. In some embodiments, Rgis -NRP(O)(NR2)2. In some embodiments, Rgis -P(O)R2. In some embodiments, Rgis -P(O)(OR)2. In some embodiments, Rgis - P(O)(OR)NR2. In some embodiments, Rgis -P(O)(NR2)2.

[0165] In some embodiments, Rgis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0166] In some embodiments, Rgis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0167] In some embodiments, Rgis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0168] In some embodiments, Rgis hydrogen, oxo, fluoro, chloro, bromo, -CN, methyl, ethyl, - CONH2, -OH, or -OMe.

[0169] In some embodiments, Riis hydrogen. In some embodiments, Riis oxo. In some embodiments, Riis is RA. In some embodiments, Riis halogen. In some embodiments, Riis -CN. In some embodiments, Riis -NO2. In some embodiments, Riis -OR. In some embodiments, Riis -SR. In some embodiments, Riis -NR2. In some embodiments, Riis -SiR3. In some embodiments, Riis -S(O)2R. In some embodiments, Riis -S(O)2NR2. In some embodiments, Riis -S(O)R. In some embodiments, Riis -C(O)R. In some embodiments, Riis -C(O)OR. In some embodiments, Riis -C(O)NR2. In some embodiments, Riis -C(O)NROR. In some embodiments, Riis -C(NOR)R. In some embodiments, Riis -OC(O)R. In some embodiments, Riis -OC(O)NR2. In some embodiments, Riis -OP(O)R2. In some embodiments, Riis -OP(O)(OR)2. In some embodiments, Riis -OP(O)(OR)NR2. In some embodiments, Riis -OP(O)(NR2)2. In some embodiments, Riis -NRC(O)OR. In some embodiments, Riis -NRC(O)R. In some embodiments, Riis -NRC(O)N(R)2. In some embodiments, Riis -NRS(O)2R. In some embodiments, Riis -NP(O)R2. In some embodiments, Riis -NRP(O)(OR)2. In some embodiments, Riis - NRP(O)(OR)NR2. In some embodiments, Riis -NRP(O)(NR2)2. In some embodiments, Riis -P(O)R2. In some embodiments, Riis -P(O)(OR)2. In some embodiments, Riis -P(O)(OR)NR2. In some embodiments, Riis -P(O)(NR2)2.

[0170] In some embodiments, Riis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0171] In some embodiments, Riis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R,-OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0172] In some embodiments, Riis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0173] In some embodiments, Riis hydrogen, oxo, fluoro, chloro, methyl, -CF3, -CH2OH, -CN, - CH2C(O)NH2, -CH2NH2, -CH2NHCH2CH2NH2, -CONHCH2CH2NH2, -CH2NHCOCH2NH2, - C(O)isobutyl, -C(O)CH2NH2, -C(O)CH2OCONH2, -CO2H, -CONH2, -C(O)cyclopropyl, -C(O)(CH2)1-6SO2Me, -OH, -OMe, -NH2, -NMe2, -NHCH2CH2NH2, -N(Me)CH2CH2CH2N(Me)C(O)CHCH2, or.

[0174] In some embodiments, Rjis hydrogen. In some embodiments, Rjis oxo. In some embodiments, Rjis is RA. In some embodiments, Rjis halogen. In some embodiments, Rjis -CN. In some embodiments, Rjis -NO2. In some embodiments, Rjis -OR. In some embodiments, Rjis -SR. In some embodiments, Rjis -NR2. In some embodiments, Rjis -SiR3. In some embodiments, Rjis -S(O)2R. In some embodiments, Rjis -S(O)2NR2. In some embodiments, Rjis -S(O)R. In some embodiments, Rjis -C(O)R. In some embodiments, Rjis -C(O)OR. In some embodiments, Rjis -C(O)NR2. In some embodiments, Rjis -C(O)NROR. In some embodiments, Rjis -C(NOR)R. In some embodiments, Rjis -OC(O)R. In some embodiments, Rjis -OC(O)NR2. In some embodiments, Rjis -OP(O)R2. In some embodiments, Rjis -OP(O)(OR)2. In some embodiments, Rjis -OP(O)(OR)NR2. In some embodiments, Rjis -OP(O)(NR2)2. In some embodiments, Rjis -NRC(O)OR. In some embodiments, Rjis -NRC(O)R. In some embodiments, Rjis -NRC(O)N(R)2. In some embodiments, Rjis -NRS(O)2R. In some embodiments, Rjis -NP(O)R2. In some embodiments, Rjis -NRP(O)(OR)2. In some embodiments, Rjis - NRP(O)(OR)NR2. In some embodiments, Rjis -NRP(O)(NR2)2. In some embodiments, Rjis -P(O)R2. In some embodiments, Rjis -P(O)(OR)2. In some embodiments, Rjis -P(O)(OR)NR2. In some embodiments, Rjis -P(O)(NR2)2.

[0175] In some embodiments, Rjis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0176] In some embodiments, Rjis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0177] In some embodiments, Rjis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0178] In some embodiments, Rjis hydrogen, oxo, fluoro, chloro, methyl, -CH2F, -CH2OH, -CH2C(O)NH2, -CH2NH2, -CH2NHCH2CH2NH2, -CONHCH2CH2NH2, -CH2NHCOCH2NH2, - CH2CH2CH2OH, -CH2CH2OCH2CH2OMe, -CH2CH2OCH2CH2OCH2CH2OMe, -C(O)CH2NH2, - C(O)CH2OCONH2, -CO2H, -C(O)CHCH2, -C(O)Et, -C(O)NH2, -NH2, -OH, -OMe, or -S(O)2NH2.

[0179] In some embodiments, Rjis -OCH2CH2NH2, -NHCH2CH2OH, -NHCH2CONH2, -

[0180] In some embodiments, an Rigroup on Ring I and an Rjgroup or Ring J are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0181] In some embodiments, Riand Rj, are taken together by -CH2CH2- or -CH2CH2CH2-.

[0182] In some embodiments, Rkis hydrogen. In some embodiments, Rkis oxo. In some embodiments, Rkis is RA. In some embodiments, Rkis halogen. In some embodiments, Rkis -CN. In some embodiments, Rkis -NO2. In some embodiments, Rkis -OR. In some embodiments, Rkis -SR. In some embodiments, Rkis -NR2. In some embodiments, Rkis -SiR3. In some embodiments, Rkis -S(O)2R. In some embodiments, Rkis -S(O)2NR2. In some embodiments, Rkis -S(O)R. In some embodiments, Rkis -C(O)R. In some embodiments, Rkis -C(O)OR. In some embodiments, Rkis - C(O)NR2. In some embodiments, Rkis -C(O)NROR. In some embodiments, Rkis -C(NOR)R. In some embodiments, Rkis -OC(O)R. In some embodiments, Rkis -OC(O)NR2. In some embodiments, Rkis - OP(O)R2. In some embodiments, Rkis -OP(O)(OR)2. In some embodiments, Rkis -OP(O)(OR)NR2. In some embodiments, Rkis -OP(O)(NR2)2. In some embodiments, Rkis -NRC(O)OR. In some embodiments, Rkis -NRC(O)R. In some embodiments, Rkis -NRC(O)N(R)2. In some embodiments, Rkis -NRS(O)2R. In some embodiments, Rkis -NP(O)R2. In some embodiments, Rkis -NRP(O)(OR)2. In some embodiments, Rkis -NRP(O)(OR)NR2. In some embodiments, Rkis -NRP(O)(NR2)2. In some embodiments, Rkis -P(O)R2. In some embodiments, Rkis -P(O)(OR)2. In some embodiments, Rkis - P(O)(OR)NR2. In some embodiments, Rkis -P(O)(NR2)2.

[0183] In some embodiments, Rkis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0184] In some embodiments, Rkis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

[0185] In some embodiments, Rkis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

[0186] In some embodiments, Rkis hydrogen, oxo, fluoro, chloro, bromo, -CN, -NO2, methyl, ethyl, n-propyl, isobutyl, cyclopropyl, benzyl, -CF3, -CO2H, -CO2Me, -CH2CF3, -CH2OH, -CH2OCONH2, - CH2CH2OH, -CH2CH2CH2OH, -CH2CO2H, -CH2CO2Me, -CH2CO2Et, -C(O)NH2, -C(O)NMe2, - CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2NH2, -CH2NHCONH2, -CH2OCONH2, -CH2CH2NH2, - CH2CH2CH2NH2, -CH(OH)Me, -CH(OH)CF3, -CH(NH2)cyclopropyl, -CH2Ph, -OH, -OMe, -OCF3, - OiPr, -Ocyclopropyl, -OPh, -OBn, -NH2, -NHiBu, -NHC(O)H, -NHC(O)Me, -NHC(O)CHCH2, -SMe, - S(O)Me, -S(O)2NH2, -CH2CH2S(O)2NH2, 1,2,3-triazolyl, thiophenyl, pyrrolidinyl, piperdinyl, N-,

[0187] In some embodiments, an Rjgroup on Ring J and an Rkgroup or Ring K are optionally taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, Rjand Rk, are taken together by -NH-.

[0189] In some embodiments, Rcc, Re, Rr, Rg, Rh, Ri, Rj, and Rkare as depicted in the compounds of Table 1A or 1B, below.

[0190] As described above and defined herein, each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0191] In some embodiments, RAis an optionally substituted C1-6 aliphatic. In some embodiments, RAis an optionally substituted phenyl. In some embodiments, RAis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, RAis an optionally substituted saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RAis an optionally substituted 5-6membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0192] In some embodiments, RAis C1-6alkyl (e.g., methyl, ethyl, isopropyl). In some embodiments, RAis C1-6haloalkyl (e.g., -CF3, -CHF2).

[0193] In some embodiment, RAis as depicted in the compounds of Table 1A or 1B, below.

[0194] As described above and defined herein, each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, naphthyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom, or on different atoms, are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom, or different atoms, to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0195] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted naphthyl. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are optionally taken together with their intervening atoms to form optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom, or on different atoms, are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom, or different atoms, to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0196] In some embodiment, R is as depicted in the compounds of Table 1A or 1B, below.

[0197] As described above and defined herein, each of X1and X2are independently a covalent bond, spiro-fusion between the two rings that X1or X2connect, or a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain areindependently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or - S(O)2-.

[0198] In some embodiments, X1is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or - S(O)2-.

[0199] In some embodiments, X1is a covalent bond. In some embodiments, X1is a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, - N(R)-, -S-, -S(O)-, or -S(O)2-. In some embodiments, X1is -CR2-. In some embodiments, X1is - CR(OR)-. In some embodiments, X1-CRF-. In some embodiments, X1is -CF2-. In some embodiments, X1is -(CR2)0-2-C(O)-. In some embodiments, X1is -CR2NRCR2-. In some embodiments, X1is -NRCR2-. In some embodiments, X1is -C(O)NR-. In some embodiments, X1is -C(NR)NR-. In some embodiments, X1is -C(S)NR-. In some embodiments, X1is -NR-. In some embodiments, X1is -O-. In some embodiments, X1is -S-. In some embodiments, X1is -S(O)2-. In some embodiments, X1represents spiro-fusion between the two rings that X1connect.

[0200] In some embodiments, X1is a covalent bond, -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, - C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0201] In some embodiments, X1is a covalent bond, -NH-, -NMe-.

[0202] In some embodiments, X2is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-6 hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or - S(O)2-.

[0203] In some embodiments, X2is a covalent bond. In some embodiments, X2is a bivalent, saturated or unsaturated, straight or branched C1-6 hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, - N(R)-, -S-, -S(O)-, or -S(O)2-. In some embodiments, X2is -CR2-. In some embodiments, X2is - CR(OR)-. In some embodiments, X2-CRF-. In some embodiments, X2is -CF2-. In some embodiments, X2is -(CR2)0-2-C(O)-. In some embodiments, X2is -CR2NRCR2-. In some embodiments, X2is -NRCR2-. In some embodiments, X2is -C(O)NR-. In some embodiments, X2is -C(NR)NR-. In some embodiments, X2is -C(S)NR-. In some embodiments, X2is -NR-. In some embodiments, X2is -O-. In some embodiments, X2is -S-. In some embodiments, X2is -S(O)2-. In some embodiments, X2represents spiro-fusion between the two rings that X2connects, e.g.,

[0204] In some embodiments, X2is a covalent bond, -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, - C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0205] In some embodiments, X2is a covalent bond, -CH2-, -CMe(OMe)-, -CMe(F)-, -CMe(CF3)-, cyclopropylenyl, difluorocyclopropylenyl, -C(O)-, -CH2CH2C(O)-, -CH2NHCH(Me)-, -NHCH2-, - N(Me)CH2-, -C(O)NH-, -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-.

[0206] In some embodiment, X1and X2are as depicted in the compounds of Table 1A or 1B, below.

[0207] As described above and defined herein, Y2is a C1-4 hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, -S(O)2-, - C(OR)=N-, -N(Rd)-, or -O-.

[0208] In some embodiments, Y2is -CR2N(Rd)-, -CR(OR)N(Rd)-, -C(O)N(Rd)-, -C(NR)N(Rd)-, - C(NOR)N(Rd)-, -S(O)N(Rd)-, -S(O)2N(Rd)-, -C(OR)=N-, -N(Rd)-, or -CO2-.

[0209] In some embodiment, Y2is as depicted in the compounds of Table 1A or 1B, below.

[0210] As described above and defined herein, Y1is a C1-3 hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2- .

[0211] In some embodiments, Y1is a C1-3 hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, -S(O)2-, or Y1is -C(OR)= in formula I-a’ where Rdis absent.

[0212] In some embodiments, Y1is a C1-3 hydrocarbon chain. In some embodiments, Y1is -CR2-. In some embodiments, Y1is -CR(OR)-. In some embodiments, Y1is -C(O)-. In some embodiments, Y1is - C(NR)-. In some embodiments, Y1is -C(NOR)-. In some embodiments, Y1is -S(O)-. In some embodiments, Y1is -S(O)2-. In some embodiments, Y1is -C(OR)= in formula I-a’ where Rdis absent.

[0213] In some embodiments, Y1is -CH2-, -CH2C(O)-, -NHCH2C(O)-, -CH2CH2C(O)-, - CH2CH(OH)C(O)-, -C(O)-, -C(NH)-, -C(NOH)-, -S(O)-, or -S(O)2-.

[0214] In some embodiment, Y1is as depicted in the compounds of Table 1A or 1B, below.

[0215] As described above and defined herein, each of s’ and s’’ are independently 0 or 1.

[0216] In some embodiments, s’ is 0. In some embodiments, s’ is 1. In some embodiments, s’’ is 0. In some embodiments, s’’ is 1.

[0217] In some embodiment, s’ and s’’ are as depicted in the compounds of Table 1A or 1B, below.

[0218] As described above and defined herein, each of e, f, g, h, i, j, and k are independently 0, 1, 2, 3, or 4.

[0219] In some embodiments, e is 0. In some embodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, e is 4.

[0220] In some embodiments, e is 0 or 1. In some embodiments, e is 1 or 2. In some embodiments, e is 2 or 3. In some embodiments, e is 3 or 4. In some embodiments, e is 1, 2, or 3.

[0221] In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3. In some embodiments, f is 4.

[0222] In some embodiments, f is 0 or 1. In some embodiments, f is 1 or 2. In some embodiments, f is 1, 2, or 3.

[0223] In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4.

[0224] In some embodiments, g is 0 or 1. In some embodiments, g is 1 or 2. In some embodiments, g is 1, 2, or 3.

[0225] In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4.

[0226] In some embodiments, h is 0 or 1. In some embodiments, h is 1 or 2. In some embodiments, h is 1, 2, or 3.

[0227] In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, i is 2. In some embodiments, i is 3. In some embodiments, i is 4.

[0228] In some embodiments, i is 0 or 1. In some embodiments, i is 1 or 2. In some embodiments, i is 1, 2, or 3.

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

[0230] In some embodiments, j is 0 or 1. In some embodiments, j is 1 or 2. In some embodiments, i is 1, 2, or 3.

[0231] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0232] In some embodiments, k is 0 or 1. In some embodiments, k is 1 or 2. In some embodiments, k is 1, 2, or 3.

[0233] In some embodiment, e, f, g, h, i, j, and k are as depicted in the compounds of Table 1A or 1B, below.

[0234] In some embodiments, DBM isIn some embodiments, DBMembodiments, DBM issome embodiments, DBM is s I

[0236] In some embodiment, DBM is as depicted in the compounds of Table 1A or 1B, below.

[0237] In certain embodiments, the present invention provides a compound of formula I-a or I-a’ represented by any one of the following formulae:or a pharmaceutically acceptable salt thereof.

[0238] In certain embodiments, the present invention provides a compound of formula I-a’ represented by any one of the following formulae:I-a-2’ or a pharmaceutically acceptable salt thereof, wherein: Y1is a C1-3hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, - C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, -S(O)2-, -C(OR)=N-; and wherein when Y1is -C(OR)= in formula I-a-1’, Rcis optionally taken together with R of -C(OR)=, and with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur.

[0239] In some embodiments, Y1is a C1-3 hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-.

[0240] In some embodiments, Y1is -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or - S(O)2-.

[0241] In some embodiments, Y1is -C(O)-.

[0242] In some embodiments, Y1is as depicted in the compounds of Table 1A or 1B, below.

[0243] In certain embodiments, the present invention provides a compound of formula I-a’ represented by any one of the following formulae:or a pharmaceutically acceptable salt thereof.

[0244] In certain embodiments, the present invention provides a compound of formula I-a or I-a’ represented by any one of the following formulae:I-a-6’ I-a-7’ or a pharmaceutically acceptable salt thereof.

[0245] In certain embodiments, the present invention provides a compound of formula I-a or I-a’ represented by any one of the following formulae:I-a-8’I-a-9’or a pharmaceutically acceptable salt thereof.

[0246] In certain embodiments, the present invention provides a compound of formula I-a or I-a’ represented by any one of the following formulae:I-a-10’ I-a-11’I-a-12’ I-a-13’ or a pharmaceutically acceptable salt thereof.

[0247] In certain embodiments, the present invention provides a compound of formula I-a or I-a’ represented by any one of the following formulae:I-a-14’ I-a-15’ or a pharmaceutically acceptable salt thereof.

[0248] In certain embodiments, the present invention provides a compound of formula I-b or I-b’ represented by any one of the following formulae:or a pharmaceutically acceptable salt thereof.

[0249] In certain embodiments, the present invention provides a compound of formula I-b or I-b’ represented by any one of the following formulae:or a pharmaceutically acceptable salt thereof.

[0250] In certain embodiments, the present invention provides a compound of formula I-b or I-b’ represented by any one of the following formulae:or a pharmaceutically acceptable salt thereof.

[0251] In certain embodiments, the present invention provides a compound of formula I-b or I-b’ represented by any one of the following formulae:I-b-18’ or a pharmaceutically acceptable salt thereof.

[0252] In certain embodiments, the present invention provides a compound of formula I-b or I-b’ represented by any one of the following formulae:I-b-19’I-b-21’ or a pharmaceutically acceptable salt thereof.

[0253] As defined above and described herein, said compound of formula I-a, I-a’, I-b, or I-b’ is optionally substituted withead group attached to a modifiable carbon, oxygen, nitrogen or sulfur atom in formula I-a, I-a’, I-b, or I-b’ or a substitution or replacement of any defined group in formula I-a, I-a’, I-b, or I-b’ (e.g., replacing one of Re, Rf, Rg, Rh, Ri, Rj, or Rk).

[0254] In some embodiments, the warhead group is –L2-Y, wherein: L2is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L2are optionally and independently replaced by cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR)—, — N═N—, or —C(═N2)—; Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Regroups; and each Reis independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group, or a C1- 6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein: Q is a covalent bond or a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and 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 —SO2N(R)—; and Z is hydrogen or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN.

[0255] In certain embodiments, L2is a covalent bond.

[0256] In certain embodiments, L2is a bivalent C1-8saturated or unsaturated, straight or branched, hydrocarbon chain. In certain embodiments, L2is —CH2—.

[0257] In certain embodiments, L2is a covalent bond, —CH2—, —NH—, —CH2NH—, — NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —NHC(O)CH2OC(O)—, or —SO2NH—.

[0258] In some embodiments, L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least one double bond and one or two additional methylene units of L2are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0259] In certain embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —C(O)—, — NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or — C(O)O—, and one or two additional methylene units of L2are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0260] In some embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —C(O)—, and one or two additional methylene units of L2are optionally and independently replaced by cyclopropylene, —O— , —N(R)—, or —C(O)—.

[0261] As described above, in certain embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond. One of ordinary skill in the art will recognize that such a double bond may exist within the hydrocarbon chain backbone or may be “exo” to the backbone chain and thus forming an alkylidene group. By way of example, such an L2group having an alkylidene branched chain includes —CH2C(═CH2)CH2—. Thus, in some embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one alkylidenyl double bond. Exemplary L2groups include —NHC(O)C(═CH2)CH2—.

[0262] In certain embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —C(O)—. In certain embodiments, L2is —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)—, —CH2CH2C(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—.

[0263] In certain embodiments, L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —OC(O)—.

[0264] In some embodiments, L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —NRC(O)—, — C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L2are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. In some embodiments, L2is —CH2OC(O)CH═CHCH2—, —CH2— O [ i [NHSO2CH═CHCH2—, —NHC(O)CH═CHCH2O—, —NHC(O)C(═CH2)CH2—, —CH2NHC(O)—, — CH2NHC(O)CH═CH—, —CH2CH2NHC(O)—, or —CH2NHC(O)cyclopropylene-.

[0267] In some embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one triple bond. In certain embodiments, L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one triple bond and one or two additional methylene units of L2are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —S—, —S(O)—, —SO2—, —C(═S)—, —C(═NR)—, —O—, —N(R)—, or —C(O)—. In some embodiments, L2has at least one triple bond and at least one methylene unit of L2is replaced by —N(R)—, —N(R)C(O)—, —C(O)—, — C(O)O—, or —OC(O)—, or —O—.

[0268] Exemplary L2groups 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—.

[0269] In certain embodiments, L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein one methylene unit of L2is replaced by cyclopropylene and one or two additional methylene units of L2are independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, or —SO2N(R)—. Exemplary L2groups include —NHC(O)-cyclopropylene-SO2— and —NHC(O)-cyclopropylene-.

[0270] As defined generally above, Y is hydrogen, C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein saidring is substituted with at 1-4 Regroups, each Reis independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group, or C1-6aliphatic, wherein Q is a covalent bond or a bivalent C1-6saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and 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 —SO2N(R)—; and, Z is hydrogen or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN.

[0271] In certain embodiments, Y is hydrogen.

[0272] In certain embodiments, Y is C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN. In some embodiments, Y is C2-6alkenyl optionally substituted with oxo, halogen, NO2, or CN. In other embodiments, Y is C2-6alkynyl optionally substituted with oxo, halogen, NO2, or CN. In some embodiments, Y is C2-6alkenyl. In other embodiments, Y is C2-4 alkynyl.

[0273] In other embodiments, Y is C1-6 alkyl substituted with oxo, halogen, NO2, or CN. Such Y groups include —CH2F, —CH2Cl, —CH2CN, and —CH2NO2.

[0274] In certain embodiments, Y is a saturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Y is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y.

[0275] In some embodiments, Y is a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group is –L2-Y. Exemplary such rings are epoxide and oxetane rings, wherein each ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group is –L2-Y.

[0276] In other embodiments, Y is a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y. Such rings include piperidine and pyrrolidine, wherein each ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group is –L2-Y. In certain embodiments, Y iswherein each R, Q, Z, and Reis as defined above in warhead group –L2-Y.

[0277] In some embodiments, Y is a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y. In certain embodiments, Y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each ring is substitutedwith 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y. In certain embodiments,rein Reis as defined above in warhead group –L2-Y.

[0278] In certain embodiments, Y is cyclopropyl optionally substituted with halogen, CN or NO2.

[0279] In certain embodiments, Y is a partially unsaturated 3-6 membered monocyclic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y.

[0280] In some embodiments, Y is a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y. In some embodiments, Y is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl wherein each ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y. In c –

[0281] In certain embodiments, Y is a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y. In certain embodiments, Y is selected from:wherein each R is as defined above and described herein and Reis as defined above in warhead group – L2-Y.

[0282] In certain embodiments, Y is a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y. In certain embodiments, Y is phenyl, pyridyl, or pyrimidinyl, wherein each ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y.

[0283] In some embodiments, Y is selected from:wherein each Reis as defined above in warhead group –L2-Y.

[0284] In other embodiments, Y is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y. In some embodiments, Y is a 5 membered partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y. Exemplary such rings are isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, thienyl, triazole, thiadiazole, and oxadiazole, wherein each ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y. In certain embodiments, Y is selected from:wherein each R is as defined above and described herein and Reis as defined above in warhead group – L2-Y.

[0285] 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, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y. 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, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y. Exemplary such bicyclic ringsinclude 2,3-dihydrobenzo[d]isothiazole, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y.

[0286] As defined generally above, each Regroup is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group, or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein Q is a covalent bond or a bivalent C1-6saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and 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 —SO2N(R)—; and Z is hydrogen or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN.

[0287] In certain embodiments, Reis C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN. In other embodiments, Reis oxo, NO2, halogen, or CN.

[0288] In some embodiments, Reis -Q-Z, wherein Q is a covalent bond and Z is hydrogen (i.e., Reis hydrogen). In other embodiments, Reis -Q-Z, wherein Q is a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO2—. In other embodiments, Q is a bivalent C2-6 straight or branched, hydrocarbon chain having at least one double bond, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO2—. In certain embodiments, the Z moiety of the Regroup is hydrogen. In some embodiments, -Q-Z is — NHC(O)CH═CH2or —C(O)CH═CH2.

[0289] In certain embodiments, each Reis independently selected from oxo, NO2, CN, fluoro, chloro, —NHC(O)CH═CH2, —C(O)CH═CH2, —CH2CH═CH2, —C≡CH, —C(O)OCH2Cl, —C(O)OCH2F, — C(O)OCH2CN, —C(O)CH2Cl, —C(O)CH2F, —C(O)CH2CN, or —CH2C(O)CH3.

[0290] In certain embodiments, Reis a suitable leaving group, i.e., a group that is subject to nucleophilic displacement. A “suitable leaving” is a chemical group that is readily displaced by a desired incoming chemical moiety such as the thiol moiety of a cysteine of interest. Suitable leaving groups are well known in the art, e.g., see, “Advanced Organic Chemistry,” Jerry March, 5thEd., pp. 351-357, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, 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).

[0291] In certain embodiments, the following embodiments and combinations of -L2-Y apply: (a) L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least onedouble bond and one or two additional methylene units of L2are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (b) L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —C(O)—, —NRC(O)—, — C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L2are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (c) L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —C(O)—, and one or two additional methylene units of L2are optionally and independently replaced by cyclopropylene, —O—, — N(R)—, or —C(O)—; and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (d) L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —C(O)—; and Y is hydrogen or C1- 6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (e) L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L2has at least one double bond and at least one methylene unit of L2is replaced by —OC(O)—; and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (f) L2is —NRC(O)CH═CH—, —NRC(O)CH═CHCH2N(CH3)—, —NRC(O)CH═CHCH2O—, —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═CHCH2O—, —NRC(O)C(═CH2)CH2—, —CH2NRC(O)—, —CH2NRC(O)CH═CH—, —CH2CH2NRC(O)—, or —CH2NRC(O)cyclopropylene-; wherein R is H or optionally substituted C1-6 aliphatic; and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (g) L2is —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)—, —NHC(O)(C═N2)C(O)—, —NHC(O)CH═CHCH2N(CH3)—, —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-; and Y is hydrogen or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN; or(h) L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least one alkylidenyl double bond and at least one methylene unit of L2is replaced by —C(O)—, —NRC(O)— , —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or — C(O)O—, and one or two additional methylene units of L2are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C1-6aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (i) L2is a bivalent C2-8straight or branched, hydrocarbon chain wherein L2has at least one triple bond and one or two additional methylene units of L2are optionally and independently replaced by — NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (j) L2is —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 C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (k) L2is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L2is replaced by cyclopropylene and one or two additional methylene units of L2are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—; and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; or (l) L2is a covalent bond and Y is selected from: (i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN; (ii) C2-6alkenyl optionally substituted with oxo, halogen, NO2, or CN; or (iii) C2-6alkynyl optionally substituted with oxo, halogen, NO2, or CN; or (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group –L2-Y.; or (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (vi)ch R, Q, Z, and Reis as defined above in warhead group –L2-Y; or(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or(x) wherein each Reis as defined above in warhead group –L2-Y; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (xiiwherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xiv)each Reis as defined above in warhead group –L2-Y; or (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xvi)wherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y; (m) L2is —C(O)— and Y is selected from: (i) C1-6alkyl substituted with oxo, halogen, NO2, or CN; or (ii) C2-6alkenyl optionally substituted with oxo, halogen, NO2, or CN; or (iii) C2-6alkynyl optionally substituted with oxo, halogen, NO2, or CN; or (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (vach R, Q, Z, and Reis as defined above in warhead group –L2-Y; or (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (x), w erein each Reis as defined above in warhead group –L2-Y; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (xwherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xwherein each Reis as defined above in warhead group –L2-Y; or (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xvi)wherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y; (n) L2is —N(R)C(O)— and Y is selected from: (i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN; or (ii) C2-6alkenyl optionally substituted with oxo, halogen, NO2, or CN; or (iii) C2-6alkynyl optionally substituted with oxo, halogen, NO2, or CN; or (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (v ach R, Q, Ze, and R is as defined above in warhead group –L2-Y; or (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or(x), w erein each Reis as defined above in warhead group –L2-Y; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (xReis as defined above in warhead group –L2-Y; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xwherein each Reis as defined above in warhead group –L2-Y; or (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xvi)wherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y; (o) L2is a bivalent C1-8saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from: (i) C1-6alkyl substituted with oxo, halogen, NO2, or CN; (ii) C2-6alkenyl optionally substituted with oxo, halogen, NO2, or CN; or (iii) C2-6alkynyl optionally substituted with oxo, halogen, NO2, or CN; or (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (v each Re, Q, Z, and R is as defined above in warhead group –L2-Y; or (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (x), w erein each Reis as defined above in warhead group –L2-Y; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or(xh R is as defined above and described herein and Reis as defined above in warhead group –L2- Y; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xwherein each Reis as defined above in warhead group –L2-Y; or (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xvi)wherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y;(p) L2is a covalent bond, —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, — NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —NHC(O)CH2OC(O)—, or —SO2NH—; and Y is selected from: (i) C1-6alkyl substituted with oxo, halogen, NO2, or CN; or (ii) C2-6alkenyl optionally substituted with oxo, halogen, NO2, or CN; or (iii) C2-6alkynyl optionally substituted with oxo, halogen, NO2, or CN; or (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or (x ein each Reis as defined above in warhead2group –L-Y; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein each Reis as defined above in warhead group –L2-Y; or( and Reis as defined above in warhead group –L2-Y; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; orwherein each Reis as defined above in warhead group –L2-Y; or (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Regroups, wherein each Regroup is as defined above in warhead group –L2-Y; or (xvi)wherein each R is as defined above and described herein and Reis as defined above in warhead group –L2-Y; or (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Regroups, wherein Reis as defined above in warhead group –L2-Y. Table 1a. Exemplary Y groupswherein each Reis independently a suitable leaving group, NO2, CN or oxo.

[0292] In certain embodiments, a warhead group is —C≡CH, —C≡CCH2NH(isopropyl), — NHC(O)C≡CCH2CH3, —CH2—C≡C≡CH3, —C≡CCH2OH, —CH2C(O)C≡CH, —C(O)C≡CH, or — CH2C(═O)C≡CH. In some embodiments, R1is selected from —NHC(O)CH═CH2, — NHC(O)CH═CHCH2N(CH3)2, or —CH2NHC(O)CH═CH2.

[0293] In certain embodiments, a warhead group is selected from those set forth in Table 1b, below, wherein each wavy line indicates the point of attachment to the rest of the molecule. Table 1b. Exemplary Warhead Groupswherein each Reis independently a suitable leaving group, NO2, CN, or oxo.

[0294] In some embodiments, Y of a warhead group is an isoxazoline compound or derivative capable of covalently binding to serine. In some embodiments, Y of a warhead group is an isoxazoline compound or derivative described in WO 2010135360, the entire content of which is incorporated herein by reference. As understood by one skilled in the art, an isoxazoline compound or derivative described in WO 2010135360, as Y of a warhead group, can covalently connect to L2of the warhead group at any reasonable position of the isoxazoline compound or derivative. In some embodiments, Y of a warhead group is:wherein G, Ra, and Rcare:

[0295] In certain embodiments, the present invention provides a compound of formula I as a compound of any one of the following formulae:or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, DBM isLinker (L)

[0297] As defined above and described herein, L is a bivalent moiety that connects TBM to DBM.

[0298] In some embodiments, L is a bivalent moiety that connects TBM to DBM.

[0299] As defined above and described herein, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, - N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-,, ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R is as defined and described herein; and each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0300] In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-50, C1-40, C1-30, C1-20, or C1-10 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, -O-, -N(R)-, -Si(R)2-, - Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, - S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, , , , , , or .

[0301] In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, - O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O- , -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or - N(R)C(O)O-.

[0302] In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, - O-, -N(R)-, -S-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, or -N(R)C(O)O-.

[0303] As defined above and described herein, each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- 10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0304] In some embodiments, –Cy– is an optionally substituted phenylenyl. In some embodiments, –Cy– is an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, –Cy– is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, –Cy– is an optionally substituted 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl. In some embodiments, –Cy– is an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, –Cy– is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, –Cy– is an optionally substituted 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, –Cy– is an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, –Cy– is an optionally substituted 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, –Cy– is an optionally substituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0305] In some embodiments, –Cy– is .In some embodiments, –Cy– is . Insome embodiments, –Cy– ismbodiments, –Cy– is . In some embodiments, –Cy– is embodiments, –Cy– is . In some embodiments, –Cy– is mbodiments, –Cy– is . In someembodiments, –Cy– is bodiments, –Cy– is . In som embodiments, –Cy– is bodiments, –Cy– is . In som embodiments, –Cy– is mbodiments, –Cy– is . In som embodiments, –Cy– is mbodiments, –Cy– is . In somembodiments, –Cy– is embodiments, –Cy– is . In some embodiments, –Cy– is embodiments, –Cy– is . Insome embodiments, –Cy– isme embodiments, –Cy– is .In some embodiments, –Cy– is e embodiments, –Cy– is . Insome embodiments, –Cy– isme embodiments, –Cy– is . In some embodiments, –Cy– is. In some embodiments, -Cy- is . In some embodiments, -Cy- is me embodiments, -Cy- is . In someembodiments, -Cy- isome embodiments, -Cy- is . In some embodiments,

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

[0307] As defined above and described herein, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0308] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0309] In some embodiments, p is selected from those depicted in Table 1B, below.

[0310] In some embodiments, L is -NR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-NR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-NR-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-NR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10aliphatic)- NR-. In some embodiments, L is -Cy-(C1-10aliphatic)-NR-(C1-10aliphatic)-. In some embodiments, L is - (C1-10aliphatic)-Cy-NR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)-NR-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)-NR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy-NR-. In some embodiments, L is -Cy-(C1-10aliphatic)- NR-Cy-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy-NR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10aliphatic)-NR-Cy-(C1-10aliphatic)-.

[0311] In some embodiments, L is -CONR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-CONR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-CONR-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-CONR-(C1-10aliphatic)-. In some embodiments, L is -Cy- (C1-10aliphatic)-CONR-. In some embodiments, L is -Cy-(C1-10aliphatic)-CONR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-Cy-CONR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)-CONR-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)- CONR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy-CONR-. In some embodiments, L is -Cy-(C1-10aliphatic)-CONR-Cy-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy- CONR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10aliphatic)-CONR-Cy-(C1-10aliphatic)-.

[0312] In some embodiments, L is -NRCO-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-NRCO-(C1-10aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-NRCO-(CH2CH2O)1- 10CH2CH2-. In some embodiments, L is -Cy-NRCO-(C1-10 aliphatic)-. In some embodiments, L is -Cy- (C1-10 aliphatic)-NRCO-. In some embodiments, L is -Cy-(C1-10 aliphatic)-NRCO-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-NRCO-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-NRCO-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)- NRCO-(C1-10 aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-Cy-NRCO-. In some embodiments, L is -Cy-(C1-10 aliphatic)-NRCO-Cy-. In some embodiments, L is -Cy-(C1-10 aliphatic)-Cy- NRCO-(C1-10 aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-NRCO-Cy-(C1-10 aliphatic)-.

[0313] In some embodiments, L is -O-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)- O-(C1-10aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-O-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-O-(C1-10 aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-O-. In some embodiments, L is -Cy-(C1-10 aliphatic)-O-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)- Cy-O-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-O-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-O-(C1-10 aliphatic)-. In some embodiments, L is - Cy-(C1-10 aliphatic)-Cy-O-.In some embodiments, L is -Cy-(C1-10 aliphatic)-O-Cy-.In some embodiments, L is -Cy-(C1-10 aliphatic)-Cy-O-(C1-10 aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-O-Cy- (C1-10 aliphatic)-.

[0314] In some embodiments, L is -Cy-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy- (C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy-(C1-10aliphatic)-Cy-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)-Cy-(C1-10aliphatic)-.

[0315] In some embodiments, L is -NR-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-NR- (CH2)1-10-. In some embodiments, L is -(CH2)1-10-NR-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-NR-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-NR-. In some embodiments, L is -Cy- (CH2)1-10-NR-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-NR-(CH2)1-10-. In some embodiments,L is -(CH2)1-10-Cy-(CH2)1-10-NR-. In some embodiments, L is -(CH2)1-10-Cy-(CH2)1-10-NR-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-Cy-NR-. In some embodiments, L is -Cy-(CH2)1-10-NR-Cy-. In some embodiments, L is -Cy-(CH2)1-10-Cy-NR-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-NR- Cy-(CH2)1-10-.

[0316] In some embodiments, L is -CONR-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-CONR- (CH2)1-10-. In some embodiments, L is -(CH2)1-10-CONR-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-CONR-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-CONR-. In some embodiments, L is -Cy-(CH2)1-10-CONR-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-CONR- (CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-(CH2)1-10-CONR-. In some embodiments, L is - (CH2)1-10-Cy-(CH2)1-10-CONR-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-Cy-CONR-. In some embodiments, L is -Cy-(CH2)1-10-CONR-Cy-. In some embodiments, L is -Cy-(CH2)1-10-Cy-CONR- (CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-CONR-Cy-(CH2)1-10-.

[0317] In some embodiments, L is -NRCO-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-NRCO- (CH2)1-10-. In some embodiments, L is -(CH2)1-10-NRCO-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-NRCO-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-NRCO-. In some embodiments, L is -Cy-(CH2)1-10-NRCO-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-NRCO- (CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-(CH2)1-10-NRCO-. In some embodiments, L is - (CH2)1-10-Cy-(CH2)1-10-NRCO-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-Cy-NRCO-. In some embodiments, L is -Cy-(CH2)1-10-NRCO-Cy-. In some embodiments, L is -Cy-(CH2)1-10-Cy-NRCO- (CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-NRCO-Cy-(CH2)1-10-.

[0318] In some embodiments, L is -O-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-O-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-O-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-O- (CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-O-. In some embodiments, L is -Cy-(CH2)1-10-O- (CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-O-(CH2)1-10-. In some embodiments, L is -(CH2)1-10- Cy-(CH2)1-10-O-. In some embodiments, L is -(CH2)1-10-Cy-(CH2)1-10-O-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-Cy-O-. In some embodiments, L is -Cy-(CH2)1-10-O-Cy-. In some embodiments, L is -Cy-(CH2)1-10-Cy-O-(CH2)1-10-. In some embodiments, L is -Cy-(CH2)1-10-O-Cy- (CH2)1-10-.

[0319] In some embodiments, L is -Cy-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-(CH2)1-10-. In some embodiments, L is -(CH2)1-10-Cy-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy- (CH2)1-10-Cy-. In some embodiments, L is -Cy-(CH2)1-10-Cy-(CH2)1-10-. In some embodiments, L is -Cy- (CH2)1-10-Cy-(CH2)1-10-Cy-. In some embodiments, L is -(CH2)1-10-Cy-(CH2)1-10-Cy-(CH2)1-10-.

[0320] In some embodiments, L is -CO-Cy-(CH2)1-10-. In some embodiments, L is -CO-(CH2)1-10- Cy-(CH2)1-10-. In some embodiments, L is -CO-Cy-(CH2CH2O)1-10CH2CH2-. In some embodiments, L is-CO-Cy-(CH2)1-10-Cy-. In some embodiments, L is -CO-Cy-(CH2)1-10-Cy-(CH2)1-10-. In some embodiments, L is -CO-Cy-(CH2)1-10-Cy-(CH2)1-10-Cy-. In some embodiments, L is -CO-(CH2)1-10-Cy- (CH2)1-10-Cy-(CH2)1-10-. In some embodiments, L is -Cy-Cy-(CH2)1-10-CO-. In some embodiments, L is - Cy-Cy-(CH2CH2O)1-10CH2-CO-. In some embodiments, L is -Cy-Cy-(CH2CH2O)1-10CH2CH2-CO-.e e

[0322] In some embodiments, L is selected from those depicted in Table B, below.

[0323] In some embodiments, L is selected from those depicted in Table 1B, below.

[0324] Without limitation, the point of attachment of L to TBM and DBM can be, for example when LTarget Binding Moiety (TBM)

[0325] As defined above and described herein, TBM is a target binding moiety.

[0326] As described herein, wherein a formula is depicted using square brackets, e..g,, attached to a modifiable carbon, oxygen, or nitrogen atom within TBM including substitution or replacement of a defined group in TBM.

[0327] In preferred aspects of the invention, the TBM group is a group, which binds to target proteins. Targets of the TBM group are numerous in kind and are selected from proteins that are expressed in a cell such that at least a portion of the sequences is found in the cell and may bind to a TBM group. The term “protein” includes oligopeptides and polypeptide sequences of sufficient length that they can bind to a TBM group according to the present invention. Any protein in a eukaryotic system, as described herein, are targets for ubiquitination mediated by the compounds according to the present invention.

[0328] TBM groups according to the present invention include, for example, include any moiety which binds to a protein specifically (binds to a target protein) and includes the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, HDM2 & MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds,immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among numerous others. The compositions described below exemplify some of the members of these nine types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest. These binding moieties are linked to the ubiquitin ligase binding moiety preferably through a linker in order to present a target protein (to which the protein target moiety is bound) in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0329] Any protein, which can bind to a target binding moiety or TBM group and acted on or degraded by an ubiquitin ligase is a target protein according to the present invention. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Proteins of interest can include proteins from eurkaryotes and prokaryotes including humans as targets for drug therapy, other animals, including domesticated animals, microbials for the determination of targets for antibiotics and other antimicrobials and plants, and even viruses, among numerous others.

[0330] In some embodiments, TBM (or target binding moiety) is a small molecule which is capable of binding to or binds to a target protein of interest. Some embodiments of the present application relates to TBMs which include but are not limited to Hsp90 inhibitors, kinase inhibitors, STAT3 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, compounds targeting cytosolic signaling protein FKBP12, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0331] In some embodiments, TBM is a BET / BRD4 binding moiety of formula I-aa:or a pharmaceutically acceptable salt thereof, wherein L and DBM are as defined above and described in embodiments herein, and wherein: Ring A’ and Ring B’ are independently an aromatic ring, a heteroaromatic ring, a 5-membered carbocyclyl, a 6-membered carbocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a pyrazine, optionally substituted by alkyl, alkoxy, halogen, nitrile or another aromatic or heteroaromatic ring; each Y1, Y2, Y3and Y4can independently be carbon, nitrogen or oxygen to form a fused 5-membered aromatic ring such as triazole or isoxazole; and Z1is methyl, or lower alkyl group.

[0332] As defined above and described herein, Ring A’ and Ring B’ are independently an aromatic ring, a heteroaromatic ring, a 5-membered carbocyclyl, a 6-membered carbocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a pyrazine, optionally substituted by alkyl, alkoxy, halogen, nitrile or another aromatic or heteroaromatic ring.

[0333] In some embodiments, Ring A’ is a 1,2-fused aromatic ring. In some embodiments, Ring A’ is 1,2-fused phenyl or benzo. In some embodiments, Ring A’ is a 1,2-fused heteroaromatic ring. In some embodiments, Ring A’ is a 1,2-fused 5-membered carbocyclyl. In some embodiments, Ring A’ is a 1,2- fused 6-membered carbocyclyl. In some embodiments, Ring A’ is a 1,2-fused 5-membered heterocyclyl. In some embodiments, Ring A’ is a 1,2-fused 6-membered heterocyclyl. In some embodiments, Ring A’ is 1,2-fused thiophene. In some embodiments, Ring A’ is 1,2-fused pyrrole. In some embodiments, Ring A’ is 1,2-fused pyrazole. In some embodiments, Ring A’ is 1,2-fused pyridine. In some embodiments, Ring A’ is 1,2-fused pyrimidine. In some embodiments, Ring A’ is 1,2-fused pyrazine. In some embodiments, Ring A’ is substituted by alkyl, alkoxy, halogen, nitrile or another aromatic or heteroaromatic ring.

[0334] In some embodiments, Ring B’ is an aromatic ring. In some embodiments, Ring B’ is phenyl. In some embodiments, Ring B’ is a heteroaromatic ring. In some embodiments, Ring B’ is a 5- membered carbocyclyl. In some embodiments, Ring B’ is a 6-membered carbocyclyl. In someembodiments, Ring B’ is a 5-membered heterocyclyl. In some embodiments, Ring B’ is a 6-membered heterocyclyl. In some embodiments, Ring B’ is thiophene. In some embodiments, Ring B’ is pyrrole. In some embodiments, Ring B’ is pyrazole. In some embodiments, Ring B’ is pyridine. In some embodiments, Ring B’ is pyrimidine. In some embodiments, Ring B’ is pyrazine. In some embodiments, Ring B’ is substituted by alkyl, alkoxy, halogen, nitrile or another aromatic or heteroaromatic ring.

[0335] In some embodiments, Ring A’ and Ring B’ are selected from those depicted in Table 1B, below.

[0336] As defined above and described herein, Y1, Y2, Y3and Y4can be carbon, nitrogen or oxygen to form a fused 5-membered aromatic ring such as triazole or isoxazole.

[0337] In some embodiments, Y1 is carbon. In some embodiments, Y1 is nitrogen. In some embodiments, Y1 is oxygen. In some embodiments, Y2 is carbon. In some embodiments, Y2 is nitrogen. In some embodiments, Y2 is oxygen. In some embodiments, Y3 is carbon. In some embodiments, Y3 is nitrogen. In some embodiments, Y3 is oxygen. In some embodiments, Y4 is carbon. In some embodiments, Y4 is nitrogen. In some embodiments, Y4 is oxygen.

[0338] In some embodiments, Y1, Y2, Y3 and Y4 are selected from those depicted in Table 1B, below.

[0339] As defined above and described herein, Z1 is methyl, or lower alkyl group.

[0340] In some embodiments, Z1 is methyl. In some embodiments, Z1 is a lower alkyl group.

[0341] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a compound of formula I-a’, thereby forming a compound of any one of the following formulae:or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined and described herein, both independently and in combination.

[0342] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a compound of formula I-b’, thereby forming a compound of any one of the following formulae:or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined and described herein, both independently and in combination.

[0343] In some embodiments, TBM is a BRD ligand selected from

[0344] In some embodiments, TBM is a CREBBP ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom, X is N or C, and n is 0 to 8.

[0345] In some embodiments, TBM is a TRIM24 / BRPF1 ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom, and n is 0 to 8.

[0346] In some embodiments, TBM is a glucocorticoid receptor ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0347] In some embodiments, TBM is an estrogen / androgen receptor ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom, X is N or C, and n is 0 to 8.

[0348] In some embodiments, TBM is a DOT1L ligand selected frommodifiable carbon, oxygen, nitrogen or sulfur atom.

[0349] In some embodiments, TBM is a BRAF ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0350] In some embodiments, TBM is a Ras ligand selected from, wherein to R or a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0351] In some embodiments, TBM is a RasG12C ligand selected from,

[0352] In some embodiments, TBM is a Her3 ligand selected from, whereinR or a modifiable carbon, oxygen, nitrogen or sulfur atom, and R’ is –CH2CH3or –CH=CH2.

[0353] In some embodiments, TBM is a Bcl-2 / Bcl-XL ligand selected from,wherein is attached to R or a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0354] In some embodiments, TBM is an HDAC ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0355] In some embodiments, TBM is a PPAR-gamma ligand selected from, whereined to R or a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0356] In some embodiments, TBM is selected from, whereined to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0357] In some embodiments, TBM is an Abl, KRAS, SHP2, cRAF, or PRMT5 ligand that are selected from the following non-limiting examples: Ablodifiable carbon, oxygen, nitrogen or sulfur atom.

[0358] In some embodiments, TBM is a EZH2ligand selected fromYPTM, and ZPTMis as defined in WO 2018 / 119357 and US 2018 / 0177750, the entirety of each of which is herein incorporated by reference.

[0359] In some embodiments, TBM is a FLT3 ligand selected from

[0360] In some embodiments, a TBM moiety is selected fromattached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0361] In some embodiments, a TBM moiety is a RAF ligand selected from, , ,ched to a modifiable carbon, oxygen, nitrogen or sulfur atom. In some embodiments, a TBM moiety is selected from,,,,,,,,,,,,,,,,modifiable carbon, oxygen, nitrogen or sulfur atom. [oxygen, nitrogen or sulfur atom.

[0363] In some embodiments, a TBM moiety is selected from

[0364] In some embodiments, a TBM moiety is selected fromcarbon, oxygen, nitrogen or sulfur atom; R is hydrogen, 5-(4-methyl-1H-imidazol-1-yl), or 4-(N- ethylpiperazin-1-yl)methyl).

[0365] In some embodiments, a TBM moiety is a RAF ligand selected from, ,

[0366] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is an receptor tyrosine kinase (RTK) binding moiety: (eutically acceptable salt thereof, wherein: each R21is independently selected from H, halogen, Cl, F, alkyl, haloalkyl, alkynyl, alkoxy, arylmethyloxy and heteroarylmethyloxy, wherein the said aryl and heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen and haloalkyl; each R22is independently selected from H, N, halogen, alkyl, haloalkyl, alkoxy, methoxy, amino, amido, alkylamino, dialkylamino, cyano, aryl, heteroaryl, furan, pyrrole, imidazole, oxazole, isoxazole, thiazole, cycloalkyl, heterocycloalkyl,wherein the said aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, cyano or R99SO2(CH2)sNHCH2-, where R99is an alkyl, and s is an integer between 0 and 3, —OR23or —NHC(O)R24, wherein R23is selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl, with the proviso that the two heteroatoms are not attached to the same carbon atom, and R24is selected from ,, ; R25and R26are independently selected from hydrogen or alkyl with the proviso that R25and R26taken together with the N atom, to which they are connected, may form a heterocycloalkyl; (ii)tically acceptable salt thereof, wherein: wherein R21is 1 to 3 substituents independently selected from H, halogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy and heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy and heteroarylalkyloxy, wherein the said aryl, heteroaryl, aryloxy and heteroaryloxy can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; R27is selected from H, alkyl, hydroxyalkyl and alkoxyalkyl; A is an aryl, a phenyl, or a heteroaryl; R28is 1 to 2 substituents independently selected from H, O, N, halogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl—wherein the said aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano;(ically acceptable salt thereof, wherein: wherein R21is selected from H, halogen, Cl, F, C1-C6 alkyl, haloalkyl, alkynyl, alkoxy, arylmethyloxy, cyano, and heteroarylmethyloxy, wherein the said aryl and heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen and haloalkyl; R29is 1 to 2 substituents independently selected from H, halogen, aryl alkyl, haloalkyl, alkoxy and cyano; R30is selected from H, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein the said alkyl could be optionally interrupted by —NHC(O)— or —C(O)NH— groups, with the proviso that two heteroatoms are not attached to the same carbon atom;(iv) , or pharmaceutically acceptable salt thereof, wherein: R31is selected from H, halogen, Cl, alkyl, haloalkyl, CF3, alkoxy, hydroxyl, cyano, amino, alkylamino, dialkylamino, aryl, heteroaryl, indole, pyrazole, imidazole, cycloalkyl, heterocycloalkyl wherein the said aryl and heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy and cyano; R32is selected from H, a 5- or 6-membered aryl or heteroaryl, a bicyclic fused aryl or heteroaryl and a bicyclic fused aryl or heteroaryl additionally optionally fused to a cycloalkyl or a heterocycloalkyl, wherein the said aryl or heteroaryl is optionally substituted with 1-2 substituents selected from alkyl, halogen, or haloalkyl; R33is selected from H, alkyl, haloalkyl, halogen, alkoxy, hydroxyl, amino, alkylamino, dialkylamino and cyano; R34is selected from H, O, alkyl, haloalkyl, halogen, amino, amido, C2-C6 alkyne, alkoxy, cyano or —NHC(O)R24, where R24is R24is selected from, , independently selected from H, N, N(CH2)1-3, or alkyl, with the proviso that R25and R26taken together with the N atom, to which they are connected optionally form a heterocycloalkyl; R35is selected from optionally substituted —OR36and — NR37R38, wherein R36is selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl with the proviso that the two heteroatoms are not attached to the same carbon atom; and R37and R38are independently selected from H, alkyl, —NR37R38, or — NR37R38taken together represent a heterocycloalkyl ring (eutically acceptable salt thereof, wherein: R31is selected from H, halogen, Cl, alkyl, haloalkyl, CF3, alkoxy, hydroxyl, cyano, amino, alkylamino, dialkylamino, aryl, heteroaryl, indole, pyrazole, imidazole, cycloalkyl, heterocycloalkyl wherein the said aryl and heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy and cyano; R33is selected from H, alkyl, haloalkyl, halogen, alkoxy, hydroxyl, amino, alkylamino, dialkylamino and cyano; R35is —NR37R38where R37and R38are independently selected from H or alkyl, or —NR37R38taken together represent a heterocycloalkyl ring, most preferably piperazine, further optionally substituted with alkyl, amino, alkylamino, dialkylamino, aminoalkyl, or —C(O)R39where R39is an alkyl; Ring B is selected from an aryl, a heteroaryl, a cycloalkyl or a heterocycloalkyl provided that in the latter case the heteroatom of the said heterocycloalkyl is separated from X by at least two carbon atoms; X is O, S or NH; R40is —NHC(O)R24, or —C(O)R24if attached to a ring nitrogen of Ring B, where R24is selected from ,,R25and R26are independently selected from hydrogen or alkyl with the proviso that R25and R26taken together with the N atom, to which they are connected, may form a heterocycloalkyl;(v) , or pharmaceutically acceptable salt thereof, wherein: wherein R41is selected from H, halogen, alkyl, haloalkyl, alkoxy and cyano; R42is 1 to 2 substituents independently selected from H, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, aryl, heteroaryl, imidazole, pyrazole, pyrrole, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl—wherein the said aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Ring C is an aryl or a heteroaryl; Ring D is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, e.g., 3-8 membered aryl or heteroaryl comprising at least one heteroatom selected from S, O, or N; Y is a bond, O, S, or NH; n is selected from 0, 1 or 2; R43is 1 to 2 substituents independently selected from H, halogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein the said aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano, —NHC(O)R24, or —C(O)R24if attached to a ring nitrogen of D; R24is selected from ,; and R25and R26are independently selected from hydrogen or alkyl with the proviso that R25and R26taken together with the N atom, to which they are connected, may form a h (lly acceptable salt thereof, wherein:wherein R42is 1 to 2 substituents independently selected from H, halogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, wherein the said aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Ring C is an aryl or a heteroaryl, e.g., imidazole, pyrazole, pyrrole; Ring D is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl; Y is a bond, O, S, or NH; n is selected from 0, 1 or 2; R43is 1 to 2 substituents independently selected from H, halogen, Cl, F, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, amido, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein the said aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano, or one of the R43substituents can be —NHC(O)R24or —C(O)R24if attached to a ring nitrogen of D; R24is as described above; and R88is a hydrogen or alkyl; (ically acceptable salt thereof, wherein: R33is selected from H, alkyl, haloalkyl, halogen, alkoxy, hydroxyl, amino, alkylamino, dialkylamino and cyano; R35is —NR37R38where R37and R38are independently selected from H or alkyl, or —NR37R38taken together represent a heterocycloalkyl ring, most preferably piperazine, further optionally substituted with alkyl, amino, alkylamino, dialkylamino, aminoalkyl, or —C(O)R39where R39is an alkyl; Ring B is selected from an aryl, a heteroaryl, a cycloalkyl or a heterocycloalkyl; R40is —NHC(O)R24, or — C(O)R24if attached to a ring nitrogen of Ring B where R24is selected from ,are independently selected from hydrogen or alkyl with the proviso that R25and R26taken together with the N atom, to which they are connected, may form a heterocycloalkyl; and R46is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl with the proviso that the two heteroatoms arenot attached to the same carbon atom and wherein the said aryl and heteroaryl can be further substituted with 1-2 substituents selected from alkyl, halogen, alkoxy, and cyano (viii)eutically acceptable salt thereof, wherein: R33is selected from H, alkyl, haloalkyl, halogen, alkoxy, hydroxyl, amino, alkylamino, dialkylamino and cyano; R35is —NR37R38where R37and R38are independently selected from H or alkyl, or —NR37R38taken together represent a heterocycloalkyl ring, most preferably piperazine, further optionally substituted with alkyl, amino, alkylamino, dialkylamino, aminoalkyl, or —C(O)R39where R39is an alkyl; Ring B is selected from an aryl, a heteroaryl, a cycloalkyl or a heterocycloalkyl; R40is —NHC(O)R24, or — C(O)R24if attached to a ring nitrogen of B where R24is selected from ,, od R26are independently selected from hydrogen or alkyl with the proviso that R25and R26taken together with the N atom, to which they are connected, may form a heterocycloalkyl; and R47is selected from H or alkyl;(ix) , or pharmaceutically acceptable salt thereof, wherein: R33is selected from H, alkyl, haloalkyl, halogen, alkoxy, hydroxyl, amino, alkylamino, dialkylamino and cyano; R35is —NR37R38where R37and R38are independently selected from H or alkyl, or —NR37R38taken together represent a heterocycloalkyl ring, most preferably piperazine, further optionally substituted with alkyl, amino, alkylamino, dialkylamino, aminoalkyl, or —C(O)R39where R39is an alkyl; Ring B is selected from an aryl, a heteroaryl, a cycloalkyl or a heterocycloalkyl; R40is —NHC(O)R24, or —C(O)R24if attached to a ring nitrogen of B where R24is selected from ,, ond R26are independently selected from hydrogen or alkyl with the proviso that R25and R26taken together with the N atom, to which they are connected, may form a heterocycloalkyl; R48is selected from H or alkyl; and R49is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;(x) , or pharmaceutically acceptable salt thereof, wherein: R50is an alkyl, alkylamino, dialkylamino, cycloalkyl or heterocycloalkyl wherein the said cycloalkyl or heterocycloalkyl are further optionally substituted with halogen, alkoxy, amino, alkylamino, dialkylamino or cyano with the proviso that any two heteroatoms are separated by at least two carbon atoms; and R51is a hydrogen and R52is —NHC(O)R53where R53is an aryl or a heteroaryl optionally substituted with 1-2 substituents independently selected from alkyl, halogen, alkoxy and cyano, or R51and R52taken together constitute a 5-6-membered aryl or heteroaryl ring optionally substituted with 1-2 substituents independently selected from alkyl, halogen, haloalkyl, alkoxy, cyano, amino, alkylamino, dialkylamino, aryl and heteroaryl;(xi) , or pharmaceutically acceptable salt thereof, wherein: G is a cycloalkyl or a heterocycloalkyl; H is an aryl or a heteroaryl; R43is 1 to 2 substituents independently selected from H, halogen, Cl, F, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, amido, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein the saidaryl or heteroaryl are optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano, or one of the R43substituents can be —NHC(O)R24or —C(O)R24if attached to a ring nitrogen of G; and R53and R54are each independently 1-2 substituents independently selected from H, halogen, Cl, F, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein the said aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; (eutically acceptable salt thereof, wherein: A is a saturated or unsaturated 4-8 atom carbocyclic or heterocyclic ring comprising 1-7 heteroatoms; Rk1is selected from H, alkyl, e.g., C1-C6 alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Rk2is selected from H, alkyl, cycloalkyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Rk3and Rk4are independently selected from H, hydroxyl, alkyl, e.g., C1-C6 alkyl, alkoxy, e.g., C1-C6 alkoxy, aryl, —SO2Rk2, or halogen, wherein the said hydroxyl, alkyl, aryl or alkoxy is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and X is N or CH or C with a double bond to the neighbor atom in the ring; (xiii)utically acceptable salt thereof, wherein: Rk5, Rk6and Rk7are independently selected from H, alkyl, alkyne, alkoxy, hydroxyl, cyano or halogen, Cl, or F, wherein the said alkyl or alkoxy is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and X is N or CH;(xiv) , or pharmaceutically acceptable salt thereof, wherein: Rk8is selected from H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein the said alkyl, aryl or heteroaryl can be further substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Rk9is selected from H, alkyl, or cycloalkyl, wherein the said alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and Rk10is selected from H, alkyl, alkylsulfone, alkylcarboxamide or aryl, wherein the said alkyl or aryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano;(xv) , or pharmaceutically acceptable salt thereof, wherein: wherein Rk11is selected from H, alkyl, alkoxy, —C(O)NHR, wherein R is selected from H, alkyl, cycloalkyl or a saturated heterocycle with 4-6 ring atoms; Rk12is selected from H, alkyl (linear or branched), aryl, cycloalkyl or heteroaryl, wherein the alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Rk13is selected from H, alkyl, —C(O)NHR, —C(O)R, —S(O)2R, wherein R is H, alkyl or cycloalkyl, which can be further substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone,alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano; and X is N or CH, (xvi)eutically acceptable salt thereof, wherein: Rk14is selected from H, N, alkyl, alkoxy, —C(O)NHR, wherein R is selected from H, alkyl, cycloalkyl or a saturated heterocycle with 4-6 ring atoms; Rk15is selected from H, alkyl (linear or branched), aryl, cycloalkyl or heteroaryl, wherein the said alkyl, aryl or heteroaryl is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; Rk16is selected from H, alkyl or cycloalkyl, which is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, alkylsulfone, alkylsulfonamide, amide, carboxamide, haloalkyl, hydroxyl, alkoxy, amino, amide, alkylamino, dialkylamino and cyano; and Rk17is selected from H, halogen, CN; whereinhed to a modifiable carbon, oxygen, nitrogen or sulfur atom, or wherein each of the variables as described and defined in WO 2018 / 119441 and US 2018 / 193470, the entirety of each of which is herein incorporated by reference.

[0367] In certain embodiments, the present invention provides a compound of formula I, wherein Tis attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0368] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is TBK1 binding moiety, or a p armaceutcaly acceptable salt thereof, wherein: X is N or CH; Y is absent or heterocyclyl, in particular pyrrolidinyl; R1is each individually halogen, in particular F; R2is selected from the group consisting of C1-6alkyl, in particular isopropyl, and C3- 6cycloalkyl, in particular cyclopentyl; wherein denotes attachment to , orwherein each of the variables is as described and defined in WO 2019 / 121562, the entirety of each of which is herein incorporated by reference.

[0369] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a BRD binding moiety: (cally acceptable salt thereof, wherein: T1 to T5 form a triazole or oxazole ring; A1 is S or C═C; A2 is NRa5 or O; nn1 is 0, 1, or 2; each Ra1 is independently C1-C3 alkyl, (CH2)0-3—CN, (CH2)0-3-halogen, (CH2)0-3—OH, (CH2)0-3—C1-C3 alkoxy, C(O)NRa5L, OL, NRa5L, or L; Ra2 is H, C1-C6 alkyl, (CH2)0-3-heterocyclyl, (CH2)0-3-phenyl, or L, wherein the heterocyclyl comprises one saturated 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S and is optionally substituted with C1-C3 alkyl, L, or C(O)L, and wherein the phenyl is optionally substituted with C1-C3alkyl, CN, halogen, OH, C1-C3alkoxy, or L; nn2 is 0, 1, 2, or 3; each Ra3is independently C1-C3alkyl, (CH2)0-3—CN, (CH2)0-3-halogen, L, or C(O)NRa5L; Ra4is C1-C3alkyl; Ra5is H or C1-C3alkyl; and L is a linker to DBM;(ii), or a p armaceutically acceptable salt thereof, wherein: T6is CRb4or N; Rb1, Rb2, and Rb5are each independently H or C1-C3alkyl; Rb3is C3-C6cycloalkyl; each Rb4is independently H, C1-C3alkyl, C1-C3alkoxy, CN, or halogen; nn3 is 0, 1, 2, or 3; each Rb6is independently C1-C3 alkyl, C1-C3 alkoxy, CN, or halogen; Rb7 is C(O)NRb8L, OL, NRb8L, or L; Rb8 is H or C1-C3 alkyl; and L is a linker to DBM; (nn4 is 0 or 1; Rc1is C(O)NRc6L, OL, NRc6L, or L; Rc2is H, C1-C3alkyl, C(O)NRc6L, OL, NRc6L, or L; Rc3is H, C1-C3alkyl, C(O)L, or L; nn5 is 0, 1, or 2; each Rc4is independently C1-C3alkyl or C1- C3alkoxy; each Rc5is independently H or C1-C3alkyl; Rc6is independently H or C1-C3alkyl; and L is a linker to DBM; CREBBP binding moiety: (each Rd1is independently H or C1-C3alkyl; nn6 is 0, 1, 2, or 3; nn7 is 0, 1, 2, or 3; each Rd2is independently C1-C3alkyl, C1-C3alkoxy, CN, or halogen; Rd3is C(O)NRd4L, OL, NRd4L, or L; Rd4is H or C1-C3alkyl; and L is a linker to DBM; (ally acceptable salt thereof, wherein: each Re1is independently H or C1-C3alkyl; nn8 is 0, 1, 2, or 3; nn9 is 0, 1, 2, or 3; each Re2is independently C1-C3alkyl, C1-C3alkoxy, CN, or halogen; Re4is NH—(CH2)1-3—C(O)NRe4L, C(O)NRe4L, OL, NRe4L, or L; Re4is H or C1-C3alkyl; and L is a linker to DBM; glucocorticoid receptor binding moietyeptable salt thereof, wherein: Rf1is C(O)NRf2L, OL, NRf2L, or L; Rf2is independently H or C1-C3alkyl; and L is a linker to DBM; FKBP binding moiety, p eutically acceptable salt thereof, wherein: T7is CH2or CH2CH2; Rg1is C(O)Rg5or (CH2)1-3Rg6; nn10 is 0, 1, 2, or 3; nn11 is 0, 1, 2, or 3; each Rg2is independently C1-C3alkyl, C1-C3alkoxy, CN, or halogen; Rg3is C(O)NRg4L, OL, NRg4L, L, O—(CH2)1-3—C(O)NRg4L, or NHC(O)—(CH2)1-3—C(O)NRg4L; Rg4is H or C1-C3alkyl; Rg5is C1-C6alkyl; Rg6is phenyl optionally substituted with C1-C3alkyl, C1-C3alkoxy, CN, or halogen; and L is a linker to DBM; or wherein each of the variables is as described and defined in US 9,694,084 and US 10,125,114, the entirety of each of which is herein incorporated by reference.

[0370] In certain embodiments, the present invention provides a compound of formula I, wherein R2O N R1n TBM is TBK1 binding moiety R3ptablesalt thereof, wherein: A is phenyl or pyridinyl; X is CH, C(C1-C3) alkyl, or N; R1is H or (C1-C3) alkyl; R2is (C6-C10) aryl, or heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R4; each R4is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, C(O)R6, C(O)OR6, C(O)NR6R7, NR6R7, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R5; each R5is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1- C4) haloalkoxy, halogen, NO2, OH, and CN; each R6is independently H or (C1-C3) alkyl; each R7is independently H or (C1-C3) alkyl; R3is (C1-Calkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, OH, or CN; each R9 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, OH, and CN; n is 0 or 1; wherein denotes attachment tohe variables is as described and defined in WO 2017 / 185036 and US 2019 / 0106417, the entirety of each of which is herein incorporated by reference.

[0371] In certain embodiments, the present invention provides a compound of formula I, whereinTBM is an androgen receptor binding moiety ,tically acceptable salt thereof, wherein: W1is aryl or heteroaryl, independently substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, C1- 6 alkyl (linear, branched, optionally substituted by 1 or more halo, C1-6 alkoxyl), C1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C2-6 alkenyl, C2-6 alkynyl; Y1, Y2are each independently NRY1, O, S; Y3, Y4, Y5are each independently a bond, O, NRY2, CRY1RY2, C═O, C═S, SO, SO2; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 RQ, each RQ, is independently H, C1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C1- 6 alkoxyl), or 2 RQgroups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R1, R2, Ra, Rb, RY1, RY2are each independently H, C1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C1-6 alkoxyl), or R1, R2together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); W2is a bond, C1-6 alkyl, C1- 6 alicyclic, heterocyclic, aryl, or heteroaryl, each optionally substituted by 1, 2 or 3 RW2; and each RW2is independently H, halo, C1-6 alkyl (optionally substituted by 1 or more F), OC1-3alkyl (optionally substituted by 1 or more —F), OH, NH2, NRY1RY2, CN; wherein ---- denotes attachment toein each of the variables is as described and defined in WO 2016 / 118666, US 2016 / 0214972, US 2017 / 327469, and WO 2019 / 023553, the entirety of each of which is herein incorporated by reference.

[0372] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is an androgen receptor binding moiety (i), or p armaceutically acceptable salt thereof, wherein: q is 0, 1 or 2; p 0 or 1; Q is NH, N(alkyl), 0, 1 or a direct bond; X is N or CH; Z is NH, N(alkyl), or CH2; B is aryl (wherein said aryl is preferably phenyl), cyclopentadienyl, cycloalkyl (wherein said cycloalkyl is preferably cyclopentanyl, cyclohexanyl, cyclopentenyl or cyclohexenyl), heteroaryl (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl), or a nine to ten membered benzo-fused heteroaryl (wherein said nine to ten membered benzo- fused heteroaryl is preferably benzothiazolyl, benzooxazolyl, benzoimidazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, or benzo [b]thiophenyl); R1 is H, -(CH2)nRa, -(E)CH=CH(CH2)nRa, - (Z)CH=CH(CH2)nRa, -CC(CH2)nRa, -(CH2)nRa, or -Rbb, wherein n is 1, 2, 3 or 4; Ra is hydrogen, heteroaryl optionally substituted with R5 (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, triazolyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, triazolyl, or pyrazinyl), hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R5, pyrrolidinonyl optionally substituted with R5, piperidinonyl optionally substituted with R5, cyclic heterodionyl optionally substituted with R5, heterocyclyl optionally substituted with R5 (wherein said heterocyclyl is preferably pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorphlinyl, thiomorpholinyl-1, 1-dioxide, piperidinyl, morpholinyl or piperazinyl), —COORy, —CONRwRx, —N(Ry)CON(Rw)(Rx), N(Rw)C(O)ORx, —N(Rw)CORy, —SRy, — SORy, —SO2Ry, —NRwSO2Ry, —NRwSO2Rx, SO3Ry, or —OSO2NRwRx; Rbb of is hydrogen, halogen, aryl, heteroaryl, or heterocyclyl; R5 is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, —C(O)alkyl, —SO2alkyl, C(O)N(alkyl)2, alkyl, —C(1-4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from hydrogen, alkyl, alkenyl, aralkyl (wherein the aryl portion of said aralkyl is preferrably phenyl), or heteroaralkyl (wherein the heteroaryl portion of said heteroaralkyl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, orpyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl), or Rwand Rxmay optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from: O, NH, N(alkyl), SO2, SO, or S, preferably selected from the group consisting of piperdinyl, morpholinyl, thiomorpholinyl, piperzinyl, N- alkylpiperzinyl, and pyrrolidinyl; Ryis selected from: hydrogen, alkyl, alkenyl, cycloalkyl (wherein said cycloalkyl is preferably cyclopentanyl or cyclohexanyl), aryl (wherein said aryl is preferably phenyl), aralkyl (wherein the aryl portion of said aralkyl is preferably phenyl), heteroaralkyl (wherein the heteroaryl portion of said heteroaralkyl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl), or heteroaryl (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N- oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl); R3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, alkoxyether, hydroxyl, thio, nitro, cycloalkyl optionally substituted with R4 (wherein said cycloalkyl is preferably cyclopentanyl or cyclohexanyl), heteroaryl optionally substituted with R4 (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide; and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl), alkylamino, heterocyclyl optionally substituted with R4 (wherein said heterocyclyl is preferably azapenyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, or piperazinyl), partially unsaturated heterocyclyl optionally substituted with R4, (wherein said partially unsaturated heterocyclyl is preferably tetrahydropyridinyl, tetrahydropyrazinyl, dihydrofuranyl, dihydrooxazinyl, dihydropyrrolyl, or dihydroimidazolyl), —O(cycloalkyl), pyrrolidinone optionally substituted with R4, phenoxy optionally substituted with R4, —CN, —OCHF2, OCF3, —CF3, halogenated alkyl, heteroaryloxy optionally substituted with R4, dialkylamino, NHSO2alkyl, thioalkyl, or —SO2alkyl; wherein R4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, —C(O)alkyl, —CO2alkyl, — SO2alkyl, C(O)N(alkyl)2, alkyl, or alkylamino;(ii), or pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl or pyridyl, either of which may be substituted with one of chloro, fluoro, methyl, —N3, —NH2, NH(alkyl), —N(alkyl)2, S(alkyl), —O(alkyl), or 4-aminophenyl; W is selected from pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including 1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl (including furan-2-yl), any of which may be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain one —Cl, —CN, —NO2, —OMe, or —CF3substitution, connected to any other carbon; R2is selected from cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chloro, fluoro, and C(1-3)alkyl (including 4,4-dimethyl cyclohexenyl, 4-methyl cyclohexenyl, 2-methyl thiophenyl, 3-methyl thiophenyl), with the proviso that tetrahydropyridyl is connected to the ring A through a carbon-carbon bond; X isor N; D1and D2III are each hydrogen or taken together form a double bond to an oxygen; D3and D4are each hydrogen or taken together form a double bond to an oxygen; D5is selected from hydrogen or —CH3, wherein said — CH3may be relatively oriented syn or anti; Raand Rbare independently selected from hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; E is selected from N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are simultaneously met: Qais absent, Qbis absent, and R3is an amino group or cyclic amino radical wherein the point of attachment to E is N; Qais selected from being absent, —CH2—, —CH2CH2—, or C(O); Qbis selected from being absent, —NH—, —CH2—, —CH2CH2—, or C(O), with the proviso that Qbmay not be C(O) if Qais C(O), and further provided that Qbmay not be —NH— if E is N and Qais absent, further provided that Qbmay not be —NH— if R3is an amino group or cyclic amino radical wherein the point of attachment to Qbis N; R3is selected from hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy ethylamino),(hydroxyalkyl)2amino, hydroxyalkyl(alkyl)amino (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino (including methylamino), aminoalkyl (including 2-amino isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl, 1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino (including dimethylamino), hydroxyalkyl (including 1-hydroxyeth-2-yl), —COOH, —CONH2, —CN, — SO2-alkyl-R4(including —SO2CH3), NH2, or a 5 or six membered ring which contains at least one heteroatom N and may optionally contain an additional heteromoiety selected from S, SO2, N, and O, and the 5 or 6 membered ring may be saturated, partially unsaturated or aromatic (including piperidinyl, morpholinyl, imidazolyl, and pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring may be present as N-oxide (including pyridyl N-oxide), and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl); R3may also be absent, with the proviso that R3is not absent when E is nitrogen; R4is selected from hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl; (rmaceutically acceptable salt thereof, wherein: W is C, N, O; X is C, N, absent; Y is C; Z is C, N; R1is H, alkoxy, hydroxyl, heterocyclic alkyl / aryl; R2is H, F, alkoxy, heterocyclic alkyl / aryl; R3is H, O, aryl, heteroaryl, C(O)heteroaryl; R4is H, alkyl, aryl, heteroaryl, CH-heteroaryl, absent; R5is H, aryl, heteroalkyl / aryl, absent; the dashed lines between WX, WY, YZ, YR3, and ZR4indicating a single or double bond, wherein the aryl, heteroaryl, heterocyclic alkyl / aryl are optionally substituted;X1 is N or CR2, X2 is N or CR6, Y1 is N or CR4, and Y2 is N or CR5, provided, however, that not more than one of X2, Y1 and Y2 is N; L1is selected from the group consisting of optionally substituted lower alkylene, —S—, —O—, —C(O)—, —C(S)—, —S(O)—, —S(O)2—, and —NR′—; L2is selected from the group consisting of a bond, optionally substituted lower alkylene, -(alk)a-S-(alk)b-, -(alk)a-O-(alk)b-, - (alk)a-OC(O)-(alk)b-, -(alk)a-C(O)O-(alk)b-, -(alk)a-OC(S)-(alk)b-, -(alk)a-C(S)O-(alk)b-, -(alk)a-C(O)- (alk)b-, -(alk)a-C(S)-(alk)b-, -(alk)a-C(O)NR9-(alk)b-, -(alk)a-OC(O)NR9-(alk)b-, -(alk)a-OC(S)NR9-(alk)b-,-(alk)a-C(S)NR9-(alk)b-, -(alk)a-S(O)-(alk)b-, -(alk)a-S(O)2-(alk)b-, -(alk)a-S(O)2NR9-(alk)b-, -(alk)a-NR9- (alk)b-, -(alk)a-NR9C(O)-(alk)b-, -(alk)a-NR9C(S)-(alk)b-, (alk)a-NR9C(O)NR9-(alk)b-, -(alk)a- NR9C(S)NR9-(alk)b-, -(alk)a-NR9C(O)O-(alk)b-, -(alk)a-NR9C(S)O-(alk)b-, -(alk)a-NR9S(O)2-(alk)b-, and - (alk)a-NR9S(O)2NR9-(alk)b-, wherein alk is optionally substituted C1-3alkylene and a and b are independently 0 or 1; R1of PTM-V is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R2, R4, R5and R6are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH2, —NO2, — CN, —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NH2, —NHC(O)NH2, —NHC(S)NH2, — NHS(O)2NH2, —NR10R11, —NHR3, —OR3, —SR3, —C(O)R3, —C(S)R3, —S(O)R3, —S(O)2R3, — C(O)OR3, —C(S)OR3, —C(O)NHR3, —C(O)NR3R3, —C(S)NHR3, —C(S)NR3R3, —S(O)2NHR3, — S(O)2NR3R3, —NHC(O)R3, —NR3C(O)R3, —NHC(S)R3, —NR3C(S)R3, —NHS(O)2R3, —NR3S(O)2R3, —NHC(O)OR3, —NR3C(O)OH, —NR3C(O)OR3, —NHC(S)OR3, —NR3C(S)OH, —NR3C(S)OR3, — NHC(O)NHR3, —NHC(O)NR3R3, —NR3C(O)NH2, —NR3C(O)NHR3, —NR3C(O)NR3R3, — NHC(S)NHR3, —NHC(S)NR3R3, —NR3C(S)NH2, —NR3C(S)NHR3, —NR3C(S)NR3R3, — NHS(O)2NHR3, —NHS(O)2NR3R3, —NR3S(O)2NH2, —NR3S(O)2NHR3, and —NR3S(O)2NR3R3; and Ar1 is a 5 or 6 membered optionally substituted heteroarylene; R of PTM-V is hydrogen or an optional substituent as defined herein for optionally substituted heteroarylene that provides a stable compound; R3at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)—, —S(O)2, —O—, —S—, or —N— of any of —OR3, —SR3, — C(O)R3, —C(S)R3, —S(O)R3, —S(O)2R3, —C(O)OR3, —C(S)OR3, —C(O)NHR3, —C(O)NR3R3, — C(S)NHR3, —C(S)NR3R3, —S(O)2NHR3, —S(O)2NR3R3, —NHR3, —NHC(O)R3, —NR3C(O)R3, — NHC(S)R3, —NR3C(S)R3, —NHS(O)2R3, —NR3S(O)2R3, —NHC(O)OR3, —NR3C(O)OH, — NR3C(O)OR3, —NHC(S)OR3, —NR3C(S)OH, —NR3C(S)OR3, —NHC(O)NHR3, —NHC(O)NR3R3, — NR3C(O)NH2, —NR3C(O)NHR3, —NR3C(O)NR3R3, —NHC(S)NHR3, —NHC(S)NR3R3, NR3C(S)NH2, —NR3C(S)NHR3, —NR3C(S)NR3R3, —NHS(O)2NHR3, —NHS(O)2NR3R3, —NR3S(O)2NH2, — NR3S(O)2NHR3, or —NR3S(O)2NR3R3, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)—, —S(O)2, —O—, —S—, or — N— of any of —OR3, —SR3, —C(O)R3, —C(S)R3, —S(O)R3, —S(O)2R3, —C(O)OR3, —C(S)OR3, — C(O)NHR3, —C(O)NR3R3, —C(S)NHR3, —C(S)NR3R3, —S(O)2NHR3, —S(O)2NR3R3, —NHR3, — NHC(O)R3, —NR3C(O)R3, —NHC(S)R3, —NR3C(S)R3, —NHS(O)2R3, —NR3S(O)2R3, —NHC(O)OR3,—NR3C(O)OH, —NR3C(O)OR3, —NHC(S)OR3, —NR3C(S)OH, —NR3C(S)OR3, —NHC(O)NHR3, — NHC(O)NR3R3, —NR3C(O)NH2, —NR3C(O)NHR3, —NR3C(O)NR3R3, —NHC(S)NHR3, — NHC(S)NR3R3, —NR3C(S)NH2, —NR3C(S)NHR3, —NR3C(S)NR3R3, —NHS(O)2NHR3, — NHS(O)2NR3R3, —NR3S(O)2NH2, —NR3S(O)2NHR3, or —NR3S(O)2NR3R3, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R7is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(O)R8, and —S(O)2R8; R8is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R9at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and —NR12R13, provided, however, that when R9is substituted lower alkyl, any substitution on the alkyl carbon bound to the —N— of NR9— is fluoro; R10and R11at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to the nitrogen of NR10R11, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen of —NR10R11, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R10and R11together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl; R12and R13combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; (y acceptable salt thereof, wherein: Ar is selected from the group consisting of optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl, when substituted, the substituents could be one or more groupsindependently selected from halogen, alkyl, haloalkyl, or hydroxyl alkyl; L is H, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted cycloalkylalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted arylalkyl, optionally substituted or unsubstituted sulfonamido, optionally substituted or unsubstituted heterocycloalkyl, optionally substituted or unsubstituted heterocycloalkylalkyl, optionally substituted or unsubstituted heteroaryl or optionally substituted or unsubstituted heteroarylalkyl; when substituted, the substituents can be one or more groups independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, amino, aminoalkyl, amido, aminocarbonyl, sulfonamido, ureido, cyano, acetyl, acyl, carboxylic acid, hydroxyl, hydroxylalkyl, alkoxyl, —NHalkylhydroxyl, —NHalkoxyalkyl, —NHalkylamnio, —NHcycloalkyl, — NHcycloalkylalkyl, —NHheterocycloalkyl, —NH heterocycloalkylalkyl, —NHaryl, —NHarylalkyl, — NHheteroaryl, or —NHheteroarylalkyl; Y is O, S, NR2R2′ or a direct bond (that means L directly connected with the left heteroaryl); X1, X2, X3 and X4 are independently N or CR1; R1 is H, or —Y-L; R, R2and R2′ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, haloalkoxyl, hydroxyl, amino, aminocarbonyl, sulfonamido, cyano, alkynyl, alkoxyl, aryloxyl, carboxylic acid, carboxylic ester or halogen, or R2, R2′ together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocycloalkyl ring, and the hetero atom could be selected from at least one of O, S or N atoms optionally substituted with a group independently selected from alkyl, cycloalkyl, methylsulfonyl, ureido, acyl, amido, aminocarbonyl, alkylamino, alkylhydroxyl, heterocycloalkyl, aryl, or heteroaryl; (L is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R1is hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OCF3, —OCCl3, —OCBr3, —OCl3, —CN, —OH, —NH2, —COOH, —C(O)OR4, —CONH2, —NO2, —SH, —NHNH2, —NR2R3, —OR4, —SR4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2and R3are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R2and R3areoptionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R5and R6are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OCF3, —OCCl3, —OCBr3, —OCl3, —CN, —OH, —NH2, — COOH, —C(O)OR9, —CONH2, —NO2, —SH, —NHNH2, —NR7R8, —OR9, —SR9, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7and R8are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R7and R8are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R9is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;salt thereof, wherein: R1is a hydrogen atom or a substituted or unsubstituted C1-6alkyl group; R2is a hydrogen atom, a substituted or unsubstituted C1-6alkyl group, a substituted or unsubstituted C2-6alkenyl group, or a substituted or unsubstituted C2-6alkynyl group; R3is a hydrogen atom, a substituted or unsubstituted C1-6alkyl group, a substituted or unsubstituted C2-6alkenyl group, or a substituted or unsubstituted C2-6alkynyl group; or R2and R3may bind together to form an atomic bond; R4is a hydrogen atom, a substituted or unsubstituted C1-6alkyl group, a substituted or unsubstituted C2-6alkenyl group, a substituted or unsubstituted C2-6alkynyl group, a substituted or unsubstituted C3-8cycloalkyl group, or an imino protecting group; m of R5are the same or different, and is a hydrogen atom or a substituted or unsubstituted C1-6alkyl group; m of R6are the same or different, and is a hydrogen atom or a substituted or unsubstituted C1-6alkyl group; or R5and R6binding to the same carbon atom may bind together to form: a substituted or unsubstituted C2-6alkylene group; an substituted or unsubstituted 0-(C1-6alkylene) group, a substitute or unsubstituted N(R13)—(C1-6alkylene) group, wherein R13is a hydrogen atom, asubstituted or unsubstituted C1-6alkyl group or an imino protecting group; a substituted or unsubstituted (C1-3alkylene)-O—(C1-3alkylene) group; a substitute or unsubstituted (C1-3alkylene)-N(R13)—(C1-3alkylene) group, wherein R13is a hydrogen atom, a substituted or unsubstituted C1-6alkyl group or an imino protecting group; n of R7are the same or different, and is a hydrogen atom or a substitute or unsubstituted C1-6alkyl group; n of R8are the same or different, and is a hydrogen atom or a substitute or unsubstituted C1-6alkyl group; or R7and R8binding to the same carbon atom may bind together to form: a substituted or unsubstituted C2-6alkylene group; an substituted or unsubstituted O—(C1-6alkylene) group; a substituted or unsubstituted N(R14)—(C1-6alkylene) group, wherein R14is a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, or an imino protecting group; a substituted or unsubstituted (C1- 3 alkylene)-O—(C1-3 alkylene) group; or a substituted or unsubstituted (C1-3 alkylene)-N(R14)—(C1- 3 alkylene) group which may be substituted, wherein R14is a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, or an imino protecting group; R9is a substituted or unsubstituted C1-6 alkyl group; a substituted or unsubstituted C3-8 cycloalkyl; a substituted or unsubstituted aryl group; a substituted or unsubstituted C1-6 alkoxy group; a substituted or unsubstituted heterocyclic group; N(R15)(R16) wherein R15is a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2- 6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, or a substituted or unsubstituted C3- 8 cycloalkyl group, and R16is a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3- 8 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, or R15and R16may form a substituted or unsubstituted cyclic amino group together with the nitrogen atom to which they bind; R10is a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-8 cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted heterocyclic group; R11is a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, or a substituted or unsubstituted C3-8 cycloalkyl group; R12is a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-8cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted carbamoyl group; X1represents a group represented by —X4—X5—, wherein X4is a substituted or unsubstituted divalent alicyclic hydrocarbon, a substituted or unsubstituted divalent aromatic hydrocarbon group, a substituted or unsubstituted divalentheterocyclic group, or a group represented byare the same or different, and is a hydrogen atom or a substituted or unsubstituted C1-6alkyl group, or one R17selected from p of R17may bind with R4to form: a substituted or unsubstituted C1-6alkylene group: a substituted or unsubstituted (C1-3alkylene)-O group: a substituted or unsubstituted (C1-3alkylene)-N(R19) group, wherein R19is a hydrogen atom, substituted or unsubstituted a C1-6alkyl group, or an imino protecting group; a substituted or unsubstituted (C1-3alkylene)-O—(C1-3alkylene) group; a substituted or unsubstituted (C1-3alkylene)-N(R19)—(C1-3alkylene) group, wherein R19is a hydrogen atom, substituted or unsubstituted a C1-6alkyl group, or an imino protecting group; p of R18are the same or different, and is a hydrogen atom or a substituted or unsubstituted C1-6alkyl group; or R17and R18binding to the same carbon atom may bind together to form: a substituted or unsubstituted C2-6alkylene group, a substituted or unsubstituted O—(C1-6alkylene); a substituted or unsubstituted N(R20)—(C1-6alkylene) group, wherein R20is a hydrogen atom; a substituted or unsubstituted C1-6alkyl group or an imino protecting group; a substituted or unsubstituted (C1-3alkylene)-O—(C1-3alkylene) group; a substituted or unsubstituted (C1-3alkylene)- N(R20)—(C1-3alkylene), wherein R20is a hydrogen atom; a substituted or unsubstituted C1-6alkyl group or an imino protecting group; and p represents an integer of 1 to 6; or an atomic bond; and X5is an oxygen atom, N(R21) wherein R21is a hydrogen atom, a substituted or unsubstituted C1-6alkyl group, a substituted or unsubstituted C2-6alkenyl group, a substituted or unsubstitute C2-6alkynyl group or an imino protecting group, or R21may bind with R4to form a substitute or unsubstituted C1-6 alkylene group; C(═O); C(═O)— N(R21) wherein R21is a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstitute C2-6 alkynyl group or an imino protecting group; or an atomic bond; X2is a bond, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkylene group, a substituted or unsubstituted divalent alicyclic hydrocarbon group, a substituted or unsubstituted divalent aromatic hydrocarbon, or a substituted or unsubstituted divalent heterocyclic group; X3is a substituted or unsubstituted C1-6 alkylene group, a substituted or unsubstituted C2-6 alkenylene group, a substituted or unsubstituted C2-6 alkynylene group, a substituted or unsubstituted O—(C1-6 alkylene) group, a substituted or unsubstituted S(O)q—(C1-6 alkylene) group wherein q represents 0, 1 or 2; a substituted or unsubstituted N(R22)—(C1-6 alkylene) group wherein R22is a hydrogen atom, a substituted or unsubstitute C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substitute or unsubstituted C2-6 alkynyl group or an imino protecting group; N(R22)—C(═O) wherein R22is a hydrogen atom, a substituted or unsubstitute C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substitute or unsubstituted C2-6 alkynyl group or an imino protectinggroup; or an atomic bond; Z1is a nitrogen atom or C(R23) wherein R23is a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-6alkyl group, a substituted or unsubstituted C3-8cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-6alkoxy group or substituted or unsubstituted a heterocyclic group; m is an integer of 0, 1, 2, 3, 4, 5, or 6; n is an integer of 0, 1, 2, 3, 4, 5, or 6); or (cally acceptable salt thereof, wherein: W is an aryl, 5-membered heteroaryl, or 6-membered heteroaryl ring, each optionally substituted with one or more RPTM1groups; X is independently selected from CRPor N; Y and Z are independently selected from a bond or CH2; m and n are each independently 1 or 2; RPis H, halogen, C1-5alkyl, CN, OH, or OC1-5alkyl; indicates either a single or double bond; each R is independently selected from H, halogen, C1-5alkyl, CN, C(O)C1-5alkyl, C(O)OC1-5alkyl, OH, or OC1-5alkyl, each optionally substituted (e.g., optionally substituted with a cycloalkyl, heterocycle, or aminoalkyl); whereinhed to a modifiable carbon, oxygen, nitrogen or sulfur atom, or ---- denotes attachment to, each of the variables are as described and defined in WO 2018 / 118598 and US 2018 / 0256586, the entirety of each of which is herein incorporated by reference.

[0373] In certain embodiments, the present invention provides a compound of formula I, whereinTBM is a HER binding moietyeptable salt thereof, wherein: XTis C—CN, or CH; one of RT1and RT2is a colvant bond to the linker and the other is C1-C4 alkoxy; YTis N or CH; Tn1 is 0, 1, 2, 3, or 4; each RT3is independently halogen, C1-C4 alkyl, C1-C4 alkyl substituted with halogen, C1-C4 alkoxy, or C1-C4 alkoxy substituted with halogen or a heteroaryl comprising a 6- membered ring and 1-2 nitrogen atoms; and RTNis H or C1-C4 alkyl; wherein e otes attachment to, h of the variables is as described and defined in WO 2017 / 117474 and US 2019 / 0016703, the entirety of each of which is herein incorporated by reference.

[0374] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a TAU binding moiety, ,eptable salt thereof, wherein: L is N or CR5; M is N or CR6; P is N or CR7; Q is N or CR8; X is a bond or substituted or unsubstituted C1-12alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO2, NH, or NC1-6alkyl optionally substituted with halogen, OH, or C1-6alkyl; R9is hydrogen, —N3, alkynyl, OH, halogen, NH2, N(C1-6alkyl)2, aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO2, NH2, or C1-6alkyl optionally substituted with halogen or C3-8cycloalkyl; R3is —(CH2)n—O—, -A-(CH2)n—O—, —(CH2)n-A-O—, -A-O—(CH2)n—(C═O)NRA—, —(CH2)n—S—, -A-(CH2)nS—, —(CH2)n-A-S—, -A-S—(CH2)n—(C═O)NRA—, —(CH2)n—NRA—, -A-(CH2)n— NRA—, —(CH2)n-A-NRA—, —(CH2)n—(C═O)NRA—, -A-(CH2)n—(C═O)NRA—, —(CH2)n-A— (C═O)NRA—, -A-NRA—(CH2)n—(C═O)NRA—, —(CH2)n—S(O)2NRA—, -A-(CH2)n—S(O)2NRA—, or —(CH2)n-A-S(O)2NRA—; A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; each of R1, R2, and R4-R8are independently hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, aryl, heteroaryl, NHR12, N(R12)2C3-8cycloalkyl, N(R12)2heterocyclyl, or —(CH2)n—R12; R12is hydrogen, —CH3, aryl, or heteroaryl; and n is 0-12; wherein one or more carbon of R1-8is optionally replaced with C(O), O, S, SO2, NH, NH-C1-6 alkyl, NC1-6 alkyl, NH2, or N(C1-6 alkyl)2; X1is CH, N, NH, O, or S; X2is CH, C, or N; X3is CR15or N; X4is CR15or N; X5is CR15or N; each occurrence of R13and R15is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NRA(C═O)Oalkyl, —NRA(C═O)Oaryl, —NRA(C═O)alkyl, —NRA(C═O)aryl, —(C═O)Oalkyl, — (C═O)Oaryl, —(C═O)alkyl, —(C═O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R14is —(CH2)n— O—, -A-(CH2)n—O—, —(CH2)n-A-O—, -A-O—(CH2)n—(C═O)NRA—, —(CH2)n—S—, -A-(CH2)n— S—, —(CH2)n-A-S—, -A-S—(CH2)n—(C═O)NRA—, —(CH2)n—NRA—, -A-(CH2)n—NRA—, —(CH2)n- A-NRA—, -A-NRA—(CH2)n—(C═O)NRA—, —(CH2)n—(C═O)NRA—, -A-(CH2)n—(C═O)NRA—, — (CH2)n-A—(C═O)NRA—, —(CH2)n—S(O)2NRA—, -A-(CH2)n—S(O)2NRA—, or —(CH2)n-A- S(O)2NRA—; A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and n is 0-12; wherein one or more carbon of R13, R14, and R15is optionally replaced with C(O), O, S, SO2, NH, NC1-6 alkyl, NH-C1-6 alkyl, NH2, or N(C1-6alkyl)2; R20and R21are independently halogen, —OH, —COOH, —SO3H, —NO2, —SH, —NRxRy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R22(CH2)n—O—, —(CH2)n—S—, —(CH2)n—NRA—, —(CH2)n—(C═O)NRA—, or —(CH2)n— S(O)2NRA—; R23is halogen, —OH, —COOH, —SO3H, —NO2, —SH, —NRxRy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R24is unsubstituted alkylene, alkylene substituted with one or more halogen or hydroxy groups, unsubstituted alkoxylene, or alkoxylene substituted with one or more halogen or hydroxy groups; Rxand Ryare independently hydrogen, or substituted or unsubstituted alkyl; n is 0-12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2; wherein denotes attachment to, of the variables is as described and defined in WO 2019 / 014429, the entirety of each of which is herein incorporated by reference.

[0375] In certain embodiments, the present invention provides a compound of formula I or II, wherein TBM is an estrogen receptor binding moiety: (lly acceptable salt thereof, wherein: XPTMis O or C═O; each of XPTM1and XPTM2is independently selected from N or CH; RPTM1is independently selected from OH, O(CO)RPTM, O-lower alkyl, wherein RPTMis an alkyl or aryl group in the ester; RPTM2and RPTM4are independently selected from H, OH, halogen, CN, CF3, SO2-alkyl, O-lower alkyl; RPTM3and RPTM5are independently selected from H, halogen; or (ally acceptable salt thereof, wherein: each XPTMis independently CH, N; each RPTM1is independently OH, halogen, alkoxy, methoxy, ethoxy, O(CO)RPTM, wherein the substitution can be a mono-, di- or tri-substitution and the RPTMis alkyl or cycloalkyl group with 1 to 6 carbons or aryl groups; each RPTM2is independently H, halogen, CN, CF3, liner or branched alkyl, alkoxy, methoxy, ethoxy, wherein the substitution can be mono- or di- substitution; each RPTM3is independently H, halogen, wherein the substitution can be mono- or di- substitution; and RPTM4is a H, alkyl, methyl, ethyl; wherein denotes attachment to, of the variables is as described and defined in WO 2018 / 144649 and US 2018 / 0215731, the entirety of each of which is herein incorporated by reference.

[0376] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a protein kinase binding moiety:(ally acceptable salt thereof, wherein: X1 is NR5 or O; each R1 and each R4 are independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; R2and R3 are each independently H, (C1-C4) alkyl, or (C1- C4) haloalkyl; R5 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or C(O)(C1-C4) alkyl; n1 is 0, 1, 2 or 3; and n2 is 0, 1, or 2; (ly acceptable salt thereof, wherein: A is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R9; X2is O, S, or NR10; X3 is N or CR11; each R6 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, NH2, (C1-C4) alkylamino, (C1-C4) dialkylamino, NHS(O)2(C1-C4) alkyl, or N((C1-C4) alkyl)S(O)2(C1-C4) alkyl; R7 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl; each R8and each R9 are independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; R10 is H or (C1-C4) alkyl; R11 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; q1 is 0, 1, 2, 3, or 4; and q2 is 0, 1, or 2; (cally acceptable salt thereof, wherein: B1 is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R15; B2 is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R16; R12 is H or (C1-C4) alkyl; each R13 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; R14 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl; each R15 and each R16 are independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; and r1 is 0, 1, 2, 3 or4; (utically acceptable salt thereof, wherein: B3is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R19; B4is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R20; R17 is H or (C1-C4) alkyl; R18 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; or each R19 and each R20 are independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; (lly acceptable salt thereof, wherein: B5 is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R26; Y1 is C(O)NR25 or NR25C(O); R21 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl; R22and R23are each independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; each R24 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, or C(O)(C1-C4) alkyl; R25is H, (C1-C4) alkyl, or (C1-C4) haloalkyl; each R26 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; and s2 is 0, 1, 2, or 3; (cceptable salt thereof, wherein: B6 is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R31; B7 is (C6-C10) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R32; X4 is O or NR33; R27 and R28 are eachindependently H, (C1-C4) alkyl, or (C1-C4) haloalkyl; each R29 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; each R30is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, or C(O)(C1-C4) alkyl; each R31 and each R32 are independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; R33is H, (C1-C4) alkyl, or (C1-C4) haloalkyl; s3 and s4 are each independently 0, 1, 2, or 3; and s5 is 1 or 2; wherein denotes attachment to, h of the variables is as described and defined in WO 2018 / 098280 and US 2019 / 263823, the entirety of each of which is herein incorporated by reference.

[0377] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a BTK binding moietypharmaceutically acceptable salt thereof, wherein: B is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R9, wherein when Y1 is absent or C(O), Y2 is NR10a or O; Y3 is C(O)NR10b or NR10bC(O); Y4 is NR5′ or, when Y1 is bonded to Y4 or when Y1 is absent and B is bonded to Y4, Y4 is N; R5′ is H, (C1-C4)alkyl, (C1-C4) haloalkyl, (C1-C4)alkoxy, (C1-C4) haloalkoxy, or halogen; each R5 is independently (C1-C4)alkyl, (C1-C4) haloalkyl, (C1-C4)alkoxy, (C1-C4) haloalkoxy, halogen, or oxo; R6 is H, (C1-C4)alkyl, or (C1-C4) haloalkyl; each R7 is independently (C1- C4)alkyl, (C1-C4) haloalkyl, (C1-C4)alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, halogen, OH, or NH2; each R8 is independently (C1-C4)alkyl, (C1-C4) haloalkyl, (C1-C4)alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; each R9 is independently (C1-C4)alkyl, (C1-C4) haloalkyl, (C1-C4)alkoxy, (C1-C4) haloalkoxy, or halogen; R10a and R10b are each independently H, (C1-C4)alkyl, or (C1-C4) haloalkyl; and o1, o2, and o3 are each independently 0, 1, 2, or 3;wherein denotes attachment to, h of the variables is as described and defined in WO 2018 / 098275 and US 2019 / 262458, the entirety of each of which is herein incorporated by reference.

[0378] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a BET / BRD4 binding moietyor a pharmaceutically acceptable salt thereof, wherein: Y1, Y2 and Y3 are independently selected from the group of carbon, nitrogen or oxygen and together with the atoms to form an aromatic fused ring; Ring A and B are independently selected from the group of a 5- membered aromatic ring, a 6-membered aromatic ring, a heteroaromatic ring, a carbocyclic, a thiophene a pyrrole ring, a pyridine, a pyrimidine, a pyrazine, a pyrazole ring each optionally substituted with alkyl, alkoxy, halogen, an aromatic and a heteroaromatic ring; wherein Ring A is fused to the central azepine (Y1=C) or diazepine (Y1=N) moiety; and Z1 is selected from the group of methyl or an alkyl group; whereinhed to one , or whereeach of the variables is as described and defined in WO 2017 / 030814 and US 2017 / 0065719, the entirety of each of which is herein incorporated by reference.

[0379] In certain embodiments, the present invention provides a compound of formula I, whereinpharmaceutically acceptable salt thereof, wherein: A, B, C, D, E, and F are independently selected from an optionally substituted 5- or 6- membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or a heterocycloalkyl, where contact between circles indicates ring fusion; each LPTM is selected from a bond, an alkyl, an alkenyl or an alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or more functional groups selected from the groups -O-, -S-, -NRPTM-, -N=N-, -SC(O)-, -SO2-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, wherein the said functional group is optionally located at either end of the linker; and RPTM is selected from H or alkyl; wherein denotes attachment to, of the variables is as described and defined in WO 2018 / 102067 and US 2018 / 0125821, the entirety of each of which is herein incorporated by reference.

[0380] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a Bcr-Abl binding moietypharmaceutically acceptable salt thereof, wherein: Y1is C(O)NR6or NR6C(O); each R1, each R3, and each R4is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; R2is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or (C1-C4) haloalkoxy; each R5is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, or oxo; R6is H, (C1-C4) alkyl, or (C1-C4) haloalkyl; n1, n2, n3, and n5 are each independently 0, 1, 2 or 3; and n4 is 0, 1, or 2;wherein enotes attachment to, h of the variables is as described and defined in WO 2018 / 089736, the entirety of each of which is herein incorporated by reference.

[0381] In certain embodiments, the present invention provides a compound of formula I, wherein R1R3TBM is an estrogen receptor binding moietyacceptable salt thereof, wherein: R1is H, -OH, -OC1-3alkyl, or a halogen; R2is -OH or -OC1-3alkyl; and R3is H or an optionally substituted a lower alkyl; R4 is a straight chain or branched C1-6alkyl, or C3-6 cycloalkyl; wherein e otes attachment to, of the variables is as described and defined in WO 2018 / 053354 and US 2018 / 072711, the entirety of each of which is herein incorporated by reference.

[0382] In certain embodiments, the present invention provides a compound of formula I, wherein N O TBM is a CDK binding moietyO or a pharmaceutically acceptable salt thereof, wherein denoes atachment toed in Olson et al., Nat. ChemBio. 2018, 14:163-170, the entirety of each of which is herein incorporated by reference.

[0383] In certain embodiments, the present invention provides a compound of formula I, wherein

[0384] In certain embodiments, the present invention provides a compound of formula I, whereinTBM is a HER binding moiety or a pharmaceutically acceptable salt thereof, wherein: XTis N or CH; RT1is absent, (CH2)0-3C(O)NH, or (CH2)0-3NHC(O); RT2is NO2or NH2; Tn1 is 0, 1, 2, 3, 4, or 5; each RT5is independently OH, halogen, CN, C1-C4alkyl, C1-C4alkyl substituted with halogen, C1- C4alkoxy, or C1-C4alkoxy substituted with halogen; Tn2 is 0, 1, 2, or 3; each RT6is independently OH, halogen, CN, C1-C4alkyl, C1-C4alkyl substituted with halogen, C1-C4alkoxy, or C1-C4alkoxy substituted with halogen; RT7is H or C1-C4alkyl; and RTN1and RTN2are each independently H or C1-C4alkyl; wherein denotes attachment to, of the variables is as described and defined in WO 2017 / 117473 and US 2020 / 216454, the entirety of each of which is herein incorporated by reference.

[0385] In certain embodiments, the present invention provides a compound of formula I, wherein TBM is a CDK4 / 6 binding moietyacceptable salt thereof, wherein: A is absent or Ceach R1 is independently (C1-C4) alkyl or (C1-C4) haloalkyl; R2is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, OH, or NH2; R3is (C6-C10) aryl or a monocyclic or bicyclic heteroaryl comprising one to fourheteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R7; or R2and R3together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl comprising one or two heteroatoms selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more R8; or R2and R3together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaryl comprising one or two heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R9; each R4is independently H or (C1-C4) alkyl; R5is H or (C1-C4) alkyl; each R6is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; each R7is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; or each R8 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, C(O)NH2, C(O)NH(C1-C4) alkyl, C(O)N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, or heterocycloalkyl, or two R8 together with the carbon to which they are attached form C(O); each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, C(O)NH2, C(O)NH(C1-C4) alkyl, C(O)N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, or heterocycloalkyl; and n and t are independently 0, 1, 2, or 3; wherein denotes attachment to, of the variables is as described and defined in WO 2017 / 185031 and US 2019 / 092768, the entirety of each of which is herein incorporated by reference.

[0386] In some embodiments, a TBM moiety is selected from PTM moieties as recited in WO 2016 / 197032 the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2016 / 197032 the recitation of a “Linker” moiety in WO 2016 / 197032 corresponds to the –L- group as defined and described herein. In some embodiments, a TBM moiety is selected from such inhibitors as described in US 2018 / 0125821, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2018 / 119441, and US 2018 / 0193470, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in US 2018 / 0147202, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2018 / 098275 at Table A, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2016 / 169989 and US 2018 / 0118733, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2015 / 181747 and US 2017 / 0121335, the entirety of each of which isherein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Shimokawa et al., Med. Chem. Lett., 2017, 8 (10), pp 1042–1047, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 079267 and US 2018 / 0186785, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Powell et al., J. Med. Chem., 2018, 61 (9), pp 4249–4255, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Zhang et al., Eur. J. Med. Chem., 2018, 151, pp 304-314, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Li et al., Eur. J. Med. Chem., 2018, 151, pp 237-247, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2016 / 169989 and US 2018 / 0118733, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 046036, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2016 / 169989 and US 2018 / 0118733, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2018 / 053354 and US 2018 / 0072711, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Olsen et al., Nat. Chem. Bio., 2018, 14, pp 163–170, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 185031, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Hatcher et al., Med. Chem. Lett., 2018, 9(6), pp 540–545, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Burslem et al., Cell Chem. Bio., 2018, 25(1), pp 67-77, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in CN106977584, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 197056, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2018 / 051107, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in US 2018 / 0050021, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 223452, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 117473, WO 2017 / 117474, and US2019 / 0016703, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2018 / 071606 and US 2018 / 0099940, the entirety of each of which is herein incorporated by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in US 2018 / 0099940, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Gechijian et al., Nat. Chem. Bio., 2018, 14, pp.405–412, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in CN 106749513, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in CN107056772, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Pawar et al., Cell Rep., 2018, 22(9), pp 2236-2245, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in US 2018 / 009779, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 180417, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2017 / 223452, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in US 2018 / 009779, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Tomoshige et al., Bioorg. Med. Chem. Lett., 2018, 28(4), pp 707-710, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in Chessum et al., J. Med. Chem., 2018, 61(3), pp.918-933, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in CN 105085620, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such protein target moieties as described in WO 2017 / 011371 and US 2017 / 008904, the entirety of each of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such protein target moieties as described in US 2016 / 045607, the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such protein target binders as described in US 2017 / 0281784, WO 2019 / 118893, and WO 2019 / 118851, the entirety of each of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such protein target binders as described in WO 2018 / 144649 and US 2017 / 0281784, the entirety of each of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such protein target binders as described in US 2018 / 0179522, WO 2018 / 119357, WO 2017 / 197056, WO 2017 / 011590, and US 2017 / 0037004, the entirety of each of which is incorporated herein by reference. In some embodiments, aTBM moiety is selected from such protein target moieties as described in WO 2017 / 007612 and US 2018 / 0134684, the entirety of each of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such protein target moieties as described in WO 2018 / 064589 and US 10,239,888, the entirety of each of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such targeting ligands as described in US 9,694,084, the entirety of which is incorporated herein by reference..

[0388] In some embodiment, TBM is selected from the compounds listed in Table 1B.

[0389] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0390] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0391] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0392] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, isselected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0393] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0394] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0395] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0396] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM is, from but not limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0397] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, isselected from those wherein DBM is, from but not limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0398] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM isimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0399] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM isimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0400] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0401] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM isbut not limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0402] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0403] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is snot limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0404] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is snot limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0405] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0406] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, isselected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0407] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is slimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0408] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is slimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0409] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is slimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0410] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, isselected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0411] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below.

[0412] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is sbut not limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0413] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM isnot limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0414] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is sbut not limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0415] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM isnot limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0416] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is snot limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0417] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM isis selected from but not limited to any of those in Table A below, and L is selected from any of those in Table B below.

[0418] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein DBM islimited to any of those in Table A below, and L is selected from any of those in Table B below. Table A. Exemplified Binders (TBM)Table B. Exemplified Linkers (L)

[0419] In some embodiments, the present invention provides a compound having an DBM binding moiety described and disclosed herein, an TBM set forth in Table A above, and a linker set forth in Table B above, or a pharmaceutically acceptable salt thereof.

[0420] Exemplary compounds of the invention are set forth in Table 1A and 1B, below. Table 1A. Exemplary Compounds

[0421] In some embodiments, the present invention provides a compound set forth in Table 1A, above, or a pharmaceutically acceptable salt thereof.

[0422] In some embodiments, the invention also provides a compound described herein (such as a compound of formulae I-a or I-b), or pharmaceutical compositions thereof, for use in a method for modulating a target protein as described herein and / or in a method for treating a target protein-mediated disorder as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of formulae I-a or I-b), or pharmaceutical compositions thereof, for use in a method of modulating a target protein as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of formulae I-a or I-b), or pharmaceutical compositions thereof, for use in a method of treating a target protein-mediated disorder as described herein.

[0423] In some embodiments, the present invention provides a compound of formulae I-a or I-b as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formulae I-a or I-b as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament, such as for modulating a target protein as described herein and / or for treating an a target protein-mediated disorder as described herein. Table 1B. Exemplary Bifunctional Compounds

[0424] In some embodiments, the present invention provides a compound set forth in Table 1B, above, or a pharmaceutically acceptable salt thereof.

[0425] In some embodiments, the invention also provides a compound described herein (such as a compound of formulae I-a, I-a’, I-b, or I-b’), or pharmaceutical compositions thereof, for use in a method for degrading a target protein as described herein and / or in a method for treating a target protein- mediated disorder as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of formulae I-a, I-a’, I-b, or I-b’), or pharmaceutical compositions thereof, for use in a method of degrading a target protein as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of formulae I-a, I-a’, I-b, or I- b’), or pharmaceutical compositions thereof, for use in a method of treating a target protein-mediated disorder as described herein.

[0426] In some embodiments, the present invention provides a compound of formulae I-a, I-a’, I-b, or I-b’ as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formulae I-a, I-a’, I-b, or I-b’ as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament, such as for degrading a target protein as described herein and / or for treating an a target protein-mediated disorder as described herein.

[0427] In some embodiments, TBM is one of the compounds in Table 2, below, whereinached to a modifiable carbon, oxygen, nitrogen or sulfur atom. Table 2. Exemplary Drugs with Disease Indications and Gene Identifier for the Target Protein4. General Methods of Providing the Present Compounds

[0428] The compounds of this invention may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

[0429] In the Schemes below, where a particular protecting group, leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5thEdition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2ndEdition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.

[0430] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2- (phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t- butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[0431] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0432] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 1 set forth below: Scheme 1: Synthesis of Compounds of the Invention

[0433] As depicted in Scheme 1, above, amine A-1 is coupled to acid A-2 using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond, , represents the portion of the linker between TBM and the terminal amino group of A-1 or the portion of the linker between DBM and the terminal carboxyl group of A-2, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[0434] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 2 set forth below: Scheme 2: Synthesis of Compounds of the Invention

[0435] As depicted in Scheme 2, above, amine A-1 is coupled to acid A-2 using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond, , represents the portion of the linker between TBM and the terminal amino group of A-1 or the portion of the linker between DBM and the terminal carboxyl group of A-2, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[0436] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 3 set forth below: Scheme 3: Synthesis of Compounds of the Invention

[0437] As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond, , represents the portion of the linker between TBM and the terminal carboxyl group of A-3 or the portion of the linker between DBM and the terminal amino group of A-4, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[0438] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 4 set forth below: Scheme 4: Synthesis of Compounds of the Invention

[0439] As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond, , represents the portion of the linker between TBM and the terminal carboxyl group of A-3 or the portion of the linker between DBM and the terminal amino group of A-4, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[0440] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 5 set forth below: Scheme 5: Synthesis of Compounds of the Invention

[0441] As depicted in Scheme 5, above, an SNAr displacement of fluoride A-6 by amine A-5 is effected in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising a secondary amine. The squiggly bond, , represents the portion of the linker between TBM and the terminal amino group of A-5.

[0442] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 6 set forth below: Scheme 6: Synthesis of Compounds of the Invention

[0443] As depicted in Scheme 6, above, an SNAr displacement of fluoride A-7 by amine A-8 is effected in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising a secondary amine. The squiggly bond, , represents the portion of the linker between DBM and the terminal amino group of A-8.

[0444] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 7 set forth below: Scheme 7: Synthesis of Compounds of the Invention

[0445] As depicted in Scheme 7, above, reductive amination of the mixture of aldehyde A-9 and amine A-10 is effected in the presence of NaHB(OAc)3and KOAc in DMF / THF to form a compound of the invention with a linker comprising a secondary amine. A linker comprising a tertiary amine can be prepared similarily using a secondary amine in place of the primary amine A-10. The squiggly bond, , represents the portion of the linker between TBM and the terminal aldehyde of A-9 or the portion of the linker between DBM and the terminal amino group of A-10, respectively.

[0446] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 8 set forth below: Scheme 8: Synthesis of Compounds of the Invention

[0447] As depicted in Scheme 8, above, reductive amination of the mixture of aldehyde A-12 and amine A-11 is effected in the presence of NaHB(OAc)3 and KOAc in DMF / THF to form a compound of the invention with a linker comprising a secondary amine. A linker comprising a tertiary amine can be prepared similarily using a secondary amine in place of the primary amine A-11. The squiggly bond, , represents the portion of the linker between TBM and the terminal amino group of A-11 or the portion of the linker between DBM and the terminal aldehyde of A-12, respectively.

[0448] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See for example, “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of each of which is herein incorporated by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification. 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions

[0449] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably bind DCAF1, or a mutant thereof, and a targeted protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0450] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0451] 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 may be used inthe compositions of this invention include, but are not limited to, 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, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0452] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[0453] As used herein, the term "active metabolite or residue thereof" means that a metabolite or residue thereof is also a binder of DCAF1, or a mutant thereof, or a targeted protein, or a mutant thereof.

[0454] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0455] For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0456] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0457] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0458] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0459] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0460] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0461] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0462] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0463] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0464] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0465] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions

[0466] Presently described are compositions and methods that relate to the discovery that an E3 ubiquitin ligase protein (e.g., DCAF1) ubiquitinates a target protein once it and the target protein are placed in proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein (e.g., DCAF1) and the target protein. Accordingly the present invention provides such compounds and compositions comprising an DCAF1 E3 ubiquintin ligase binding moiety (“DBM”) coupled to a protein target binding moiety (“TBM”), which result in the ubiquitination of a chosen target protein, which leads to degradation of the target protein by the proteasome.

[0467] In some embodiments, compounds and compositions described herein are useful in medicine. Compounds and compositions described herein are generally useful for the modulation of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degradedand / or otherwise inhibited. Compounds and compositions described herein exhibit a broad range of pharmacological activities, consistent with the degradation / inhibition of targeted polypeptides.

[0468] Even though DCAF1 binders are known in the art, there is a continuing need to provide novel binders having more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased activity, selectivity over other E3 ligases, and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, the present invention provides binders of DCAF1 which show selectivity over other E3 ligases. Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the binding of E3 ligases.

[0469] The activity of a compound utilized in this invention as an binder of DCAF1, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the subsequent functional consequences, or activity of activated DCAF1, or a mutant thereof. Alternate in vitro assays quantitate the ability of the compound to bind to DCAF1. Binding may be measured by radiolabeling the compound prior to binding, isolating the compound / DCAF1 complex and determining the amount of radiolabel bound. Alternatively, compound binding may be determined by running a competition experiment where new compounds are incubated with DCAF1 bound to known radioligands.

[0470] The term “ubiquitin ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono- ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. Accordingly in some embodiments, a provided compound specifically recognizes proteins with a diglycine (Gly-Gly) at the C-terminus, leading to their ubiquitination and degradation.

[0471] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptomsthereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0472] The description provides therapeutic compositions as described herein for effectuating the degradation of proteins of interest for the treatment or amelioration of a disease, e.g., cancer. As such, in another aspect, the description provides a method of ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein comprising, e.g., a DBM and a TBM, linked through a linker moiety, as otherwise described herein, wherein the DBM is coupled to the TBM and wherein the DBM recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligase such as, e.g., DCAF1) and the TBM recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation / inhibition of the effects of the target protein and control of protein levels. The control of protein levels afforded by the present invention provides treatment of a disease state or condition, which...

Claims

CLAIMS 1. A compound of formula I-a’I-a’ or a pharmaceutically acceptable salt thereof, wherein: Ring E is phenyl, naphthyl, a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring F is phenyl, a 4-11 membered partially unsaturated monocyclic or bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Y2is a C1-4 hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, - C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, -S(O)2-, -C(OR)=N-, -N(Rd)-, or -O-; Rais hydrogen, an optionally substituted C1-6 aliphatic, or ;Ring G is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rbis hydrogen, an optionally substituted C1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Raand Rbare taken together with their intervening atoms to form an optionally substituted 9-10 membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: when Y2includes -C(NR)-, Rbis taken together with R of -C(NR)- with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur;Rcis halogen, -CN, -CFR2, -CF2R, -CF3, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)(NR)R, -S(O)R, -C(O)R, -CR=NOR, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -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, -P(O)(NR2)2, -CR2CN, -CR2CFR2, -CR2CF2R, -CR2CF3, -CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, -CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, - CR2C(O)NR2, -CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2OP(O)R2, - CR2OP(O)(OR)2, -CR2OP(O)(OR)NR2, -CR2OP(O)(NR2)2, -CR2NRC(O)OR, -CR2NRC(O)R, - CR2NRC(O)N(R)2, -CR2NRS(O)2R, -CR2NP(O)R2, -CR2NRP(O)(OR)2, -CR2NRP(O)(OR)NR2, - CR2NRP(O)(NR2)2, -CR2P(O)R2, -CR2P(O)(OR)2, -CR2P(O)(OR)NR2, -CR2P(O)(NR2)2, - CR2CR2CN, -CR2CR2CFR2, -CR2CR2CF2R, -CR2CR2CF3, -CR2CR2NO2, -CR2CR2OR, - CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, - CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, -CR2CR2CR=NOR, -CR2CR2C(O)OR, - CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2OP(O)R2, -CR2CR2OP(O)(OR)2, -CR2CR2OP(O)(OR)NR2, - CR2CR2OP(O)(NR2)2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, - CR2CR2NRS(O)2R, -CR2CR2NP(O)R2, -CR2CR2NRP(O)(OR)2, -CR2CR2NRP(O)(OR)NR2, - CR2CR2NRP(O)(NR2)2, -CR2CR2P(O)R2, -CR2CR2P(O)(OR)2, -CR2CR2P(O)(OR)NR2, - CR2CR2P(O)(NR2)2, -CR2CR(OR)CR2OR, or an optionally substituted group selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: -(CR2)0-2C(O)Rccor -(CR2)0-2S(O)0-2Rcc; or: Rband Rcare taken together with their intervening atoms to form an optionally substituted 4-6 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:Rais absent and Rband Rcare taken together with their intervening atoms to form an optionally substituted phenyl; Rdis hydrogen or an optionally substituted C1-6aliphatic, or: when Rcis -CR2CONR2, Rdis taken together with a single R of -CR2CONR2with their intervening atoms to form a 5-7 membered saturated or partially unsaturated heterocyclyl with 0-3 heteroatoms, in addition to the nitrogen atom to which Rdis attached, independently selected from nitrogen, oxygen, and sulfur; Re, Rf, and Rgare each independently selected from hydrogen, RA, 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, -C(NOR)R, -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; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rccis RA, halogen, -CN, -OR, -SR, -NR2, -NROR, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -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; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, naphthyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, or on different atoms, are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom, or different atoms, to which they are attached, independently selected from nitrogen, oxygen, and sulfur; s” is 0 or 1; each of e, f, and g are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, -O-, -N(R)-,-Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, - N(R)C(O)O-,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and TBM is a target protein binding moiety; wherein said compound of formula I-a’ is optionally substituted with , and whereead group.

2. The compound of claim 1, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof, wherein: Y1is a C1-3hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, - C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, -S(O)2-; or: Y1is -C(OR)= in formula I-a-1, Rdis absent, and Rcis optionally taken together with R of - C(OR)=, and with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur.

3. The compound of claim 2, wherein Y1is a C1-3hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-.

4. The compound of claim 2 or claim 3, wherein Y1is -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, - C(NOR)-, -S(O)-, or -S(O)2-.

5. The compound of any one of claims 2-4, wherein Y1is -C(O)-.

6. The compound of any one of claims 1-5, wherein the compound is any one of the following formulae:I-a-4’ or a pharmaceutically acceptable salt thereof.

7. A compound of formula I-a:or a pharmaceutically acceptable salt thereof, wherein: Ring E is phenyl, a 4-7 membered partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring F is phenylenyl, a 4-10 membered partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Y1is a C1-3hydrocarbon chain wherein each methylene is optionally substituted with -CR2-, -CR(OR)-, - C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-; Rais an optionally substituted C1-6 aliphatic orRing G is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rbis hydrogen, an optionally substituted C1-6aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Raand Rbare optionally taken together with their intervening atoms to form an optionally substituted 9-10 membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: when Y1is -C(NR)-, Rbis optionally taken together with R of -C(NR)- with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms,in addition to the 2 nitrogen atoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur; Rcis -CR2CONR2, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rdis hydrogen, or: when Rcis -CR2CONR2, Rdis optionally taken together with a single R of -CR2CONR2with their intervening atoms to form a 5-7 membered saturated or partially unsaturated heterocyclyl with 0-3 heteroatoms, in addition to the nitrogen atom to which Rdis attached, independently selected from nitrogen, oxygen, and sulfur; Re, Rf, and Rgare each independently selected from hydrogen, oxo, RA, 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; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; each of s’ and s’’ are independently 0 or 1; and each of e, f, and g are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, - N(R)C(O)O-,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and TBM is a target protein binding moiety; wherein said compound of formula I-a is optionally substituted with , and wheis a warhead group.

8. The compound of any one of claims 1-7, wherein the compound is any one of the following formulae:I-a-5’or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-8, wherein Ring E is phenyl, naphthyl, or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

10. The compound of any one of claims 1-9, wherein Ring E is phenyl or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

11. The compound of any one of claims 1-10, wherein Ring E is phenyl or a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

12. The compound of any one of claims 1-11, wherein Ring E is phenyl or a 5-6-membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

13. The compound of any one of claims 1-12, Ring E is phenyl.

14. The compound of any one of claims 1-8, wherein Ring E is a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl.

15. The compound of any one of claims 1-8, wherein Ring E is a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

16. The compound of any one of claims 1-13, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1-16, wherein Ring F is phenyl or a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

18. The compound of any one of claims 1-17, wherein Ring F is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

19. The compound of any one of claims 1-18, Ring F is a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

20. The compound of any one of claims 1-19, Ring F is a 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

21. The compound of any one of claims 1-20, Ring F is a 5-membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

22. The compound of any one of claims 1-21, Ring F is a 5-membered heteroaryl with 1-2 nitrogen heteroatoms.

23. The compound of any one of claims 1-16, wherein Ring F is a 4-11 membered partially unsaturated monocyclic or bicyclic carbocyclylenyl.

24. The compound of any one of claims 1-16, wherein Ring F is a 4-11 membered partially unsaturated monocyclic or bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

25. The compound of any one of claims 1-24, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-25, wherein Ring G is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

27. The compound of any one of claims 1-26, wherein Ring G is phenyl or a 6-membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

28. The compound of any one of claims 1-27, wherein Ring G is phenyl.

29. The compound of any one of claims 1-25, wherein Ring G is a 5-7 membered saturated or partially unsaturated carbocyclyl.

30. The compound of any one of claims 1-25, wherein Ring G is a 5-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

31. The compound of any one of claims 1-30, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-31, wherein e is 1, 2, or 3.

33. The compound of any one of claims 1-32, wherein e is 1 or 2.

34. The compound of any one of claims 1-33, wherein e is 1.

35. The compound of any one of claims 1-31, wherein e is 0.

36. The compound of any one of claims 1-34, wherein Reis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

37. The compound of any one of claims 1-34, wherein Reis optionally substituted C1-6 aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

38. The compound of any one of claims 1-34, wherein Reis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, - CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

39. The compound of any one of claims 1-38, wherein f is 1, 2, or 3.

40. The compound of any one of claims 1-39, wherein f is 1 or 2.

41. The compound of any one of claims 1-40, wherein f is 1.

42. The compound of any one of claims 1-38, wherein f is 0.

43. The compound of any one of claims 1-41, wherein Rfis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

44. The compound of any one of claims 1-41, wherein Rfis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

45. The compound of any one of claims 1-41, wherein Rfis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, - CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

46. The compound of any one of claims 1-45, wherein g is 1, 2, or 3.

47. The compound of any one of claims 1-46, wherein g is 1 or 2.

48. The compound of any one of claims 1-47, wherein g is 1.

49. The compound of any one of claims 1-45, wherein g is 0.

50. The compound of any one of claims 1-48, wherein Rgis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

51. The compound of any one of claims 1-48, wherein Rgis optionally substituted C1-6 aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

52. The compound of any one of claims 1-48, wherein Rgis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, - CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

53. The compound of any one of claims 1-52, wherein Rbis hydrogen, an optionally substituted C1-6aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

54. The compound of any one of claims 1-53, wherein Rbis hydrogen or an optionally substituted C1-6aliphatic.

55. The compound of any one of claims 1-54, wherein Rbis hydrogen or C1-6alkyl.

56. The compound of any one of claims 1-55, wherein Rbis hydrogen.

57. The compound of any one of claims 1-56, wherein Rcis halogen, -CN, -CFR2, -CF2R, -CF3, - NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)(NR)R, -S(O)R, -C(O)R, -CR=NOR, -C(O)OR, - C(O)NR2, -C(O)NROR, -C(NOR)R, -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, -P(O)(NR2)2, -CR2CN, - CR2CFR2, -CR2CF2R, -CR2CF3, -CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, - CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, -CR2C(O)NR2, - CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2OP(O)R2, -CR2OP(O)(OR)2, - CR2OP(O)(OR)NR2, -CR2OP(O)(NR2)2, -CR2NRC(O)OR, -CR2NRC(O)R, -CR2NRC(O)N(R)2, - CR2NRS(O)2R, -CR2NP(O)R2, -CR2NRP(O)(OR)2, -CR2NRP(O)(OR)NR2, -CR2NRP(O)(NR2)2, - CR2P(O)R2, -CR2P(O)(OR)2, -CR2P(O)(OR)NR2, -CR2P(O)(NR2)2, -CR2CR2CN, -CR2CR2CFR2, - CR2CR2CF2R, -CR2CR2CF3, -CR2CR2NO2, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, - CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2OP(O)R2, -CR2CR2OP(O)(OR)2, - CR2CR2OP(O)(OR)NR2, -CR2CR2OP(O)(NR2)2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, -CR2CR2NRS(O)2R, -CR2CR2NP(O)R2, -CR2CR2NRP(O)(OR)2, - CR2CR2NRP(O)(OR)NR2, -CR2CR2NRP(O)(NR2)2, -CR2CR2P(O)R2, -CR2CR2P(O)(OR)2, - CR2CR2P(O)(OR)NR2, -CR2CR2P(O)(NR2)2, -CR2CR(OR)CR2OR, , or an optionally substituted group selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

58. The compound of any one of claims 1-57, wherein Rcis -CO2R, -CONR2, -CR2CN, -CR2CFR2, - CR2CF2R, -CR2CF3, -CR2NO2, -CR2OR, -CR2SR, -CR2NR2, -CR2SiR3, -CR2S(O)2R, -CR2S(O)2NR2, - CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, -CR2CR=NOR, -CR2C(O)OR, -CR2C(O)NR2, - CR2C(O)NROR, -CR2C(NOR)R, -CR2OC(O)R, -CR2OC(O)NR2, -CR2NRC(O)OR, -CR2NRC(O)R, - CR2NRC(O)N(R)2, -CR2NRS(O)2R, -CR2CR2CN, -CR2CR2CFR2, -CR2CR2CF2R, -CR2CR2CF3, - CR2CR2NO2, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2SiR3, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, -CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR2OC(O)R, -CR2CR2OC(O)NR2, -CR2CR2NRC(O)OR, -CR2CR2NRC(O)R, -CR2CR2NRC(O)N(R)2, - CR2CR2NRS(O)2R, -CR2CR(OR)CR2OR; or: –(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

59. The compound of any one of claims 1-58, wherein Rcis -CO2R, -CONR2, -CR2CN, -CR2CF2R, - CR2OR, -CR2SR, -CR2NR2, -CR2S(O)2R, -CR2S(O)2NR2, -CR2S(O)(NR)R, -CR2S(O)R, -CR2C(O)R, - CR2CR=NOR, -CR2C(O)OR, -CR2C(O)NR2, -CR2CR2CN, -CR2CR2CF2R, -CR2CR2OR, -CR2CR2SR, -CR2CR2NR2, -CR2CR2S(O)2R, -CR2CR2S(O)2NR2, -CR2CR2S(O)(NR)R, -CR2CR2S(O)R, -CR2CRC(O)R, -CR2CR2CR=NOR, -CR2CR2C(O)OR, -CR2CR2C(O)NR2, -CR2CR2C(O)NROR, -CR2CR2C(NOR)R, -CR2CR(OR)CR2OR; or: –(CR2)1-2-Xa, wherein Xais an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

60. The compound of any one of claims 1-59, wherein Rcis -CO2R, -CONR2, -CR2CN, -CR2CF2R, - CR2CONR2, -CR2C(O)R, -CR2CO2R, -CR2NR2, -CR2OR, -CR2S(O)NR2, -CR2SO2NR2, -CR2S(O)R, - CR2SO2R, -CR2S(O)(NR)R, -CR2CN, -CR2CR2NR2, -CR2CR2OR, -CR2CR=NOR, -CR2CR(OR)CR2OR.

61. The compound of any one of claims 1-60, wherein Rcis -CR2CN, -CR2CF2R, -CR2CONR2, - CR2C(O)R, -CR2CO2R, -CR2NR2, -CR2OR, -CR2SONR2, -CR2SO2NR2, -CR2S(O)R, -CR2SO2R, - CR2S(O)(NR)R, or -CR2CN.

62. The compound of any one of claims 1-61, wherein Rcis -CR2CN, -CR2CONR2, -CR2C(O)R, - CR2CO2R, -CR2S(O)NR2, -CR2SO2NR2, -CR2S(O)R, -CR2SO2R, or -CR2CR2NR2.

63. The compound of any one of claims 1-62, wherein the compound of any one of the following formulae:or a pharmaceutically acceptable salt thereof.

64. The compound of any one of claims 1-63, wherein Rcis -CH2CONH2, -CH2CONHMe, - CH2CONHEt, -CH2CON(Me)CH2CH2NH2, -CH2CONHCONH2, -CH2CONHCH2Ph, - CH2CONHcyclopropyl, -CH2SO2Me, -CH2SO2Et, -CH2SO2iPr, -CH2CH2NH2, or -CH2CH2NMe2.

65. The compound of any one of claims 1-64, wherein Rcis -CH2CONH2, -CH2SO2Me, or - CH2CH2NH2.

66. The compound of any one of claims 1-65, wherein Rcis -CH2CONH2.

67. The compound of any one of claims 1-65, wherein Rcis -CH2SO2Me.

68. The compound of any one of claims 1-65, wherein Rcis -CH2CH2NH2.

69. The compound of any one of claims 1-68, wherein Ring E is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring F is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Ring G is phenyl or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

70. The compound of any one of claims 1-69, wherein Ring E is phenyl or a 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring F is phenyl or a 5- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Ring G is phenyl or a 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

71. The compound of any one of claims 1-5 and 7, wherein the compound of any one of the following formulae:or a pharmaceutically acceptable salt thereof.

72. The compound of any one of claims 1-5 and 7, wherein the compound of any one of the following formulae:-a- 9or a pharmaceutically acceptable salt thereof.

73. A compound of formula I-b’:or a pharmaceutically acceptable salt thereof, wherein: Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring I is phenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl with 1- 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring J is phenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring K is phenyl, naphthyl, a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroaryl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rh, Ri, Rj, and Rkare each independently selected from hydrogen, RA, 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: an Rigroup on Ring I and an Rjgroup or Ring J are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: an Rjgroup on Ring J and an Rkgroup or Ring K are optionally taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, naphthyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom, or on different atoms, are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturatedring having 0-3 heteroatoms, in addition to the atom, or different atoms, to which they are attached, independently selected from nitrogen, oxygen, and sulfur; each of X1and X2are independently a covalent bond, spiro-fusion between the two rings that X1or X2connect, or a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, - CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-; s” is 0 or 1; each of w, x, y, and z are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, - N(R)C(O)O-,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and TBM is a target protein binding moiety; wherein said compound of formula I-b’ is optionally substituted with , and wheead group.

74. A compound of formula I-b:or a pharmaceutically acceptable salt thereof, wherein: Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring I is phenylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring K is phenyl, naphthyl, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroarylenyl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rh, Ri, Rj, and Rkare each independently selected from hydrogen, oxo, RA, 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: an Rigroup on Ring I and an Rjgroup or Ring J are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; each of X1and X2is independently a covalent bond, spiro-fusion between the two rings that X1or X2connect, -CR2-, -CR(OR)-, -CRF-, -CF2-, -NR-, -O-, -S-, or -S(O)2-; each of s’ and s’’ are independently 0 or 1; each of w, x, y, and z are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CRF-, -CF2-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-,, , ; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; andTBM is a target protein binding moiety; wherein said compound of formula I-b is optionally substituted with , and whis a warhead group.

75. The compound of claim 73 or claim 74, wherein X1is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, - S(O)-, or -S(O)2-.

76. The compound of any one of claims 73-75, wherein X1is a covalent bond, -CR2-, -CR(OR)-, - CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

77. The compound of any one of claims 73-76, wherein X1is a covalent bond.

78. The compound of any one of claims 73-77, wherein X2is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of the hydrocarbon chain are independently replaced by -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, - N(R)-, -S-, -S(O)-, or -S(O)2-.

79. The compound of any one of claims 73-78, wherein X2is a covalent bond, -CR2-, -CR(OR)-, - CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

80. The compound of any one of claims 73-79, wherein X2is a covalent bond, -CR2-, or -N(R)-.

81. The compound of any one of claims 73-80, wherein Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

82. The compound of any one of claims 73-81, wherein Ring H is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

83. The compound of any one of claims 73-82, wherein Ring H is a 6-membered saturated orpartially unsaturated monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

84. The compound of any one of claims 73-83, wherein Ring H is a 6-membered saturated monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen and oxygen.

85. The compound of any one of claims 73-84, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

86. The compound of any one of claims 73-85, wherein Ring I is phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

87. The compound of any one of claims 73-86, wherein Ring I is phenyl or a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

88. The compound of any one of claims 73-87, wherein Ring I is phenyl or a 6-membered monocyclic heteroaryl with 1-2 nitrogen heteroatoms.

89. The compound of any one of claims 73-85, wherein Ring I is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

90. The compound of any one of claims 73-85, wherein Ring I is a 3-11 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

91. The compound of any one of claims 73-85, wherein Ring I is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl with 1-2 nitrogen heteroatoms.

92. The compound of any one of claims 73-91, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

93. The compound of any one of claims 73-92, Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

94. The compound of any one of claims 73-93, Ring J is a 6-9 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

95. The compound of any one of claims 73-94, Ring J is a 6-membered saturated monocyclic carbocyclyl or heterocyclyl with 1 nitrogen heteroatoms.

96. The compound of any one of claims 73-94, Ring J is a 9-membered saturated monocyclic heterocyclyl with 1-2 nitrogen heteroatoms.

97. The compound of any one of claims 73-94, Ring J is a 10-membered bicyclic heteroaryl ring having 1-2 nitrogen heteroatoms.

98. The compound of any one of claims 73-97, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

99. The compound of any one of claims 73-98, wherein Ring K is phenyl, a 3-7 membered saturatedor partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

100. The compound of any one of claims 73-99, wherein Ring K is phenyl or a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

101. The compound of any one of claims 73-100, wherein Ring K is phenyl or a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

102. The compound of any one of claims 73-101, wherein Ring K is phenyl or a 6-membered saturated carbocyclyl or heterocyclyl with 1-2 nitrogen heteroatoms.

103. The compound of any one of claims 73-102, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

104. The compound of any one of claims 73-103, wherein h is 1, 2, or 3.

105. The compound of any one of claims 73-104, wherein h is 1 or 2.

106. The compound of any one of claims 73-105, wherein h is 1.

107. The compound of any one of claims 73-103, wherein h is 0.

108. The compound of any one of claims 73-106, wherein Rhis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

109. The compound of any one of claims 73-106, wherein Rhis optionally substituted C1-6 aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

110. The compound of any one of claims 73-106, wherein Rhis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

111. The compound of any one of claims 73-110, wherein i is 1, 2, or 3.

112. The compound of any one of claims 73-111, wherein i is 1 or 2.

113. The compound of any one of claims 73-112, wherein i is 1.

114. The compound of any one of claims 73-110, wherein i is 0.

115. The compound of any one of claims 73-113, wherein Riis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

116. The compound of any one of claims 73-113, wherein Riis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

117. The compound of any one of claims 73-113, wherein Riis C1-6alkyl, C1-6haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

118. The compound of any one of claims 73-117, wherein j is 1, 2, or 3.

119. The compound of any one of claims 73-118, wherein j is 1 or 2.

120. The compound of any one of claims 73-119, wherein j is 1.

121. The compound of any one of claims 73-117, wherein j is 0.

122. The compound of any one of claims 73-120, wherein Rjis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

123. The compound of any one of claims 73-120, wherein Rjis optionally substituted C1-6 aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

124. The compound of any one of claims 73-118, wherein Rjis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

125. The compound of any one of claims 73-124, wherein k is 1, 2, or 3.

126. The compound of any one of claims 73-125, wherein k is 1 or 2.

127. The compound of any one of claims 73-126, wherein k is 1.

128. The compound of any one of claims 73-124, wherein k is 0.

129. The compound of any one of claims 73-127, wherein Rkis RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

130. The compound of any one of claims 73-127, wherein Rkis optionally substituted C1-6aliphatic, fluoro, chloro, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

131. The compound of any one of claims 73-127, wherein Rkis C1-6 alkyl, C1-6 haloalkyl, fluoro, chloro, -CN, -OR, -NR2, -C(O)R, -C(O)OR, or -C(O)NR2.

132. The compound of any one of claims 73-131, wherein Ring H is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring I is phenyl or a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 3-11 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring J is a 6-9 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Ring K is phenyl or a 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

133. The compound of any one of claims 73-132, wherein Ring H is a 6-membered saturated monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen and oxygen; Ring I is phenyl, a 6-membered monocyclic heteroaryl with 1-2 nitrogen heteroatoms, or a 9-membered saturated or partially unsaturated bicyclic heterocyclyl with 1-2 nitrogen heteroatoms; Ring J is a 6- membered saturated monocyclic carbocyclyl or heterocyclyl with 1 nitrogen heteroatoms, a 9-membered saturated monocyclic heterocyclyl with 1-2 nitrogen heteroatoms, a 10-membered bicyclic heteroaryl ring having 1-2 nitrogen heteroatoms; and Ring K is phenyl or a 6-membered saturated carbocyclyl or heterocyclyl with 1-2 nitrogen heteroatoms.

134. The compound of any one of claims 73-133, wherein the compound is any one of the following formulae:or a pharmaceutically acceptable salt thereof.

135. The compound of any one of claims 1-134, wherein the compound is any one of the following formulae:or pharmaceutically acceptable salt thereof, wherein: Ring A’ and Ring B’ are independently an aromatic ring, a heteroaromatic ring, a 5-membered carbocyclyl, a 6-membered carbocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl,a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a pyrazine, optionally substituted by alkyl, alkoxy, halogen, nitrile or another aromatic or heteroaromatic ring; each Y1, Y2, Y3and Y4can independently be carbon, nitrogen or oxygen to form a fused 5-membered aromatic ring such as triazole or isoxazole; and Z1is methyl, or lower alkyl group.

136. The compound of any one of claims 1-134, TBM is, ,.

137. The compound of any one of claims 1-136, wherein L is a bivalent, saturated or unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy- -CRF-, -CF2-, -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, or -C(O)N(R)-.

138. The compound of any one of claims 1-137, wherein said compound is selected from those depicted in Table 1A or Table 1B of the specification, or a pharmaceutically acceptable salt thereof.

139. A pharmaceutical composition comprising a compound of any one of claims 1-138, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

140. A method of degrading a target protein in a biological sample comprising contacting the sample with the compound of any one of claims 1-138, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

141. A method of treating a target protein-mediated disorder, disease, or condition in a patient comprising administering to said patient the compound of any one of claims 1-138, or a pharmaceutical composition thereof.

142. The method of claim 141, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

143. The method of claim 142, wherein the proliferative disorder is a cancer.

144. The method of claim 143, wherein the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

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