Akt inhibitors

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Description

AKT INHIBITORS CROSS-REFERNCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 510,039, filed June 23, 2023, the contents of which is herein incorporated by reference. TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods for inhibiting Protein Kinase B ("Akt") protein via deubiquitination. 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] The ubiquitination of proteins is a dynamic multifaceted post-translational modification that allows the body to mark proteins for degradation, activation, sub-cellular localization, and translocation. The best-characterized function of ubiquitin is as a marker for protein degradation. However, protein deubiquitination can result in outcomes other than preventing degradation, stabilization and enhancement of protein levels. The specific lysine being ubiquitinated influences whether the ubiquitinated protein is targeted for proteasomal degradation, activation or trafficking. For example, the most common linkage, on K48, is closely associated with degradation by the proteasome. K63-linked ubiquitination is associated with pathway activation, protein trafficking, DNA repair, and inflammation. Monoubiquitination also is not typically associated with degradation, and in some cases may regulate protein function by impeding or facilitating protein-protein association.

[0004] A deubiquitinase protein ("DUB") is a protein that partially or fully removes ubiquitin molecules from proteins. Deubiquitinases (DUBs) can be classified into six main classes: ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Joseph disease protein domain proteases (MJDs), ovarian tumor proteases (OTUs), JAB1 / MPN / MOV34 metalloenzymes (JAMMs), and motif interacting with ubiquitin-containing novel DUB family (MINDY) DUBs (Mevissen et. al., “Mechanisms of Deubiquitinase Specificity and Regulation” Annu. Rev. Biochem.2017 (86) 159).

[0005] Bifunctional compounds composed of a target protein-binding ligand and a DUB, induced deubiquitination of selected proteins via their recruitment to the DUB. E3 ubiquitin ligase and subsequent ubiquitination. Bifunctional molecules for targeted protein deubiquitination are described in WO2021 / 146386A1, WO2020 / 169650 and Henning, Nathaniel J et al. “Deubiquitinase-targeting chimerasfor targeted protein stabilization.” Nature chemical biology vol.18,4 (2022): 412-421. doi:10.1038 / s41589- 022-00971-2.

[0006] Akt (also known as Protein Kinase B ("PKB")) is a serine / threonine protein kinase, which is a key player in growth factor and cytokine-mediated signaling cascade (Datta et al., 1999; Brazil et al., 2002; Cantley, 2002; Gonzalez and McGraw, 2009; Yang et al., 2010a). Given that Akt regulates numerous biological functions, such as cell growth, survival, cell migration, and metabolism, by phosphorylating several downstream effectors, the activity of Akt must be strictly controlled. Aberrant Akt activation is observed in various human cancers, and importantly, Akt1, Akt2, and Akt3 isoforms are found to be overexpressed in human cancers (Staal, 1987; Cheng et al., 1992, 1996; Bellacosa et al., 1995; Nakatani et al., 1999; Stahl et al., 2004). Recent studies show that Akt1 mutations are observed in a subset of human cancers and are associated with Akt hyperactivation (Carpten et al., 2007; Kim et al., 2008a; Malanga et al., 2008; Mohamedali et al., 2008; Askham et al., 2010; Shoji et al., 2009; Zilberman et al., 2009). The role of Akt in cancer development has been supported by numerous animal tumor models. For example, Pten+ / − mice with aberrant Akt activation develop multiple tumors, which can be inhibited by Akt1 deficiency (Di Cristofano et al., 2001; Chen et al., 2006). In addition, the prostate-specific expression of constitutively active Akt1 in mice leads to prostate intraepithelial neoplasia (Majumder et al., 2003, 2004). These results highlight the critical role of the Akt pathway in cancer development. Accordingly, there remains a need to find compounds that are Akt inhibitors useful as therapeutic agents. SUMMARY OF THE INVENTION

[0007] The present application relates to novel bifunctional compounds, which function to recruit Akt protein to DUBs for deubiquitination, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as inducers of targeted deubiquitination of Akt resulting in inhibition.

[0008] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of Akt protein. Such compounds have the general formula I:I or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0009] Compounds of the present invention, and pharmaceutically acceptable compositions thereof,are useful for treating a variety of diseases, disorders or conditions, associated with regulation of Akt protein. Such diseases, disorders, or conditions include those described herein. DETAILED DESCRIPTION OF SOME EMBODIMENTS 1. General Description of Some Embodiments of the Invention:

[0010] Compounds of the present invention, and compositions thereof, are useful as inhibitors of Akt protein. In some embodiments, a provided compound inhibits Akt protein.

[0011] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: PBM is a protein binding moiety capable of binding Akt; L is a bivalent moiety that connects PBM to DIM; and DIM is a deubiquitination inducing moiety, such as a deubiquitinase binding moiety (DBM). 2. Compounds and Definitions:

[0012] Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes.

[0013] The terms “Akt protein” and “Akt” refer to all members of the Akt protein kinase family, including, but not limited to Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ).

[0014] 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.

[0015] 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 orthat contains one or more units of unsaturation, or a monocyclic, bicyclic, bridged bicyclic, or spirocyclic 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-C6 hydrocarbon 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.

[0016] 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: NHO HN O O ONHNH NH NH

[0017] lary lower alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0018] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0019] 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)).

[0020] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] As used herein, a term containing the suffix “-ylenyl” generally refers to a bivalent group. For example, as used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group, for example,of the following structure: . In some embodiments, the suffix “-ylenyl” may refer to a moiety that can be a monovalent struc or example, if ring X as depicted below:is described or defined as phenylenyl, one t would understand that if x is 0 then ring X ismonovalent, i.e., the only substituents on the ring are hydrogen.

[0025] The term “halogen” means F, Cl, Br, or I.

[0026] 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 some 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.

[0027] 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 π 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. A heteroaryl ring may include one or more oxo (=O) or thioxo (=S) substituent. 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.

[0028] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10– 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).

[0029] 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, 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 monocyclic, bicyclic, bridged bicyclic, or spirocyclic. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0030] 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.

[0031] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted” 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, thesubstituent 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 some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0032] 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°; – (CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; –SC(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)0–4P(O)(OR ^)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–membered saturated, 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.

[0033] 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^, –(C1–4 straight or branched alkylene)C(O)OR^, or – SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or morehalogens, and is independently selected from 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. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S.

[0034] 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, C1–6aliphatic 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. 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.

[0035] 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 C1–4 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.

[0036] 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, C1–6 aliphatic 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.

[0037] 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 C1–4 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.

[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)4 salts. 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. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein and are readily apparent to those having skill in the art.

[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, and Z and E conformational isomers. 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

[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 “inhibitor” is defined as a compound that binds to and / or inhibits Akt with measurable affinity. In some embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0043] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in Akt activity between a sample comprising a compound of the present invention, or composition thereof, and Akt, and an equivalent sample comprising Akt, in the absence of said compound, or composition thereof.

[0044] As used herein, the term “independently” means independently for each occurrence. 3. Description of Exemplary Embodiments:

[0045] As described above, in some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: PBM is a protein binding moiety capable of binding Akt; L is a bivalent moiety that connects PBM to DIM; and DIM is a deubiquitination inducing moiety, such as a deubiquitinase binding moiety (DBM). Protein Binding Moiety (PBM)

[0046] As defined herein and described above, PBM is a protein binding moiety capable of bindingAkt. In some embodiments, PBM binds to Akt protein which then undergoes deubiquitination thereby deactivating the Akt protein.

[0047] As defined herein and described below, wherein a formula is depicted using square brackets, , L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom within PBM or replacement of a defined group in PBM.

[0048] In some embodiments, the present invention provides a compound of formula I, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-a:or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring A and Ring B are independently fused rings selected from benzo, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, an 8-10 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;L1and LAare independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L1or LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and a, b, c, and d are independently 0, 1, 2, 3, or 4.

[0049] In some embodiments, the present invention provides a compound of formula I, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-a': or a pharmaceutically acc, d above and described herein, and wherein:Ring A and Ring B are independently fused rings selected from benzo, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 8-10 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L1or LAare independently replaced by -O-, -NR-, -S-, -OC(O)- , -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L1or LAare independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or - OC(O)NR-, –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and a, b, c, and d are independently 0, 1, 2, 3, or 4.

[0050] In some embodiments, the present invention provides a compound of formula I-a, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-b: or a pharmaceutically acceptab, efined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 memberedsaturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and a, b, c, and d are independently 0, 1, 2, 3, or 4.

[0051] In some embodiments, the present invention provides a compound of formula I-a', wherein PBM is an Akt binding moiety thereby forming a compound of formula I-b':or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)- , -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and a, b, c, and d are independently 0, 1, 2, 3, or 4.

[0052] In some embodiments, the present invention provides a compound of formula I-b or I-b', wherein PBM is an Akt binding moiety thereby forming a compound of formula I-b-1:I-b-1 or a pharmaceutically acceptable salt thereof, wherein each of ring D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, and DIM is as defined above and described in embodiments herein, both singly and in combination, wherein X1and X2are independently nitrogen or carbon.

[0053] In some embodiments, the present invention provides a compound of formula I-a, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-c:or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and a, b, c, and d are independently 0, 1, 2, 3, or 4.

[0054] In some embodiments, the present invention provides a compound of formula I-a', wherein PBM is an Akt binding moiety thereby forming a compound of formula I-c':or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)- , -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and a, b, c, and d are independently 0, 1, 2, 3, or 4.

[0055] In some embodiments, the present invention provides a compound of formula I-c or I-c', wherein PBM is an Akt binding moiety thereby forming a compound of formula I-c-1:or a pharmaceutically acceptable salt thereof, wherein each of ring D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, and DIM is as defined above and described in embodiments herein, both singly and in combination, wherein X1and X2are independently nitrogen or carbon.

[0056] In some embodiments, a provided compound or pharmaceutically acceptable salt thereof, is selected from those wherein PBM is A-443654, A-674563, Afuresertib (GSK2110183), Akt Kinase Inhibitor (CAS No.: 842148-40-7), (E)-Akt inhibitor-IV ((E)-AKTIV), Akt Inhibitor XIX (3CAI), Akt2- IN-1, Akt2-IN-2, Akt1-IN-1, Akti-1 / 2 (Akt Inhibitor VIII), Akt-IN-1, Akt-IN-10, Akt-IN-12, Akt-IN-13, Akt-IN-2, Akt-IN-3, Akt-IN-5, Akt-IN-6, Akt-IN-7, Akt-IN-8, Akt-IN-9, ALM301, Alobresib (GS-5829), API-1, AT13148, AT7867, BAY1125976, Borussertib, Capivasertib (AZD5363), CCT128930, Cinobufagin (Cinobufagine), Daphnoretin (Dephnoretin; Thymelol), DB07107, Deguelin ((-)-Deguelin; (-)-cis- Deguelin), Esculetin, FPA-124, GSK2110183 analog 1, GSK690693, Guggulsterone, Hematein, Honokiol (NSC 293100), Hu7691, Ipatasertib (GDC0068), Isoginkgetin, KP372-1, Loureirin A, M2698 (MSC2363318A), 24-Methylenecycloartanyl ferulate, Methyl-Hesperidin, Miltefosine (Hexadecylphosphocholine), Miransertib (ARQ092), MK-2206, ML-9 HCl, MMP-9-IN-3, MMP-9-IN-5, NTQ1062, oridonin (NSC-250682), Oroxin B (Hypocretin-2), Pachymic acid (3-O-Acetyltumulosic acid), Perifosine (KRX-0401), PF-04691502, PF-AKT400, PHT-427 (CS-0223), PI3K / Akt / mTOR-IN-3, Pifusertib (TAS-117), PP2A Cancerous-IN-1, Praeruptorin A, Resibufogenin (Bufogenin; Recibufogenin), RPI-1, SC66, Scutellarin (Breviscapine; Breviscapin; Scutellarein-7-glucuronide), SM-020, SPP-86,SR13668, STL1 (ZINC2429155), swertiamarin, TAS0612, TASP0415914, TIC10 (ONC201), TIC10 Analogue, Triciribine, Trigonelline (Trigenolline), Uprosertib (GSK2141795), Urolithin B, Usnic acid (Usniacin), or Vevorisertib (ARQ 751).

[0057] In some embodiments, PBM is capivasertib (AZD5363).

[0058] In some embodiments, L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom within PBM including substitution or replacement of a defined group in PBM. For example, in some embodiments, PBM comprises, e.g., a hydroxyl group that can be modified to create a leaving group that is subsequently replaced by a nucleophilic group of L such that PBM and L are thereby attached. One of skill in the art will appreciate that various methods are available in the art to facilitate such modifications.

[0059] As defined above and described herein, Ring A and Ring B are independently fused rings selected from benzo, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0060] In some embodiments, Ring A is a fused benzo ring. In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0061] In some embodiments, ring A is selected from those depicted in the compounds of Table 1 below.

[0062] In some embodiments, Ring B is a fused benzo ring. In some embodiments, Ring B is a 4-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring B is a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0063] In some embodiments, ring B is selected from those depicted in the compounds of Table 1 below.

[0064] As defined above and described herein, Ring C is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 8-10 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0065] In some embodiments, ring C is a phenylenyl. In some embodiments, ring C is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, ring C is a 8-10 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl. In some embodiments, ring C is a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 8-10 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0066] In some embodiments, ring C is , wherein X1and X2are independently carbonor nitrogen. In some embodiments, ring C is .

[0067] In some embodiments, ring Cm those depicted in the compounds of Table 1 below.

[0068] As defined above and described herein, X1and X2are independently nitrogen or carbon.

[0069] In some embodiments, X1and X2are independently nitrogen or carbon. In some embodiments, at least one of X1and X2is nitrogen. In some embodiments, X1is nitrogen and X2is carbon. In some embodiments, X1is carbon and X2is nitrogen. In some embodiments, X1and X2are nitrogen.

[0070] In some embodiments, X1is selected from those depicted in the compounds of Table 1 below.

[0071] In some embodiments, X2is selected from those depicted in the compounds of Table 1 below.

[0072] As defined above and described herein, ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0073] In some embodiments, ring D is a phenyl. In some embodiments, ring D is a 4-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring D is a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0074] In some embodiments, ring D is selected from those depicted in the compounds of Table 1 below.

[0075] As defined above and described herein, ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0076] As defined above and described herein, L1is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L1, L2or LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0077] In some embodiments, L1is a covalent bond. In some embodiments, L1is a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0078] In some embodiments, L1is -O-. In some embodiments, L1is -NR-. In some embodiments, L1is -S-. In some embodiments, L1is -OC(O)-. In some embodiments, L1is -C(O)O-. In some embodiments, L1is -C(O)-. In some embodiments, L1is -S(O)-. In some embodiments, L1is -S(O)2-. In some embodiments, L1is -NRS(O)2-. In some embodiments, L1is -S(O)2NR-. In some embodiments, L1is -NRC(O)-. In some embodiments, L1is -C(O)NR-. In some embodiments, L1is or -OC(O)NR-. In some embodiments, L1is –NRC(O)O-.

[0079] In some embodiments, L1is selected from those depicted in the compounds of Table 1 below.

[0080] As defined above and described herein, LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0081] In some embodiments, LAis a covalent bond. In some embodiments, LAis a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0082] In some embodiments, LAis -O-. In some embodiments, LAis -NR-. In some embodiments, LAis -S-. In some embodiments, LAis -OC(O)-. In some embodiments, LAis -C(O)O-. In someembodiments, LAis -C(O)-. In some embodiments, LAis -S(O)-. In some embodiments, LAis -S(O)2-. In some embodiments, LAis -NRS(O)3-. In some embodiments, LAis -S(O)2NR-. In some embodiments, LAis -NRC(O)-. In some embodiments, LAis -C(O)NR-. In some embodiments, LAis or -OC(O)NR-. In some embodiments, LAis –NRC(O)O-.

[0083] In some embodiments, LAis -CH2-.

[0084] In some embodiments, LAis selected from those depicted in the compounds of Table 1 below.

[0085] As defined above and described herein, each Rais independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0086] In some embodiments, one or more of Rais hydrogen. In some embodiments, one or more of Rais RA. In some embodiments, one or more of Rais halogen. In some embodiments, one or more of Rais -CN. In some embodiments, one or more of Rais -NO2. In some embodiments, one or more of Rais - OR. In some embodiments, one or more of Rais -SR. In some embodiments, one or more of Rais -NR2. In some embodiments, one or more of Rais -S(O)2R. In some embodiments, one or more of Rais -S(O)2NR2. In some embodiments, one or more of Rais -S(O)R. In some embodiments, one or more of Rais -C(O)R. In some embodiments, one or more of Rais -C(O)OR. In some embodiments, one or more of Rais - C(O)NR2. In some embodiments, one or more of Rais -C(O)NROR. In some embodiments, one or more of Rais -OC(O)R. In some embodiments, one or more of Rais -OC(O)NR2. In some embodiments, one or more of Rais -NRC(O)OR. In some embodiments, one or more of Rais -NRC(O)R. In some embodiments, one or more of Rais -NRC(O)N(R)2. In some embodiments, one or more of Rais -NRS(O)2R.

[0087] In some embodiments, one or more Rais -OH. In some embodiments, one or more Rais methyl.

[0088] In some embodiments, Rais selected from those depicted in the compounds of Table 1 below.

[0089] As defined above and described herein, each Rbis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0090] In some embodiments, one or more of Rbis hydrogen. In some embodiments, one or more of Rbis RA. In some embodiments, one or more of Rbis halogen. In some embodiments, one or more of Rbis -CN. In some embodiments, one or more of Rbis -NO2. In some embodiments, one or more of Rbis - OR. In some embodiments, one or more of Rbis -SR. In some embodiments, one or more of Rbis -NR2. In some embodiments, one or more of Rbis -S(O)2R. In some embodiments, one or more of Rbis -S(O)2NR2.In some embodiments, one or more of Rbis -S(O)R. In some embodiments, one or more of Rbis -C(O)R. In some embodiments, one or more of Rbis -C(O)OR. In some embodiments, one or more of Rbis - C(O)NR2. In some embodiments, one or more of Rbis -C(O)NROR. In some embodiments, one or more of Rbis -OC(O)R. In some embodiments, one or more of Rbis -OC(O)NR2. In some embodiments, one or more of Rbis -NRC(O)OR. In some embodiments, one or more of Rbis -NRC(O)R. In some embodiments, one or more of Rbis -NRC(O)N(R)2. In some embodiments, one or more of Rbis -NRS(O)2R.

[0091] In some embodiments, Rbis selected from those depicted in the compounds of Table 1 below.

[0092] As defined above and described herein, each Rcis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0093] In some embodiments, one or more of Rcis hydrogen. In some embodiments, one or more of Rcis RA. In some embodiments, one or more of Rcis halogen. In some embodiments, one or more of Rcis -CN. In some embodiments, one or more of Rcis -NO2. In some embodiments, one or more of Rcis - OR. In some embodiments, one or more of Rcis -SR. In some embodiments, one or more of Rcis -NR2. In some embodiments, one or more of Rcis -S(O)2R. In some embodiments, one or more of Rcis -S(O)2NR2. In some embodiments, one or more of Rcis -S(O)R. In some embodiments, one or more of Rcis -C(O)R. In some embodiments, one or more of Rcis -C(O)OR. In some embodiments, one or more of Rcis - C(O)NR2. In some embodiments, one or more of Rcis -C(O)NROR. In some embodiments, one or more of Rcis -OC(O)R. In some embodiments, one or more of Rcis -OC(O)NR2. In some embodiments, one or more of Rcis -NRC(O)OR. In some embodiments, one or more of Rcis -NRC(O)R. In some embodiments, one or more of Rcis -NRC(O)N(R)2. In some embodiments, one or more of Rcis -NRS(O)2R.

[0094] In some embodiments, Rcis selected from those depicted in the compounds of Table 1 below.

[0095] As defined above and described herein, each Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0096] In some embodiments, one or more of Rdis hydrogen. In some embodiments, one or more of Rdis RA. In some embodiments, one or more of Rdis halogen. In some embodiments, one or more of Rdis -CN. In some embodiments, one or more of Rdis -NO2. In some embodiments, one or more of Rdis - OR. In some embodiments, one or more of Rdis -SR. In some embodiments, one or more of Rdis -NR2. In some embodiments, one or more of Rdis -S(O)2R. In some embodiments, one or more of Rdis -S(O)2NR2.In some embodiments, one or more of Rdis -S(O)R. In some embodiments, one or more of Rdis -C(O)R. In some embodiments, one or more of Rdis -C(O)OR. In some embodiments, one or more of Rdis - C(O)NR2. In some embodiments, one or more of Rdis -C(O)NROR. In some embodiments, one or more of Rdis -OC(O)R. In some embodiments, one or more of Rdis -OC(O)NR2. In some embodiments, one or more of Rdis -NRC(O)OR. In some embodiments, one or more of Rdis -NRC(O)R. In some embodiments, one or more of Rdis -NRC(O)N(R)2. In some embodiments, one or more of Rdis -NRS(O)2R.

[0097] In some embodiments, one or more of Rdis halogen. In some embodiments, one or more of Rdis chloro.

[0098] In some embodiments, Rdis selected from those depicted in the compounds of Table 1 below.

[0099] As defined above and described herein, each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, RAis an optionally substituted C1-6 aliphatic. In some embodiments, RAis a phenyl. In some embodiments, RAis a 3-12 membered saturated or partially unsaturated monocyclic. In some embodiments, RAis an optionally substituted bicyclic. In some embodiments, RAis an optionally substituted bridged bicyclic or spirocyclic carbocyclyl. In some embodiments, RAis a heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RAis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, RAis selected from those depicted in the compounds of Table 1 below.

[0102] As defined above and described herein, each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, one or more of R is hydrogen. In some embodiments, one or more of R is a C1-6aliphatic. In some embodiments, one or more of R is phenyl. In some embodiments, one or more of R is a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some embodiments, one or more of R is and a 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0104] In some embodiments, R is selected from those depicted in the compounds of Table 1 below.

[0105] As defined above and described herein, a is 0, 1, 2, 3, or 4. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4.

[0106] In some embodiments, a is selected from those depicted in the compounds of Table 1 below.

[0107] As defined above and described herein, b is 0, 1, 2, 3, or 4. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4.

[0108] In some embodiments, b is selected from those depicted in the compounds of Table 1 below.

[0109] As defined above and described herein, c is 0, 1, 2, 3, or 4. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3. In some embodiments, c is 4.

[0110] In some embodiments, c is selected from those depicted in the compounds of Table 1 below.

[0111] As defined above and described herein, d is 0, 1, 2, 3, or 4. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4.

[0112] In some embodiments, d is selected from those depicted in the compounds of Table 1 below.

[0113] In some embodiments, PBM is ,or , ,, me isis nts,. In some embodiments, PBM isCl is

[0118] In some embodiments, PBM is selected from those depicted in paragraph

[0056] , above. Deubiquitinase Binding Moiety (DBM)

[0119] In some embodiments, DIM is DBM. In some embodiments, DIM is a DUB ligand well known to one of ordinary skill in the art including those described in Caba et al., Biomolecules. 2022, 12(5):703; Harrigan et al., Nat Rev Drug Discov.2018, 17(1), 57-78; Lange et al., Mol Cell.2022, 82(1), 15-29; Pinto- Fernández et al., Front Chem.2019, 7, 592; Schauer et al., J Med Chem.2020, 63(6), 2731-2750; and Wertz et al., Cell Chem Biol.2019, 26(2), 156-177, the entirety of each of which is hereby incorporated herein by reference.

[0120] In some embodiments, the DBM binds to OTUD1, OTUD7B, OTUB1, USP2, USP5, USP7, USP21, USP28, USP7, USP10, USP15, and / or AMSH. In some embodiments, the DBM binds to OTUD1.In some embodiments, the DBM binds to OTUD7B. In some embodiments, the DBM binds to OTUB1. In some embodiments, the DBM binds to USP2. In some embodiments, the DBM binds to USP5. In some embodiments, the DBM binds to USP7. In some embodiments, the DBM binds to USP21. In some embodiments, the DBM binds to USP28. In some embodiments, the DBM binds to USP7. In some embodiments, the DBM binds to USP10. In some embodiments, the DBM binds to USP15. In some embodiments, the DBM binds to AMSH.

[0121] As defined herein and described below, wherein a formula is depicted using square brackets, , L is attached to a modifiable carbon, oxygen, or nitrogen atom n or replacement of a defined group in DIM or DBM.

[0122] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as described above and herein, and DIM is a deubiquitination inducing moiety, such as a deubiquitinase binding moiety (DBM).

[0123] In some embodiments, DIM is a DBM as described above and herein.

[0124] In some embodiments, the present invention provides a compound of formula I, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-aa:-aa or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, an 8-10 membered bicyclic aromatic carbocyclylenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LB, L1', L2'and L3'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', L2'or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and m, n, and o are independently 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0125] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;each LB, L1', and L3'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0126] In some embodiments, the present invention provides a compound of formula I, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb:I-bb or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic,bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-8 membered saturated or partially unsaturated carbocyclylenyl, a 4-8 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic having 1-2 heteroatoms independentlyselected 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; X1'is carbon or nitrogen; m, n, o, and p are independently 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0127] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-1:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Y, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0128] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-2:I-bb-2 or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0129] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-3:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0130] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-4 or I-bb- 4’:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0131] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-5 or I-bb- 5’:I-bb-5' or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w,x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0132] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-6:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Y, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0133] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-7:- - or a pharmaceutically acceptable salt thereof, wherein each of ring W, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0134] In some embodiments, the present invention provides a compound of formula I-bb or I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb-8:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0135] In some embodiments, the present invention provides a compound of formula I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb'-1:

[0136] or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rx, Rz, w, x, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination

[0137] In some embodiments, the present invention provides a compound of formula I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb'-2:I-bb'-2 or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Z, LB, L3', L1', Rw, Rz, w, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0138] In some embodiments, the present invention provides a compound of formula I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb'-3:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring X, ring Y, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0139] In some embodiments, the present invention provides a compound of formula I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb'-4:- - or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Y, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0140] In some embodiments, the present invention provides a compound of formula I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb'-5:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring X, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0141] In some embodiments, the present invention provides a compound of formula I-bb', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb'-6:or a pharmaceutically acceptable salt thereof, wherein each of ring W, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0142] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc: (Rx)x (Ry)yz)zI-cc or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LB, L1', and L2'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

[0143] In some embodiments, the present invention provides a compound of formula I-aa, whereinDBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc':or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-8 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heterocyclylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LB, L1', and L2'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L2'are independently replaced by –Cy'–, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, - S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R;each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each –Cy'– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

[0144] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc-1:I-cc-1 or a pharmaceutically acceptable salt thereof, wherein each of ring Y, ring Z, LB, L1', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0145] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc-2: or a pharmaceutically acce', Rx, Ry, Rz, x, y, z, L, and PBMis as defined above and described in embodiments herein, both singly and in combination.

[0146] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc-3 or I-cc-3’:-cc- or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, L1', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0147] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc-4:or a pharmaceutically acceptable salt thereof, wherein each of ring Y, LB, L1', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0148] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc-5:or a pharmaceutically acceptable salt thereof, wherein each of LB, L1', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0149] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-dd-1:-dd- or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Y, LB, Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination, wherein Y3is sulfur or oxygen.

[0150] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-dd-2:or a pharmaceutically acceptable salt thereof, wherein ring X, LB, Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination, wherein Y3is sulfur or oxygen.

[0151] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-dd-3 or I-dd-3':or a pharmaceutically acceptable salt thereof, wherein each of ring X, LB, Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination, wherein Y3is sulfur or oxygen.

[0152] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-dd-3:I-dd-4 or a pharmaceutically acceptable salt thereof, wherein each of ring Y, LB, Ry, Rz, y, z, L, and PBM is asdefined above and described in embodiments herein, both singly and in combination, wherein Y3is sulfur or oxygen.

[0153] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-dd-5:or a pharmaceutically acceptable salt thereof, wherein each of LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination, wherein Y3is sulfur or oxygen.

[0154] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ee-1:or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Y, LB, L1', Rx, Ry, x, y, L, and PBM is as defined above and described in embodiments herein.

[0155] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ee-2:I-ee-2 or a pharmaceutically acceptable salt thereof, wherein each of ring X, LB, L1', Rx, Ry, x, y, L, and PBM is as defined above and described in embodiments herein.

[0156] In some embodiments, the present invention provides a compound of formula I-cc, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ee-3:or a pharmaceutically acceptable salt thereof, wherein each of ring Y, LB, L1', Rx, Ry, x, y, L, and PBM is as defined above and described in embodiments herein.

[0157] In some embodiments, the present invention provides a compound of formula I-cc', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc'-1:or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Z, LB, L1', L2', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein.

[0158] In some embodiments, the present invention provides a compound of formula I-cc', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc'-2:I-cc -2

[0159] or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, L1', L2', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein.

[0160] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LBand L2'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

[0161] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff':or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 3-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LBand L2'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by –Cy'–, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2- , -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each –Cy'– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independentlyselected from nitrogen, oxygen, and sulfur; n and p are independently 0 or 1; and x, y, and z are independently 0, 1, 2, 3, or 4.

[0162] In some embodiments, the present invention provides a compound of formula I-ff or I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff-2:or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Z, LB, L2', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0163] In some embodiments, the present invention provides a compound of formula I-ff or I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff-2’:- - or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Y, LB, L2', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0164] In some embodiments, the present invention provides a compound of formula I-ff or I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff-3:or a pharmaceutically acceptable salt thereof, wherein each of ring X, LB, L2', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0165] In some embodiments, the present invention provides a compound of formula I-ff or I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff-4:or a pharmaceutically acceptable salt thereof, wherein each of ring X, LB, L2', Rx, Ry, Rz, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0166] In some embodiments, the present invention provides a compound of formula I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff'-1: (Ry)yz)zI-ff -1 or a pharmaceutically acceptable salt thereof, wherein each of ring Y, ring Z, LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0167] In some embodiments, the present invention provides a compound of formula I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff'-2:or a pharmaceutically acceptable salt thereof, wherein each of ring Y, ring Z, LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination; and wherein X1is carbon or nitrogen.

[0168] In some embodiments, the present invention provides a compound of formula I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff'-3:or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0169] In some embodiments, the present invention provides a compound of formula I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff'-4: or a pharmaceutically acceptab, LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0170] In some embodiments, the present invention provides a compound of formula I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff'-5:I-ff'-5

[0171] or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.In some embodiments, the present invention provides a compound of formula I-ff', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff'-6:or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0172] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LBand L1'is independently a covalent bond or a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBor L1'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and y and z are independently 0, 1, 2, 3, or 4.

[0173] In some embodiments, the present invention provides a compound of formula I-gg, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg-1:-gg- or a pharmaceutically acceptable salt thereof, wherein each of ring Y, LB, L1', Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0174] In some embodiments, the present invention provides a compound of formula I-gg, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg-2:or a pharmaceutically acceptable salt thereof, wherein each of LB, L1', Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0175] In some embodiments, the present invention provides a compound of formula I-gg, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg-3:or a pharmaceutically acceptable salt thereof, wherein each of ring Y, LB, L1', Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0176] In some embodiments, the present invention provides a compound of formula I-gg, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg-4: or a pharmaceutically accept1' y zL , R , R, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0177] In some embodiments, the present invention provides a compound of formula I-gg, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg-5:I-gg-5or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, L1', Rz, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0178] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-hh:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LBand L2'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

[0179] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-hh': (Rx)xy)z- or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8-10 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LBand L2'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by -Cy, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

[0180] In some embodiments, the present invention provides a compound of formula I-hh or I-hh', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-hh-1:or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Y, LB, L2', Rx, Ry, Rz, R, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination; wherein Y1'is nitrogen or carbon.

[0181] In some embodiments, the present invention provides a compound of formula I-hh or I-hh', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-hh-2:I-hh-2 or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Y, LB, L2', Rx, Ry, Rz, R, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination; wherein Y1'is nitrogen or carbon.

[0182] In some embodiments, the present invention provides a compound of formula I-hh or I-hh', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-hh-3:or a pharmaceutically acceptable salt thereof, wherein each of ring X, LB, L2', Rx, Ry, Rz, R, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination; wherein Y1is nitrogen or carbon.

[0183] In some embodiments, the present invention provides a compound of formula I-hh or I-hh', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-hh-4 or I-hh'- 4:- - - - or a pharmaceutically acceptable salt thereof, wherein each of ring X, LB, L2', Rx, Ry, Rz, R, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination; wherein Y1is nitrogen or carbon.

[0184] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ii:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LBand L1'is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1- 5 hydrocarbon chain, wherein 0-3 methylene units of LBor L1'are independently replaced by -O-, -NR- , -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or - OC(O)NR-, –NRC(O)O-; each Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and y, and z are independently 0, 1, 2, 3, or 4.

[0185] In some embodiments, the present invention provides a compound of formula I-ii, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ii-1:or a pharmaceutically acceptable salt thereof, wherein each of ring Z, L1', LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0186] In some embodiments, the present invention provides a compound of formula I-ii, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ii-2:- - or a pharmaceutically acceptable salt thereof, wherein each of ring Z, L1', LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0187] In some embodiments, the present invention provides a compound of formula I-ii, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-jj-1:I-jj-1 or a pharmaceutically acceptable salt thereof, wherein each of ring Y, L1', LB, Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0188] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-kk:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; LBis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBare independently replaced by -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and z is 0, 1, 2, 3, or 4.

[0189] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-kk-1:or a pharmaceutically acceptable salt thereof, wherein each of Rz, z, LB, L, and PBM is as defined above and described in embodiments herein, both singly and in combination, wherein Y1and Y2are independently carbon or nitrogen.

[0190] In some embodiments, the present invention provides a compound of formula I-kk, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-kk-2:- - or a pharmaceutically acceptable salt thereof, wherein each of Rz, LB, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0191] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0192] In some embodiments, the present invention provides a compound of formula I, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll':or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; p is independently 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0193] In some embodiments, the present invention provides a compound of formula I-ll or I-ll', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll-1: (Rw)w(Rx)x (Ry)y (Rz)zI-ll-1 or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring Y, ring Z, LB, L3', L2', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0194] In some embodiments, the present invention provides a compound of formula I-ll or I-ll', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll-2:or a pharmaceutically acceptable salt thereof, wherein each of ring W, ring X, ring Z, LB, L3', L2', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0195] In some embodiments, the present invention provides a compound of formula I-ll or I-ll', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll-3: or a pharmaceuticallyLB, L3', L2', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0196] In some embodiments, the present invention provides a compound of formula I-ll or I-ll', wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll-4:I-ll-4or a pharmaceutically acceptable salt thereof, wherein each of ring X, ring Y, ring Z, LB, L3', L2', L1', Rw, Rx, Ry, Rz, w, x, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0197] In some embodiments, DBM is a covalent deubiquitinase binder. In some embodiments, DBM covalently binds OTUB1. In some embodiments, the DBM comprises a Michael accepter, e.g., α, β- unsaturated ketone which is capable of covalently binding to a deubiquitinase, e.g., OTUB1.

[0198] In some embodiments, the present invention provides a compound of formula I-aa, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-mm:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LB, and L1', is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, or L1', are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and y, and z are independently 0, 1, 2, 3, or 4.

[0199] In some embodiments, the present invention provides a compound of formula I-mm, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-mm-1:or a pharmaceutically acceptable salt thereof, wherein each of ring Y, LB, L1', Ry, y, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0200] In some embodiments, the present invention provides a compound of formula I-mm, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-mm-2:I-mm-2 or a pharmaceutically acceptable salt thereof, wherein each of ring Z, LB, L1', Ry, Rz, y, z, L, and PBM is as defined above and described in embodiments herein, both singly and in combination.

[0201] As defined above and described herein, ring Z is a ring selected from phenyl, a 4-7 memberedsaturated or partially unsaturated carbocyclic ring , phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0202] As defined above and described herein, Ring Z is a ring selected from phenyl a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0203] In some embodiments, ring Z is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, ring Z is a phenyl. In some embodiments, ring Z is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, ring Z is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring Z is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring Z is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0204] In some embodiments, ring Z is a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring. In some embodiments, ring Z is a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Z is a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0205] In some embodiments, ring Z is cyclopropyl.

[0206] In some embodiments, ring Z is ,,

[0207] In some embodiments, ring Z is . In some embodiments, ring Z is . In someembodiments, ring Z is . In some embodiments, ring Z is . In some embodiments, ring Zis . In some embodiments, ring Z i . In some embodiments, ring Z. In some embodiments, ring Z i . In some embo . In someembodiments, ring .

[0208] In some e s of Table 1 below.

[0209] As defined above and described herein, ring Y is a ring selected from phenylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl, an 8-10 membered bicyclic aromatic carbocyclylenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0210] In some embodiments, ring Y is a phenylenyl. In some embodiments, ring Y is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, ring Y is an 8-10 membered bicyclic aromatic carbocyclylenyl. In some embodiments, ring Y is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring Y is a 5-6 membered monocyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring Y is an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.,me meembodiments, ring .

[0213] In some ering Y is selected from those depicted in the compounds of Table 1 below.

[0214] As defined above and described herein, ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0215] In some embodiments, ring X is a phenylenyl. In some embodiments, ring X is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, ring X is a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring X is and a 5-6 membered heteroarylenyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0216] In some embodiments, ring X is selected from those depicted in the compounds of Table 1 below.

[0217] As defined above and described herein, ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0218] In some embodiments, ring W is a phenylenyl. In some embodiments, ring W is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, ring W is a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is and a 5-6 membered heteroarylenyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0219] In some embodiments, ring W is cyclohexyl.

[0220] In some embodiments, ring W is selected from those depicted in the compounds of Table 1 below.

[0221] As defined above and described herein, L1', is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L1', L2'or LBare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0222] In some embodiments, L1'is a covalent bond. In some embodiments, L1'is a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L1'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0223] In some embodiments, L1'is -O-. In some embodiments, L1'is -NR-. In some embodiments, L1'is -S-. In some embodiments, L1'is -OC(O)-. In some embodiments, L1'is -C(O)O-. In some embodiments, L1'is -C(O)-. In some embodiments, L1'is -S(O)-. In some embodiments, L1'is -S(O)2-. In some embodiments, L1'is -NRS(O)2-. In some embodiments, L1'is -S(O)2NR-. In some embodiments, L1'is - NRC(O)-. In some embodiments, L1'is -C(O)NR-. In some embodiments, L1'is or -OC(O)NR-. In some embodiments, L1'is –NRC(O)O-.

[0224] In some embodiments, L1'is -CH2-.

[0225] In some embodiments, L1'i . In some embodiments, L1'Insome embodiments, L1'i . In some embodiments, L1'. In some embodiments,.

[0226] In some embodiments L1'i .

[0227] In some embodiments m those depicted in the compounds of Table 1 below.

[0228] As defined above anddescribed herein, L2', is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0229] In some embodiments, L2'is a covalent bond. In some embodiments, L2'is a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0230] In some embodiments, L2'is -O-. In some embodiments, L2'is -NR-. In some embodiments, L2'is -S-. In some embodiments, L2'is -OC(O)-. In some embodiments, L2'is -C(O)O-. In some embodiments, L2'is -C(O)-. In some embodiments, L2'is -S(O)-. In some embodiments, L2'is -S(O)2-. In some embodiments, L2'is -NRS(O)2-. In some embodiments, L2'is -S(O)2NR-. In some embodiments, L2'is - NRC(O)-. In some embodiments, L2'is -C(O)NR-. In some embodiments, L2'is or -OC(O)NR-. In some embodiments, L2'is –NRC(O)O-. In some embodiments, L2'. In some embodiments,L2'. In some embodiments, L2'. In some embodiments, L2'i . In some embodiments, L2'.

[0231] In some embodiments, L2', is -CH2-. In some embodiment . In some O HN embodiments, L2'i .

[0232] In some embodiments, L2'is selected from those depicted in the compounds of Table 1 below.

[0233] As defined above and described herein, L3'is a covalent bond or a bivalent, saturated or partiallyunsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0234] In some embodiments, L3'is a covalent bond. In some embodiments, L3'is a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0235] In some embodiments, L3'is -O-. In some embodiments, L3'is -NR-. In some embodiments, L3'is -S-. In some embodiments, L3'is -OC(O)-. In some embodiments, L3'is -C(O)O-. In some embodiments, L3'is -C(O)-. In some embodiments, L3'is -S(O)-. In some embodiments, L3'is -S(O)2-. In some embodiments, L3'is -NRS(O)3-. In some embodiments, L3'is -S(O)2NR-. In some embodiments, L3'is - NRC(O)-. In some embodiments, L3'is -C(O)NR-. In some embodiments, L3'is or -OC(O)NR-. In some embodiments, L3'is –NRC(O)O-.

[0236] In some embodiments, L3'is selected from those depicted in the compounds of Table 1 below.

[0237] As defined above and described herein, LB, is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0238] In some embodiments, LBis a covalent bond. In some embodiments, LBis a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-.

[0239] In some embodiments, LBis -O-. In some embodiments, LBis -NR-. In some embodiments, LBis -S-. In some embodiments, LBis -OC(O)-. In some embodiments, LBis -C(O)O-. In some embodiments, LBis -C(O)-. In some embodiments, LBis -S(O)-. In some embodiments, LBis -S(O)2-. In some embodiments, LBis -NRS(O)3-. In some embodiments, LBis -S(O)2NR-. In some embodiments, LBis - NRC(O)-. In some embodiments, LBis -C(O)NR-. In some embodiments, LBis or -OC(O)NR-. In some embodiments, LBis –NRC(O)O-.

[0240] In some embodiments, LBis selected from those depicted in the compounds of Table 1 below.

[0241] As defined above and described herein, each Rwis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0242] In some embodiments, one or more of Rwis hydrogen. In some embodiments, one or more of Rwis RB. In some embodiments, one or more of Rwis halogen. In some embodiments, one or more of Rwis - CN. In some embodiments, one or more of Rwis -NO2. In some embodiments, one or more of Rwis -OR. In some embodiments, one or more of Rwis -SR. In some embodiments, one or more of Rwis -NR2. In some embodiments, one or more of Rwis -S(O)2R. In some embodiments, one or more of Rwis -S(O)2NR2.In some embodiments, one or more of Rwis -S(O)R. In some embodiments, one or more of Rwis -C(O)R. In some embodiments, one or more of Rwis -C(O)OR. In some embodiments, one or more of Rwis - C(O)NR2. In some embodiments, one or more of Rwis -C(O)NROR. In some embodiments, one or more of Rwis -OC(O)R. In some embodiments, one or more of Rwis -OC(O)NR2. In some embodiments, one or more of Rwis -NRC(O)OR. In some embodiments, one or more of Rwis -NRC(O)R. In some embodiments, one or more of Rwis -NRC(O)N(R)2. In some embodiments, one or more of Rwis - NRS(O)2R.

[0243] In some embodiments .

[0244] In some embodimentsom those depicted in the compounds of Table 1 below.

[0245] As defined above and described herein, each Rxis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0246] In some embodiments, one or more of Rxis hydrogen. In some embodiments, one or more of Rxis RB. In some embodiments, one or more of Rxis halogen. In some embodiments, one or more of Rxis -CN. In some embodiments, one or more of Rxis -NO2. In some embodiments, one or more of Rxis -OR. In some embodiments, one or more of Rxis -SR. In some embodiments, one or more of Rxis -NR2. In some embodiments, one or more of Rxis -S(O)2R. In some embodiments, one or more of Rxis -S(O)2NR2.In some embodiments, one or more of Rxis -S(O)R. In some embodiments, one or more of Rxis -C(O)R. In some embodiments, one or more of Rxis -C(O)OR. In some embodiments, one or more of Rxis -C(O)NR2. In some embodiments, one or more of Rxis -C(O)NROR. In some embodiments, one or more of Rxis -OC(O)R. In some embodiments, one or more of Rxis -OC(O)NR2. In some embodiments, one or more of Rxis -NRC(O)OR. In some embodiments, one or more of Rxis -NRC(O)R. In some embodiments, one or more of Rxis -NRC(O)N(R)2. In some embodiments, one or more of Rxis -NRS(O)2R.In me me is is,

[0250] As defined above and described herein, each Ryis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0251] In some embodiments, one or more of Ryis hydrogen. In some embodiments, one or more of Ryis RB. In some embodiments, one or more of Ryis halogen. In some embodiments, one or more of Ryis -CN. In some embodiments, one or more of Ryis -NO2. In some embodiments, one or more of Ryis -OR. In some embodiments, one or more of Ryis -SR. In some embodiments, one or more of Ryis -NR2. In someembodiments, one or more of Ryis -S(O)2R. In some embodiments, one or more of Ryis -S(O)2NR2.In some embodiments, one or more of Ryis -S(O)R. In some embodiments, one or more of Ryis -C(O)R. In some embodiments, one or more of Ryis -C(O)OR. In some embodiments, one or more of Ryis -C(O)NR2. In some embodiments, one or more of Ryis -C(O)NROR. In some embodiments, one or more of Ryis -OC(O)R. In some embodiments, one or more of Ryis -OC(O)NR2. In some embodiments, one or more of Ryis -NRC(O)OR. In some embodiments, one or more of Ryis -NRC(O)R. In some embodiments, one or more of Ryis -NRC(O)N(R)2. In some embodiments, one or more of Ryis -NRS(O)2R.

[0252] In some embodiments, one or more of Ryis fluoro. is is is is

[0255] As defined above and described herein, each Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

[0256] In some embodiments, one or more of Rzis hydrogen. In some embodiments, one or more of Rzis RB. In some embodiments, one or more of Rzis halogen. In some embodiments, one or more of Rzis -CN. In some embodiments, one or more of Rzis -NO2. In some embodiments, one or more of Rzis -OR. Insome embodiments, one or more of Rzis -SR. In some embodiments, one or more of Rzis -NR2. In some embodiments, one or more of Rzis -S(O)2R. In some embodiments, one or more of Rzis -S(O)2NR2.In some embodiments, one or more of Rzis -S(O)R. In some embodiments, one or more of Rzis -C(O)R. In some embodiments, one or more of Rzis -C(O)OR. In some embodiments, one or more of Rzis -C(O)NR2. In some embodiments, one or more of Rzis -C(O)NROR. In some embodiments, one or more of Rzis -OC(O)R. In some embodiments, one or more of Rzis -OC(O)NR2. In some embodiments, one or more of Rzis -NRC(O)OR. In some embodiments, one or more of Rzis -NRC(O)R. In some embodiments, one or more of Rzis -NRC(O)N(R)2. In some embodiments, one or more of Rzis -NRS(O)2R.

[0257] In some embodiments, one or more of Rzis methyl. In some embodiments, one or more of Rzis ethyl. In meembodiments, . In someembodiments, . In someembodiments, .

[0259] In some embodiments In some embodiment In someembodiments, .

[0260] In som lected from those depicted in the compounds of Table 1 below.

[0261] As defined above and described herein, each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0262] In some embodiments, of RBis an optionally substituted C1-6 aliphatic. In some embodiments, RBis a phenyl. In some embodiments, RBis a 3-12 membered saturated or partially unsaturated monocyclic. In some embodiments, RBis an optionally substituted bicyclic. In some embodiments, of RBis an optionally substituted bridged bicyclic or spirocyclic carbocyclyl. In some embodiments, RBis a heterocyclyl with 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RBis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0263] In some embodiments, RBis selected from those depicted in the compounds of Table 1 below.

[0264] 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 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0265] In some embodiments, one or more –Cy'– is an optionally substituted phenylenyl. In some embodiments, one or more –Cy'– is an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, one or more –Cy'– is an optionally substituted 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl. In some embodiments,one or more –Cy'– is an optionally substituted 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more –Cy'– is an optionally substituted 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more –Cy'– is an optionally substituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0266] In some embodiments, -Cy'- is selected from those depicted in the compounds of Table 1 below.

[0267] As defined above and described herein, each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0268] In some embodiments, one or more of R is hydrogen. In some embodiments, one or more of R is a C1-6 aliphatic. In some embodiments, one or more of R is phenyl. In some embodiments, one or more of R is a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, one or more of R is and a 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0269] In some embodiments, R is selected from those depicted in the compounds of Table 1 below.

[0270] As defined above and described herein, m is independently 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0271] In some embodiments, m is selected from those depicted in the compounds of Table 1 below.

[0272] As defined above and described herein, n is independently 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0273] In some embodiments, n is selected from those depicted in the compounds of Table 1 below.

[0274] As defined above and described herein, o is independently 0 or 1. In some embodiments, o is 0. Insome embodiments, o is 1.

[0275] In some embodiments, o is selected from those depicted in the compounds of Table 1 below.

[0276] As defined above and described herein, w is 0, 1, 2, 3, or 4. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0277] In some embodiments, w is selected from those depicted in the compounds of Table 1 below.

[0278] As defined above and described herein, x is 0, 1, 2, 3, or 4. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0279] In some embodiments, x is selected from those depicted in the compounds of Table 1 below.

[0280] As defined above and described herein, y is 0, 1, 2, 3, or 4. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4.

[0281] In some embodiments, y is selected from those depicted in the compounds of Table 1 below.

[0282] As defined above and described herein, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4.

[0283] In some embodiments, z is selected from those depicted in the compounds of Table 1 below. , ,, , , , , or, , , , ,, , , , , ,, , , , , , ,, , , , , ,, , , , ,nts, is is .is In is me is. In some embodiments, DBM isis isme isis is is is is is. In some embodiments, DBM is . In some embodiments, DBM is . In some embodiments, DBM is . In some embodiments, DBM is . In some embodiments, DBM is . In some embodiments, DBM isis InIn some embodiments, DBMis is isis is is is. is. In some embodiments, DBM isis is is isO. In some embodiments, . In some embodiments, DBM isme isis isis me isme is Inis isme is

[0291] In some embodiments, DBM is selected from those depicted in Table A, below. Linker (L)

[0292] As defined above and described herein, L is a bivalent moiety that connects PBM to DIM (e.g., DBM). In some embodiments, L is a bivalent moiety that connects PBM to DIM. In some embodiments, L is a bivalent moiety that connects PBM to DBM.

[0293] In some embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, –NRC(O)O--10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur, and; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0294] In some embodiments, each –Cy– is independently an optionally substituted bivalent phenylenyl. In some embodiments, each –Cy– is independently an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, each –Cy– is independently an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each –Cy– is independently an optionally substituted 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl. In some embodiments, each –Cy– is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each –Cy– is independently 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, each –Cy– is independently an optionally substituted 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each –Cy– is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each –Cy– is independently an optionally substituted 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each –Cy– is independently an optionally substituted 8-10 memberedbicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0295] In some embodiments, -Cy- is substituted with C1-6alkyl (e.g., methyl, ethyl, isopropyl). In some embodiments, -Cy- is substituted with oxo. In some embodiments, -Cy- is substituted with halogen. In some embodiments, -Cy- is substituted with fluoro. In some embodiments, -Cy- is substituted with geminal difluoro. In some embodiments, -Cy- is substituted with -OH. In some embodiments, -Cy- is substituted with -NR2.

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

[0297] In some embodiments, -Cy- is selected from those depicted in Table B, below.

[0298] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.

[0299] In some embodiments, r is selected from those depicted in Table 1, below.

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

[0301] In some embodiments, L is -O(CH2)1-10-O-. In some embodiments, L is -O(CH2)1-10-NR-. In some embodiments, L is -O(CH2)1-10-C(O)-. In some embodiments, L is -O(CH2)1-10-OCH2CH2NR-. In some embodiments, L is -O(CH2)1-10-NRCH2C(O)-. In some embodiments, L is -O(CH2)1-10- CH2CH2OCH2C(O)-. In some embodiments, L is -O(CH2)1-10-(OCH2CH2)1-10-NR-. In some embodiments, L is -O(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -O(CH2)1-10- NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NR(CH2)1-10-O-. In some embodiments, L is - NR(CH2)1-10-NR-. In some embodiments, L is -NR(CH2)1-10-C(O)-. In some embodiments, L is -NR(CH2)1- 10-OCH2CH2NR-. In some embodiments, L is -NR(CH2)1-10-NRCH2C(O)-. In some embodiments, L is - NR(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -NR(CH2)1-10-(OCH2CH2)1-10-NR-. In some embodiments, L is -NR(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -NR(CH2)1-10- NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)(CH2)1-10-O-. In some embodiments, L is - C(O)(CH2)1-10-NR-. In some embodiments, L is -C(O)(CH2)1-10-C(O)-. In some embodiments, L is - C(O)(CH2)1-10-OCH2CH2NR-. In some embodiments, L is -C(O)(CH2)1-10-NRCH2C(O)-. In some embodiments, L is -C(O)(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -C(O)(CH2)1-10- (OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)(CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2O(CH2)1-10-O-. In some embodiments, L is -NRCH2CH2O(CH2)1-10-NR-. In some embodiments, L is -NRCH2CH2O(CH2)1-10-C(O)-. In some embodiments, L is -NRCH2CH2O(CH2)1-10-OCH2CH2NR-. Insome embodiments, L is -NRCH2CH2O(CH2)1-10-NRCH2C(O)-. In some embodiments, L is - NRCH2CH2O(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -NRCH2CH2O(CH2)1-10- (OCH2CH2)1-10-NR-. In some embodiments, L is -NRCH2CH2O(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2O(CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-O-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-NR-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-C(O)-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-OCH2CH2NR-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-NRCH2C(O)-. In some embodiments, L is - C(O)CH2NR(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -C(O)CH2NR(CH2)1-10- (OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - C(O)CH2OCH2CH2(CH2)1-10-O-. In some embodiments, L is -C(O)CH2OCH2CH2(CH2)1-10-NR-. In some embodiments, L is -C(O)CH2OCH2CH2(CH2)1-10-C(O)-. In some embodiments, L is - C(O)CH2OCH2CH2(CH2)1-10-OCH2CH2NR-. In some embodiments, L is -C(O)CH2OCH2CH2(CH2)1-10- NRCH2C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2(CH2)1-10-(OCH2CH2)1-10-NR-. In some embodiments, L is - C(O)CH2OCH2CH2(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - C(O)CH2OCH2CH2(CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NR(CH2CH2O)1- 10-(CH2)1-10-O-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1-10-NR-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1-10-C(O)-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1-10- OCH2CH2NR-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1-10-NRCH2C(O)-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is - NR(CH2CH2O)1-10-(CH2)1-10-(OCH2CH2)1-10-NR-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1- 10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -NR(CH2CH2O)1-10-(CH2)1-10- NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2(CH2)1-10-O-. In some embodiments, L is -NRCH2CH2NRC(O)CH2(CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(CH2)1-10-C(O)-. In some embodiments, L is -NRCH2CH2NRC(O)CH2(CH2)1-10- NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2(CH2)1-10-NRCH2C(O)-. In some embodiments, L is -NRCH2CH2NRC(O)CH2(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(CH2)1-10-(OCH2CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2)1-10-O-. In some embodiments, L is -NRCH2CH2NRC(O)CH2NR(CH2)1-10-NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2NR(CH2)1-10-C(O)-. In some embodiments, L is -NRCH2CH2NRC(O)CH2NR(CH2)1-10-OCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2)1-10-NRCH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2)1-10-(OCH2CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2)1-10-NRCH2C(O)NRCH2CH2NR-.

[0302] In some embodiments, L is -(OCH2CH2)1-10-O-. In some embodiments, L is -(OCH2CH2)1-10- Cy-. In some embodiments, L is -(OCH2CH2)1-10-NR-. In some embodiments, L is -(OCH2CH2)1-10-C(O)-. In some embodiments, L is -(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is -(OCH2CH2)1-10- NR-. In some embodiments, L is -(OCH2CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1-10-O-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1-10-Cy-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1- 10-C(O)-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is -NRCH2CH2(OCH2CH2)1-10- NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)CH2CH2(OCH2CH2)1-10-O-. In some embodiments, L is -C(O)CH2CH2(OCH2CH2)1-10-Cy-. In some embodiments, L is - C(O)CH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)CH2CH2(OCH2CH2)1-10-C(O)-. In some embodiments, L is -C(O)CH2CH2(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is - C(O)CH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)CH2CH2(OCH2CH2)1-10- NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)CH2OCH2CH2(OCH2CH2)1-10-O-. In some embodiments, L is -C(O)CH2OCH2CH2(OCH2CH2)1-10-Cy-. In some embodiments, L is - C(O)CH2OCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)CH2OCH2CH2(OCH2CH2)1-10- C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is - C(O)CH2OCH2CH2(OCH2CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - C(O)CH2NRCH2CH2(OCH2CH2)1-10-O-. In some embodiments, L is -C(O)CH2NRCH2CH2(OCH2CH2)1-10- Cy-. In some embodiments, L is -C(O)CH2NRCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is - C(O)CH2NRCH2CH2(OCH2CH2)1-10-C(O)-. In some embodiments, L is - C(O)CH2NRCH2CH2(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is - C(O)CH2NRCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)CH2NRCH2CH2(OCH2CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-O-.In some embodiments, L is -NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-Cy-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2(OCH2CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-O-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-Cy-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-NRCH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2CH2(OCH2CH2)1-10-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -O(CH2CH2O)1-10-CH2CH2O-. In some embodiments, L is -Cy-(CH2CH2O)1-10-CH2CH2O-. In some embodiments, L is -NR(CH2CH2O)1-10-CH2CH2O-. In some embodiments, L is -C(O)(CH2CH2O)1-10- CH2CH2O-. In some embodiments, L is -C(O)CH2NR(CH2CH2O)1-10-CH2CH2O-. In some embodiments, L is -NRCH2CH2O(CH2CH2O)1-10-CH2CH2O-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2CH2O-. In some embodiments, L is -O(CH2CH2O)1-10- CH2CH2NR-. In some embodiments, L is -Cy-(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is - NR(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is -C(O)(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is -C(O)CH2NR(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is - NRCH2CH2O(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is -O(CH2CH2O)1-10- CH2CH2C(O)-. In some embodiments, L is -Cy-(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is -NR(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is -C(O)(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is -C(O)CH2NR(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is - NRCH2CH2O(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is -O(CH2CH2O)1-10- CH2CH2OCH2C(O)-. In some embodiments, L is -Cy-(CH2CH2O)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -NR(CH2CH2O)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is - C(O)(CH2CH2O)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -C(O)CH2NR(CH2CH2O)1-10- CH2CH2OCH2C(O)-. In some embodiments, L is -NRCH2CH2O(CH2CH2O)1-10-CH2CH2OCH2C(O)-. Insome embodiments, L is -NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -O(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is -Cy-(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is -NR(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is -C(O)(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is - C(O)CH2NR(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is - NRCH2CH2O(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2CH2NRCH2C(O)-. In some embodiments, L is - O(CH2CH2O)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -Cy-(CH2CH2O)1-10- CH2C(O)NRCH2CH2NR-. In some embodiments, L is -NR(CH2CH2O)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)(CH2CH2O)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - C(O)CH2NR(CH2CH2O)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2O(CH2CH2O)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - O(CH2CH2O)1-10-CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -Cy-(CH2CH2O)1-10- CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NR(CH2CH2O)1-10- CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)(CH2CH2O)1-10- CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)CH2NR(CH2CH2O)1-10- CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2O(CH2CH2O)1-10- CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR(CH2CH2O)1-10-CH2CH2NRCH2C(O)NRCH2CH2NR-.

[0303] In some embodiments, L is -NRCH2CH2-Cy-CH2O-. In some embodiments, L is -OCH2-Cy- CH2CH2NR-. In some embodiments, L is -NRCH2CH2-Cy-CH2CH2NR-. In some embodiments, L is - NRCH2CH2-Cy-CH2C(O)-. In some embodiments, L is -C(O)CH2-Cy-CH2CH2NR-. In some embodiments, L is -C(O)CH2NRCH2CH2-Cy-CH2NR-. In some embodiments, L is -NRCH2-Cy-CH2CH2NRCH2C(O)-. In some embodiments, L is -C(O)CH2CH2-Cy-CH2C(O)-. In some embodiments, L is -C(O)CH2-Cy- CH2CH2C(O)-. In some embodiments, L is -C(O)CH2CH2-Cy-CH2CH2NR-. In some embodiments, L is - NRCH2CH2-Cy-CH2CH2C(O)-. In some embodiments, L is -NRCH2CH2NRC(O)CH2NRCH2CH2-Cy- CH2NR-. In some embodiments, L is -NRCH2-Cy-CH2CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2-Cy-SO2NR-. In some embodiments, L is -NRSO2-Cy-CH2CH2NR-. In some embodiments, L is -Cy-(OCH2CH2)1-10-NR-. In some embodiments, L is -Cy-(OCH2CH2)1-10-O-. In some embodiments, L is -O(CH2CH2O)1-10-Cy-. In some embodiments, L is -NR(CH2CH2O)1-10-Cy-. In some embodiments, L is -(OCH2CH2)1-10-Cy-C(O)-. In some embodiments, L is -C(O)-Cy-(CH2CH2O)1-10-. In some embodiments, L is -NR(CH2CH2O)1-10-Cy-NRCH2C(O)-. In some embodiments, L is - C(O)CH2NR-Cy-(OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)CH2-Cy-NRCH2C(O)-. In some embodiments, L is -C(O)CH2NR-Cy-CH2C(O)-. In some embodiments, L is -NRCH2CH2NRC(O)CH2-Cy- C(O)-. In some embodiments, L is -C(O)-Cy-CH2C(O)NRCH2CH2NR-. In some embodiments, L is - NR(CH2CH2O)1-10-Cy-CH2CH2C(O)-. In some embodiments, L is -C(O)CH2CH2-Cy-(OCH2CH2)1-10-NR-. In some embodiments, L is -OCH2CH2-Cy-O-. In some embodiments, L is -O-Cy-CH2CH2O-. In some embodiments, L is -NRCH2CH2O-Cy-NR-. In some embodiments, L is -NR-Cy-OCH2CH2NR-. In some embodiments, L is -C(O)CH2-Cy-C(O)-. In some embodiments, L is -C(O)-Cy-CH2C(O)-. In some embodiments, L is -NRCH2CH2O-Cy-NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NR-Cy-OCH2CH2NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2-Cy- NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2NR-Cy- CH2C(O)NRCH2CH2NR-.

[0304] In some embodiments, L is -Cy-CH2-Cy-. In some embodiments, L is -Cy-CH2-Cy-CH2C(O)- . In some embodiments, L is -C(O)CH2-Cy-CH2-Cy-. In some embodiments, L is -Cy-CH2-Cy-CH2CH2O- . In some embodiments, L is -OCH2CH2-Cy-CH2-Cy-. In some embodiments, L is -Cy-CH2-Cy- CH2CH2NR-. In some embodiments, L is -NRCH2CH2-Cy-CH2-Cy-. In some embodiments, L is -Cy-CH2- Cy-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -NRCH2CH2NRC(O)CH2-Cy-CH2-Cy-. In some embodiments, L is -O-CH2CH2-Cy-CH2-Cy-. In some embodiments, L is -C(O)CH2-Cy-CH2-Cy-. In some embodiments, L is -C(O)CH2-Cy-CH2-Cy-CH2C(O)-. In some embodiments, L is -C(O)CH2-Cy-CH2-Cy- CH2CH2OCH2C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2-Cy-CH2-Cy-CH2C(O)-. In some embodiments, L is -NRCH2CH2NRC(O)CH2-Cy-CH2-Cy-. In some embodiments, L is -Cy-CH2-Cy-C(O)- . In some embodiments, L is -C(O)-Cy-CH2-Cy-. In some embodiments, L is -Cy-CH2-Cy-NR-. In some embodiments, L is -NR-Cy-CH2-Cy-. In some embodiments, L is -OCH2CH2-Cy-CH2-Cy-NR-. In some embodiments, L is -NR-Cy-CH2-Cy-CH2CH2O-. In some embodiments, L is -NR-Cy-CH2-Cy-C(O)CH2-. In some embodiments, L is -NRCH2CH2NRC(O)CH2-Cy-CH2C(O)-. In some embodiments, L is - C(O)CH2-Cy-CH2C(O)NRCH2CH2NR-. In some embodiments, L is -C(O)-Cy-CH2NRCH2C(O)-. In some embodiments, L is -NR-Cy-CH2NRCH2C(O)NRCH2CH2NR-. In some embodiments, L is - NRCH2CH2NRC(O)CH2NRCH2-Cy-NR-.

[0305] In some embodiments, L is a covalent bond.

[0306] In some embodiments, L is -C(O)-CH2-Cy-CH2-Cy-. In some embodiments, L is -C(O)-CH2- Cy-O-Cy-. In some embodiments, L is -C(O)-CH2-Cy-. In some embodiments, wherein L is -Cy-CH2-Cy- . In some embodiments, L is -Cy-O-Cy-.

[0307] Without limitation, the point of attachment of L to PBM and DIM can be, for example when L , , , , , , , , , ,, , , , , , , , , ,

[0309] In some embodiments L is , , , , , , , , , , ,, , , , , , , , , , , ,, , , , , , , , , ,, , , ,

[0310] In some embodiments, L is . In some embodiments, L isnts, meembodiments, L is . In some embodiments, L is. In someembodiments L is . In some embodiments L is Insome embodiments, L is . In some embodiments, L i .In some embodiments, L is . In some embodiments, L is. In someembodiments, L is . In some embodiments, L isme is Insome embodiments, L is . In some embodiments, L isis is is is. In some embodiments L is is is is is. In some embodiments,me is meL is In someembodiments, . In some embodiments, L isme is Insome embodiments, L is . In some embodiments, L is. In someembodiments, L is . In some embodiments, L is. In someis is. In someembodiments, L is . In some embodiments, L isis .In some embodiments, L is . In some embodiments, L is. In some embodiments, L is . In some embodiments, L isme isis is is is isis nts,. In someis is is is isInsome embodiments, L is . In some embodiments, L is.In me.is isIn someis is is is Insome embodiments, L is . In some embodiments, L ismeis is is isInsome embodiments, L is . In some embodiments, L isis Insome embodiments, L i . In some embodiments, L . In someme is is meis isis is is meis. In some embodiments, . In some embodiments, L is. Insome embodiments, L is . In some embodiments, L ismeembodiments, L i . In some embodiments, L .

[0312] In soed from those depicted in Ta

[0313] In some embodiments, L is selected from those depicted in Table B, below.

[0314] In some embodiments, the present invention provides the compound of formula I-a, wherein from formula I-bb, to provide a compound ofor a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ring C, ring, D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, ring W, ring X, ring Y, ring Z, LB, L3', L1', Rw, Rx, Ry, Rz, w, x, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0315] In some embodiments, the present invention provides the compound of formula I-a, wherein from formula I-cc, to provide aor a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ring C, ring, D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, ring X, ring Y, ring Z, LB, L2', L1', Rx, Ry, Rz, x, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0316] In some embodiments, the present invention provides the compound of formula I-a, wherein from formula I-ff, to provide a compound of formula I-aff:or a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ring C, ring, D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, ring X, ring Y, ring Z, LB, L2', Rx, Ry, Rz, x, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0317] In some embodiments, the present invention provides the compound of formula I-a, wherein of Ra, Rb, Rc, Rd, a, b, c, d, L, ring Y, ring Z, LB, L1', Ry, Rz, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0318] In some embodiments, the present invention provides the compound of formula I-a, whereinfrom formula I-hh, to provide a compound of formulaor a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ring C, ring, D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, ring X, ring Y, ring Z, LB, L2', Rx, Ry, Rz, x, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0319] In some embodiments, the present invention provides the compound of formula I-a, wherein from formula I-ii, to provide a compound ofI-aii or a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ring C, ring, D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, ring Y, ring Z, LB, L1', Ry, Rz, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0320] In some embodiments, the present invention provides the compound of formula I-a, wherein DBM is from formula I-kk, to provide a compound of formula I-akk:or a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ring C, ring, D, L1, LA, Ra, Rb, Rc, Rd, a, b, c, d, L, ring Z, LB, Rz, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0321] In some embodiments, the present invention provides the compound of formula I-a, wherein e a, , , , , , , , Ra, Rb, Rc, Rd, a, b, c, d, L, ring W, ring X, ring Y, ring Z, LB, L3', L2', L1', Rw, Rx, Ry, Rz, w, x, y, z, is independently as defined above and described in embodiments herein, both singly and in combination.

[0322] Table A. Exemplified Deubiquitinase binding moiety (DBM) d), g), j), o),), s), ), ), a), c),), e), ), ), i), l), ),), r), s), t), ), ),z), c), ),), j),), ), ),t), ), ), a),c), e), ), i), ),), ), ), s), ),), ), a), c), e),g), i), k), ), o),), s), ), ), ), a),c), e), ), i), ), ),), ), s), ), ), ),a), c), f), ), i), j), ),l), ), ), ), ), ), r),t), ), ), ),), ), i), ), ),), ), s), ), ),), a), c), e), ), i), ),), ), q), s),), ), ), c), e),), i), ), ),s), ), ),b), ), y), a), c), e),), i), ),), r), t), ), ), ),), ), f), ),), ), ),), v), ), ), ), z),a), ), ), f), ), j),l), ), ), r), t), ),), z), ), ), f), ), i),j), l), ), ), r),s), t), ), ), z),c), e), ),i), ), ), ), r),t), ), ), z),c), e), ), j), ),(qn), (qo), r), t), v), x), ),), a), f), ),j), ), l), ), ), ),p), q), r), s), t), u),), ), ), a),), c), ), e), f), ),), i), j), ), l), ),(sn), O p), ), u), ),(sx), O N N N N H H N O O (sy), z), a), b), c),e), ), i), ), ),), ), s), ), ), ),a), c), e), ), i),), ), ), ), s), ),), ), a), c), e), ),i), ), ), ), ),s), ), ), ), a), c),e), g), i), k), ), o), q),s), ), ), ), a), c),), e), f), ), i),), ), ), s), ),), ), a), c), e),), i), ), ), ),), s), ), ), ),a), c), e), ),l), ),), ), ),e), ), j), ), ),s), ), ), ),i), ), ), ), ),N N HONHON N N s), ), ), ), a), ),O ), j), l), ), ), t),F O ), ),), ), s), v), ), ),e), ), ), ), ), t), ),z), c), f), i), l), ),), ), ), ), ), ), ),O N ), ), e), ),i), ), ), ), ),N N s), ), ), ), z),c), e), f), ), ),), o), r), u),Table B. Exemplified Linkers (L)1 2 ), , ,),,), ,),, ), ),), ),

[0323] In some embodiments, the present invention provides a compound having PBM described and disclosed herein, DBM set forth in Table A above, and a linker set forth in Table B above, or a pharmaceutically acceptable salt thereof.

[0324] Exemplary compounds of the invention are set forth in Table 1, below. Table 1. Exemplary Compounds ID# StructureI-3I-7I-11I-16I-23I-30I-35I-39I-44I-50I-54I-66I-74I-79I-83I-87I-91I-97I-103I-109I-114I-120I-125I-131I-136I-140I-146I-152I-156I-161I-166 N NI-169I-172I-177I-181I-186I-191I-197I-201I-205I-211OHN NI-215I-219I-224I-229I-234I-239I-244I-249I-254I-259I-264I-269I-272I-275I-279I-284I-289I-293I-299I-303I-308I-313I-318I-323I-329I-333I-336 OH NI-339

[0325] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4. General Methods of Providing the Present Compounds

[0326] 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.

[0327] 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 OrganicTransformations, 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.

[0328] 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-benylbenzoate, 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.

[0329] 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.

[0330] In the schemes below, where a provided compound is formed having a reactive moiety (e.g., amine, alcohol, etc.), it is not shown but it is generally appreciated and well known by those having ordinary skill in the art that the reactivity of said reactive moiety may be masked by employing a suitable protectinggroup that can thereafter be removed in situ or during a separate synthetic step.

[0331] In some embodiments, compounds of the present invention are generally prepared according to Scheme 1 set forth below: Scheme 1: Synthesis of Compounds of Formula I

[0033] s epcte n Sc eme , a ove, amne nt- s coup e to ac nt- us ng a coup ng reagent (e.g., EDCI) in the presence of the base (e.g., NMM) in a solvent (e.g., DMF) to form a compound of formula I with a linker comprising an amide bond. The squiggly bond, , represents the portion of the linker between PBM and the terminal amino group of Int-1 or the portion of the linker between DIM and the terminal carboxyl group of Int-2, respectively. The amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[0333] In some embodiments, compounds of the present invention are generally prepared according to Scheme 2 set forth below: Scheme 2: Synthesis of Compounds of Formula I H2N DIM IM

[0334] As depicted in Scheme 2, above, acid Int-3 is coupled to amine Int-4 using a coupling reagent (e.g., EDCI) in the presence of the base (e.g., NMM) in a solvent (e.g., DMF) to form a compound of formula I with a linker comprising an amide bond. The squiggly bond, , represents the portion of the linker between PBM and the terminal carboxyl group of Int-3 or the portion of the linker between DIM and the terminal amino group of Int-4, respectively. The amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[0335] 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 andnitriles 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. “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein 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

[0336] In some embodiments, 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. In some embodiments, the amount of compound in compositions of this invention is such that it is effective to measurably inhibit an Akt protein, or a mutant thereof, in a biological sample or in a patient. In some 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.

[0337] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0338] 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 in the 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.

[0339] 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.

[0340] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of an Akt protein, or a mutant thereof.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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 asuitable 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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 otherembodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0351] 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.

[0352] 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

[0353] Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes.

[0354] As used herein, the terms “AKT-mediated”, “AKT1-mediated”, “AKT2-mediated”, and / or “AKT3-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which one or more of AKT1, AKT2, and / or AKT3, or a mutant thereof (e.g., E17K AKT), are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which one or more of AKT1, AKT2, and / or AKT3, or a mutant thereof, are known to play a role.

[0355] Compounds of the present disclosure can inhibit AKT1, AKT2, or AKT3 and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by AKT1, AKT2, and / or AKT3. Such diseases include cancer and other diseases with proliferation disorder. In some embodiments, the present disclosure provides treatment of an individual or a patient in vivo using a provided compound or a pharmaceutically acceptable salt thereof such that growth of cancerous tumors is inhibited. A provided compound or a pharmaceutically acceptable salt thereof can be used to inhibit the growth of cancerous tumors with aberrations that activate AKT1, AKT2, and / or AKT3 activity. These include, but not limited to, disease (e.g., cancers) that are characterized by amplification or overexpression of AKT1, AKT2, and / or AKT3 such as ovarian cancer, uterine carcinosarcoma and breast cancer and p27 inactivation such as breast cancer and melanomas. Accordingly, in some embodiments of the methods, the patient has been previously determined to have an amplification of the Akt gene in a biological sampleobtained from the human subject that is higher than a control expression level of Akt. Alternatively, a provided compound or a pharmaceutically acceptable salt thereof can be used in conjunction with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells with Akt amplification and overexpression in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof.

[0356] In some embodiments, compounds of the present disclosure can inhibit E17K AKT.

[0357] In some embodiments, provided herein is a method of inhibiting Akt, comprising contacting the Akt with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of inhibiting Akt in a patient, comprising administering to the patient a provided compound or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, provided herein is a method for treating cancer. In some embodiments, the cancer is associated with irregularities in the activity of Akt and / or downstream cellular targets of Akt. Such cancers include, but are not limited to, ovarian, pancreatic, breast and prostate cancer, as well as cancers (including glioblastoma) where the tumor suppressor PTEN is mutated as described in: Cheng et al., Proc. Natl. Acad. Sci. (1992) 89:9267-9271; Cheng et al., Proc. Natl. Acad. Sci. (1996) 93:3636-3641; Bellacosa et al., Int. J. Cancer (1995) 64:280-285; Nakatani et al., J. Biol Chem. (1999) 274:21528-21532; Graff, Expert. Opin. Ther. Targets(2002) 6(1):103-113; and Yamadaand Araki,J. Cell Science. (2001) 114:2375-2382; Mischel and Cloughesy, Brain Pathol. (2003) 13(1):52-61). Cancers where Akt itself is activated by gene amplification or mutations may also be treated by the compounds. Human breast, colorectal and ovarian cancers where a somatic mutation in a pleckstrin homology domain (PH) of AKT1 (E17K mutant; the glutamic acid (E) at position 17 of the amino acid sequence of the PH domain of AKT1 is replaced by a lysine (K)) is reported (Carpten et al, Nature 448: 439-444 (2007), the entirety of each of which is hereby incorporated herein by reference.).The method includes administering to a patient (in need thereof), a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the cancer is characterized by amplification or overexpression of Akt. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of Akt.

[0359] In some embodiments, provided herein is a method of treating a disease or disorder associatedwith Akt in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with Akt is associated with an amplification of the Akt gene and / or overexpression of Akt.

[0360] In some embodiments, the disease or disorder associated with Akt is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0361] In some embodiments, the disease or disorder associated with Akt is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

[0362] In some embodiments, the disease or disorder associated with Akt is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0363] In some embodiments, the disease or disorder associated with Akt is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0364] In some embodiments, the disease or disorder associated with Akt is a cancer.

[0365] In some embodiments, the cancer is characterized by amplification or overexpression of Akt. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of Akt.

[0366] Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancersincluding those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

[0367] In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSIhigh). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

[0368] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: non-small cell lung, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarciaoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma],glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.

[0369] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

[0370] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer.

[0371] In some embodiments, the compounds of the present disclosure can be used to treat sickle celldisease and sickle cell anemia.

[0372] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0373] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).

[0374] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

[0375] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0376] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0377] Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0378] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0379] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

[0380] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0381] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

[0382] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0383] In some embodiments, the method comprises killing one or more cancer cells in a patient with cancer. As such, the methods of the disclosure may be used to treat a tumor derived from a neoplasm or a cancer. In some embodiments, the tumor is harboring a mutation. In some embodiments, the mutation is a AKTE17K mutation. In some embodiments, the tumor is harboring PTEN inactivation. In some embodiments, the tumor is harboring one or more PI3K pathway mutations. In some embodiments, the tumor is harboring one or more KRAS pathway mutations.

[0384] In some embodiments, the cancer is HR+ / HER breast cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the cancer is HER2-positive breast cancer.

[0385] It is believed that a provided compound or a pharmaceutically acceptable salt thereof may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.

[0386] 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 symptoms thereof, 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.

[0387] The terms “individual” or “patient,” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0388] The phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0389] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0390] In some embodiments, compounds of the present disclosure are useful for treating tumors. In some embodiments, the tumor has a BRAF mutation. Co-Administration with One or More Other Therapeutic Agent(s)

[0391] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0392] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compounddisclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0393] A compound of the current invention can also be used in combination with other types of therapies to treat disease. Diseases characterized by Akt activation that could benefit from administration of the compounds include all forms of cancer, precancerous lesions, cardiovascular disease, rheumatologic disease, pulmonary disease, dermatologic disease, gynecological diseases, vascular disease, neurologic disease, and infectious disease, including bacterial, viral, retroviral, and parasitic diseases. Moreover, these compounds could be utilized to prevent above said diseases.

[0394] A compound of the current invention can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In some embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0395] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides, or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible, as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0396] One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.

[0397] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0398] The amount of a compound of the invention and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of a compound of the invention can be administered.

[0399] In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and a compound of the invention can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 ^g / kg body weight / day of the one or more other therapeutic agent(s) can be administered.

[0400] The amount of one or more other therapeutic agent(s) present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is provided for dosing per the FDA label insert.

[0401] The compounds of this invention, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

[0402] In some embodiments, one or more other therapeutic agent is a ATM kinase inhibitor.

[0403] In some embodiments, one or more other therapeutic agent is a ATR kinase inhibitor.

[0404] In some embodiments, one or more other therapeutic agent is a CHK1 kinase inhibitor.

[0405] In some embodiments, one or more other therapeutic agent is a WEE1 inhibitor.

[0406] In some embodiments, one or more other therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist, an OX40 agonist, a CD137 (also called 4-1BB) agonist, a CD27 agonist Exemplary Other Therapeutic Agents

[0407] In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB- 290 (BeiGene, Inc.).

[0408] In some embodiments, one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).

[0409] In some embodiments, one or more other therapeutic agent is a CDK inhibitor, such as a CDK4 / CDK6 inhibitor. In some embodiments, a CDK 4 / 6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0410] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941,Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0411] In some embodiments, one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. In some embodiments, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0412] In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis / Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0413] In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[0414] In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)- imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor,tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology).

[0415] In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech / Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech / Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis / Genentech / Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech / Roche / Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech / Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRUVICA®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (RYDAPT®, Novartis).

[0416] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0417] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).

[0418] In some embodiments, one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).

[0419] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).

[0420] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).

[0421] In some embodiments, one or more other therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.

[0422] In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).

[0423] In some embodiments, one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).

[0424] In some embodiments, one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0425] In some embodiments, one or more other therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acutemyeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0426] In some embodiments, one or more other therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).

[0427] In some embodiments, one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (RITUXAN®, Genentech / BiogenIdec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline); obinutuzumab (anti- CD20, GAZYVA®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti- glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, KADCYLA®, Genentech); and pertuzumab (anti-HER2, PERJETA®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, ADCETRIS®, Seattle Genetics).

[0428] In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).

[0429] In some embodiments, one or more other therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie / Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0430] In some embodiments, one or more other therapeutic agent is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas / Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor / Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).

[0431] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs usefulin the present invention include raloxifene (EVISTA®, Eli Lilly).

[0432] In some embodiments, the selective estrogen receptor modulator (SERM) is lasofoxifene.

[0433] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor degrader (SERD). Approved SERDs useful in the present invention include Elacestrant (Orserdu).

[0434] In some embodiments, one or more other therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).

[0435] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN- 6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0436] In some embodiments, one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFß). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD-L1 / TGF-β trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF- β“trap.”

[0437] In some embodiments, one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells’ ability to metastasize.

[0438] In some embodiments, one or more other therapeutic agents is an antiproliferative compound. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting / decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17- dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, TEMODAL CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[0439] The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name AROMASIN™. Formestane is marketed under the trade name LENTARON™. Fadrozole is marketed under the trade name AFEMA™. Anastrozole is marketed under the trade name ARIMIDEX™. Letrozole is marketed under the trade names FEMARA™ or FEMAr™. Aminoglutethimide is marketed under the trade name ORIMETEN™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0440] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name NOLVADEX™.Raloxifene hydrochloride is marketed under the trade name EVISTA™. Fulvestrant can be administered under the trade name FASLODEX™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[0441] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEX™.

[0442] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR™. Topotecan is marketed under the trade name HYCAMPTIN™.

[0443] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYX™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name ETOPOPHOS™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name ACRIBLASTIN™ or ADRIAMYCIN™. Epirubicin is marketed under the trade name FARMORUBICIN™. Idarubicin is marketed. under the trade name ZAVEDOS™. Mitoxantrone is marketed under the trade name NOVANTRON™.

[0444] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name TAXOL™. Docetaxel is marketed under the trade name TAXOTERE™. Vinblastine sulfate is marketed under the trade name VINBLASTIN R.P™. Vincristine sulfate is marketed under the trade name FARMISTIN™.

[0445] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTIN™. Ifosfamide is marketed under the trade name HOLOXAN™.

[0446] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limitedto, suberoylanilide hydroxamic acid (SAHA).

[0447] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name XELODA™. Gemcitabine is marketed under the trade name GEMZAR™.

[0448] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis- platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN™.

[0449] The term "compounds targeting / decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor- receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the AxI receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N- phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing orinhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family, and / or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC™) or tyrphostin such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (HERCEPTIN™), cetuximab (ERBITUX™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3- d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c- Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT- 062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0450] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds havinginhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK- 474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0451] The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT- 731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl- 2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.

[0452] The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[0453] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0454] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.

[0455] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.

[0456] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.

[0457] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943,WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.

[0458] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition e.g., thalidomide (THALOMID™) and TNP- 470.

[0459] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0460] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[0461] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ- tocopherol or α- γ- or δ-tocotrienol.

[0462] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[0463] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name DIDRONEL™. Clodronic acid is marketed under the trade name BONEFOS™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name AREDIA™. Alendronic acid is marketed under the trade name FOSAMAX™. Ibandronic acid is marketed under the trade name BONDRANAT™. Risedronic acid is marketed under the trade name ACTONEL™. Zoledronic acid is marketed under the trade name ZOMETA™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICAN™), CCI-779 and ABT578.

[0464] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[0465] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (ZARNESTRA™). The term"telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

[0466] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0467] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADE™) and MLN 341.

[0468] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB- 2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MMI270B or AAJ996.

[0469] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D- arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.

[0470] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[0471] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[0472] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DM1, erbitux, bevacizumab (AVASTIN™), rituximab(RITUXAN®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[0473] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

[0474] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)- ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4thEdition, Vol.1, pp.248-275 (1993).

[0475] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5- fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0476] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATIN™; ENDOSTATIN™; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTIN™).

[0477] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNE™ and porfimer sodium.

[0478] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α- hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0479] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[0480] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[0481] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications). Exemplary Immune Checkpoint Inhibitors

[0482] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0483] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.

[0484] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and TLymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0485] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL- 1, thus overriding the ability of tumors to suppress the host anti-tumor immune response.

[0486] In some embodiments, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0487] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, γδ, and memory CD8+(αβ) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limitedto, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS- 936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA- 4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

[0488] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD- L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech).

[0489] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.

[0490] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroidcancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[0491] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).

[0492] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0493] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0494] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists that are being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti- OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[0495] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB)agonists. CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti- CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).

[0496] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0497] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).

[0498] Checkpoint inhibitors that can be used in the present invention include inducible T-cell co- stimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an...

Claims

CLAIMS 1. A compound of formula I,or a pharmaceutically acceptable salt thereof, wherein: PBM is a protein binding moiety capable of binding Akt; L is a bivalent moiety that connects PBM to DIM; and DIM is a deubiquitination inducing moiety.

2. The compound of claim 1, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-a: or a pharmaceutically accd above and described herein, and wherein: Ring A and Ring B are independently fused rings selected from benzo, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, an 8-10 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1and LAare independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L1or LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; a, b, c, and d are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, – 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)-, - ,, wherein: eac lected from phenylenyl, an 8-10membered b cyc c aryeny , a 4-7 membered saturated or part a y unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR- ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

3. The compound of claim 1, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-a':or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring A and Ring B are independently fused rings selected from benzo, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4-7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 8-10 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L1or LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of L1or LAare independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or - OC(O)NR-, –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independentlyselected from nitrogen, oxygen, and sulfur; a, b, c, and d are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, – 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)-, - , eac -10membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR- ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The compound of claim 1, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-b:or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl and a 5-6 membered heteroaryl with 1-4 heteroatoms independentlyselected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; a, b, c, and d are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, – 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)-, - ,, wherein: eac lected from phenylenyl, an 8-10membered b cyc c aryeny , a 4-7 membered saturated or part a y unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR- ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. The compound of claim 1, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-b':or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)- , -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; a, b, c, and d are independently 0, 1, 2, 3, or 4 L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, – 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)-, -, eac 8-10membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR- ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

6. The compound of claim 1, wherein PBM is an Akt binding moiety thereby forming a compound of formula I-c:or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-;LAare independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or - OC(O)NR-, –NRC(O)O-; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; a, b, c, and d are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, – 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)-, - , eac, -10membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR- ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. The compound of claim 1, PBM is an Akt binding moiety thereby forming a compound of formulaI-c':or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein: Ring C is a ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 3-12 membered saturated or partially unsaturated bridged bicyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-12 membered saturated or partially unsaturated bridged bicyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclyl, a 4- 7 membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is a covalent bond, -CR2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; LAare independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LAare independently replaced by -Cy-, -O-, - NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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, a6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ra, Rb, Rc, and Rdis independently selected from hydrogen, 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, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; a, b, c, and d are independently 0, 1, 2, 3, or 4; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2- ,, wherein: ted bivalent ring selected from phenylenyl, an 8-10membered b cyc c aryeny , a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, –SiR2–, –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-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR- ,each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 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 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

8. The compound of any one of claims 1-7, wherein ring D is a phenyl.

9. The compound of claim 8, wherein Rdis one or more halogen.

10. The compound of claim 9, wherein the halogen is chloro.

11. The compound of claim any one of claims 1-10, wherein ring C is , wherein X1and X2are independently carbon or nitrogen.

12. The compound of claim 11, wherein at least one of X1and X2is nitrogen.

13. The compound of claim 12, wherein X1is nitrogen and X2is carbon.

14. The compound of claim 12, wherein X1is carbon and X2is nitrogen.

15. The compound of claim 12, wherein X1and X2are nitrogen.

16. The compound of any one of claims 1-15, wherein one or more Rais -OH.

17. The compound of any one of claims 1-16, wherein one or more Rais methyl.

18. The compound of any one of claims 1-17, wherein L1is -C(O)-.

19. The compound of any one of claims 1-18, wherein LAis -CH2-.

20. The compound of claim 4 or 5, wherein PBM is: .I-b-1 wherein X1and X2are independently carbon or nitrogen.

21. The compound of claim 6 or 7, wherein PBM is: ,wherein X1and X2are independently carbon or nitrogen.

22. The compound of any one of claims 1-21, wherein DIM is a deubiquitinase binding moiety (DBM).

23. The compound of any one of claims 1-22, wherein DBM is deubiquitinase binding moiety and said compound is of formula I-bb: or a pharmaceuticallyefined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

24. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-bb:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-8 membered saturated or partially unsaturated carbocyclylenyl, a 4-8 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 4-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; X1is carbon or nitrogen; m, n, o, and p are independently 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

25. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc:-cc or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LB, L1', and L2'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

26. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-cc':or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-8 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heterocyclylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LB, L1', and L2'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L2'are independently replaced by –Cy'–, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, - S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocycliccarbocyclyl or heterocyclyl with 1-3 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 –Cy'– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

27. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff: or a pharmaceutically acceptab, re as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring,a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LBand L2'is independently a covalent bond or a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

28. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ff':or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic ring, a 4-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 3-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LBand L2'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by –Cy'–, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2- , -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-;each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-12 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, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each –Cy'– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; n and p are independently 0 or 1; and x, y, and z are independently 0, 1, 2, 3, or 4.

29. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-gg:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of LBand L1'is independently a covalent bond or a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LBor L1'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and y and z are independently 0, 1, 2, 3, or 4.

30. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety therebyforming a compound of formula I-hh: (Rx)xX (Ry)y)zor a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LBand L2'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LBor L2'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and x, y, and z are independently 0, 1, 2, 3, or 4.

31. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ii:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and an 8-10 membered bicyclic heterocyclylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur; each LBand L1'is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LBor L1'are independently replaced by -O-, -NR- , -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or - OC(O)NR-, –NRC(O)O-; each Ry, and Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and y, and z are independently 0, 1, 2, 3, or 4.

32. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-kk: I-kk or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rzis independently selected from hydrogen, RB, halogen, CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; LBis a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LBare independently replaced by -O-, -NR-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, – NRC(O)O-; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and z is 0, 1, 2, 3, or 4.

33. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll:or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic having 1-2 heteroatoms independentlyselected 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

34. The compound of any one of claims 1-22, wherein DBM is a deubiquitinase binding moiety thereby forming a compound of formula I-ll':or a pharmaceutically acceptable salt thereof, wherein L and PBM are as defined above and described herein, and wherein: Ring Z is a ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl, a 3-7 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each LB, L1', and L3'is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein 0-3 methylene units of LB, L1', or L3'are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, or -OC(O)NR-, –NRC(O)O-; each Rw, Rx, Ry, and Rzis independently selected from hydrogen, RB, halogen, -CN, -NO2, -OR, - SR, -NR2, -S(O)2R, -S(O)2NR2,-S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; each RBis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-12 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, 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 heterocyclic 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 nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; p is independently 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

35. The compound of any one of claims 1-34, wherein ring W is cyclohexyl.

36. The compound of any one of claims 1-35, wherein ring X is a phenylenyl.

37. The compound of any one of claims 1-36, wherein ring Y is a phenylenyl.

38. The compound of any one of claims 1-36, wherein rin .

39. The compound of any one of claims 1-36, wherein ring Y .

40. The compound of any one of claims 1-39, wherein one orlogen.

41. The compound of claim 40, wherein the halogen is fluoro.

42. The compound of any one of claims 1-41, wherein ring Z is a phenyl.

43. The compound of any one of claims 1-41, wherein ring Z is a cyclopropyl.

44. The compound of any one of claims 1-42, wherein one or more Rzis methyl.

45. The compound of any one of claims 1-42, wherein one or more Rzis ethyl.

46. The compound of claim 23 or 24, wherein said compound is a compound of any of the following formulae: , ,I-bb-2, , , ,I-bb-5 , ,I-bb-8- - or a pharmaceutically acceptable salt thereof.

47. The compound of claim 25 or 26, wherein said compound is a compound of any of the following formulae: ,I-cc-1 , , ,, , , , ,I-dd-4 ,I-cc'-1,or a pharmaceutically acceptable salt thereof.

48. The compound of claim 27 or 28, wherein said compound is a compound of any of the following formulae: , , ,I-ff-3, )z, , , ,I-ff'-4, ,or a pharmaceutically acceptable salt thereof.

49. The compound of claim 29, wherein said compound is a compound of any of the following formulae: , ,I-gg-3or a pharmaceutically acceptable salt thereof.

50. The compound of claim 30, wherein said compound is a compound of any of the following formulae:

51. The compound of claim 31, wherein said compound is a compound of any of the following formulae: ,I-ii-2, or a pharmaceutically accepta52. The compound of claim 32, wherein said compound is a compound of any of the following formulae: , or a pharmaceutically accept53. The compound of claim 33 or 34, wherein said compound is a compound of any of the following formulae: (Rw)w(Rx)x(Ry)y(Rz)z,, , ,or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 1-53, wherein said compound is a compound of any of the following formulae: , ,I-acc , , , ,I-aii, or pha55. The compound of any one of claims 1-54, wherein the AKT binding moiety is selected from , ,Cl , ,56. The compound of any one of claims 1-55, wherein the deubiquitinase binding moiety is selected from ,, , , , ,, , , , ,, , , , , ,, , , , , , ,, , , , , ,, , , , and57. The compound of any one of claims 1-56, wherein L is a covalent bond or a bivalent, saturated orpartially unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -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-.

58. The compound of claim 57, wherein L is -C(O)-CH2-Cy-CH2-Cy-.

59. The compound of claim 57, wherein L is -C(O)-CH2-Cy-O-Cy-.

60. The compound of claim 57, wherein L is -C(O)-CH2-Cy-.

61. The compound of claim 57, wherein L is -Cy-CH2-Cy-.

62. The compound of claim 57, wherein L is -Cy-O-Cy-.

63. The compound of any one of claims 1-62, wherein DBM is selected from those depicted in Table A.

64. The compound of any one of claims 1-62, wherein L is selected from those depicted in Table B.

65. The compound of any one of claims 1-62, wherein said compound is selected from any one of the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition comprising a compound of any one of claims 1-64, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

67. The pharmaceutical composition according to claim 65, further comprising an additional therapeutic agent.

68. A method of inhibiting AKT in a patient or biological sample comprising administering to said patient, or contacting said biological sample, with a compound according to any one of claims 1-64, or a pharmaceutical composition thereof.

69. A method of treating a AKT-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound according to any of one claims 1-64, or a pharmaceutical composition thereof.

70. The method of claim 69, wherein AKT-mediated disorder, disease, or condition is cancer.

71. The method of claim 70, wherein the cancer the cancer is characterized by amplification or overexpression of AKT.