IMIDAZO [1,5-a] PYRIDINE- 1,5-DIONES AS MNK INHIBITORS AND DEGRADERS

Abstract

The present disclosure provides imidazo[1,5-a]pyridine-1,5-diones useful as MNK degraders and inhibitors, fashioned as bifunctional compounds comprising a MNK protein binding moiety (inhibitor) conjugated through a linker to an E3 ligase ligand, designed to recruit the MNK protein to an E3 ubiquitin ligase for degradation. Further provided are methods for treating neuropathic pain utilizing the inventive bifunctional compounds, and compositions thereof.

Description

IMIDAZO [1,5-a] PYRIDINE- 1,5-DIONES AS MNK INHIBITORS AND DEGRADERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 664,977, filed June 27, 2024, the contents of which are herein incorporated by reference.STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under grant No. 1U44NS115692 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Inadequate treatment of pain is a devastating health problem in the United States. One third of all Americans suffer from some form of chronic pain and a third of these have pain that is resistant to current medical therapies. The economic impact of pain is equally large at approximately $100 billion annually. Opioid or narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance which requires escalating doses to achieve equivalent pain relief. Furthermore, opioids and narcotic analgesics are often ineffective for neuropathic pain treatment, and patients using these drugs often experience worse quality of life due to the resulting drug-induced sedation, reduced physical activity, constipation, respiratory depression, high potential for addiction, and other side effects.

[0004] Compounds that inhibit or degrade MNK are a promising alternative to opioid and narcotic analgesics for treatment of neuropathic pain and other indications. Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptor sensitization may be blocked by inhibiting activitydependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signals to the eukaryotic translation initiation factor (elF) 4E complex to regulate the sensitization of nociceptors. MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). Inhibition of MNK has been shown to disrupt the MAPK pathway, thereby decreasing sensitization of nociceptors, which may achieve a therapeutic effect on neuropathic pain.

[0005] The ubiquitin-proteasome system is crucial for regulating protein homeostasis in cells by degrading misfolded or abnormal proteins. As part of the ubiquitin-proteasome system, E3 ubiquitin ligase transfers a ubiquitin molecule to a target protein, thereby tagging the protein for degradation via the 26S proteasome. The ubiquitin-proteasome system can be taken advantage of for selective degradation of a protein of interest using bifunctional small molecules comprising a protein-binding moiety, which binds the protein of interest, and an E3 ubiquitin ligase-binding moiety, which recruits E3 ubiquitin ligase to the protein of interest, leading to its ubiquitination and subsequent degradation.SUMMARY

[0006] The present disclosure provides bifunctional compounds designed to recruit MNK protein to an E3 ubiquitin ligase for degradation, as well as compositions and methods of use thereof. The present disclosure also relates to chemical compounds that inhibit MKNK1 kinase (also known as MAP Kinase interacting Kinase, Mnkl) and MKNK2 kinase (also known as MAP Kinase interacting Kinase, Mnk2) and conjugates thereof.

[0007] In some embodiments, the present disclosure provides compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein MBM, L, and LBM are defined herein.

[0008] The present disclosure also provides compounds that are MNK inhibitors, as well as compositions and methods of use thereofDETAILED DESCRIPTIONCompounds and Definitions

[0009] Compounds of the present disclosure 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 disclosure, 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 organicchemistry 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.

[0010] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0011] Unless otherwise indicated, structures depicted herein are 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 replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure. In certain embodiments, isotopes that can be incorporated into compounds according to Formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, or iodine. Illustrative of such isotopes are2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35P,18F,36Cl,123I, and125I, respectively.

[0012] The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.

[0013] The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1- 10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH2-).

[0014] The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0015] The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0016] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0017] The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8hydrocarbon, or an optionally substituted C5-C10bicyclic 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. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon- carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0018] The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. 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 (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl. 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.

[0019] The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.

[0020] As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety or a 10- to 16-membered polycyclic (i.e., comprising three or more rings) moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as 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). 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, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3 -dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic or polycyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 6- to 11 -membered spirocyclic bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic or polycyclic heterocyclic ring can also be a bridged ring system (e.g., 6- to 11-membered bridged bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).

[0021] As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0022] As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0023] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0024] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4Rº; –(CH2)0–4ORº; -O(CH2)0–4Rº, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(ORº)2; –(CH2)0–4SRº; –(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(Rº)2; –(CH2)0–4N(Rº)C(O)Rº; –N(Rº)C(S)Rº; –(CH2)0–4N(Rº)C(O)NRº2; -N(Rº)C(S)NRº2; –(CH2)0–4N(Rº)C(O)ORº; – N(Rº)N(Rº)C(O)Rº; -N(Rº)N(Rº)C(O)NRº2; -N(Rº)N(Rº)C(O)ORº; –(CH2)0–4C(O)Rº; – C(S)Rº; –(CH2)0–4C(O)ORº; –(CH2)0–4C(O)SRº; -(CH2)0–4C(O)OSiRº3; –(CH2)0–4OC(O)Rº; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)Rº; –(CH2)0–4C(O)NRº2; –C(S)NRº2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NRº2; -C(O)N(ORº)Rº; –C(O)C(O)Rº; –C(O)CH2C(O)Rº; – C(NORº)Rº; -(CH2)0–4SSRº; –(CH2)0–4S(O)2Rº; –(CH2)0–4S(O)2ORº; –(CH2)0–4OS(O)2Rº; – S(O)2NRº2; -(CH2)0–4S(O)Rº; -N(Rº)S(O)2NRº2; –N(Rº)S(O)2Rº; –N(ORº)Rº; –C(NH)NRº2; – (CH2)0–4P(O)2Rº; –(CH2)0–4P(O)Rº2; –(CH2)0–4P(O)(ORº)2; –(CH2)0–4OP(O)Rº2; –(CH2)0–4OP(O)(ORº)2; SiRº3; –(C1–4straight or branched alkylene)O–N(Rº)2; or –(C1–4straight or branched alkylene)C(O)O–N(Rº)2, wherein each Rº may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –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 Rº, 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.

[0025] Suitable monovalent substituents on Rº (or the ring formed by taking two independent occurrences of Rº together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR●,–(C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – 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 Rº include =O and =S.

[0026] 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.

[0027] Suitable substituents on the aliphatic group of R* include halogen, –R●, -(haloR●), -OH, – OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of asubject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.MNK Binding Moiety (MBM)

[0031] As defined herein and described above, MBM is a protein binding moiety capable of binding MNK. In some embodiments, MBM binds or inhibits MKNK1 kinase (also known as MAP Kinase interacting Kinase, Mnkl). In some embodiments, MBM binds or inhibits MKNK2 kinase (also known as MAP Kinase interacting Kinase, Mnk2).

[0032] As defined herein and described below, wherein a formula is depicted using square brackets, e.g.,L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom within MBM including substitution or replacement of a defined group in MBM.

[0033] In some embodiments, the present invention provides a compound of formula I , whereinMBM is the MNK binding moietythereby forming a compound of formula I-a:or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described herein, and wherein:X1and X2are each independently a bond, -(CRxRx)p-, or -CRx=CRx-; Y is a covalent bond, -N(R)-, -CH2N(R)-, -N(R)CH2-, -C(O)N(R)-, -N(R)C(O)-, -SO2N(R)-, or - N(R)S(O)2-; Ring Y is a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring Z is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rvis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; Rwis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; each Rxis independently hydrogen, halogen, optionally substituted C1-6aliphatic, -N(R)C(O)R', or -N(R)S(O)2R', or two Rxare taken together to form a 3- to 7-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ryis independently halogen, -C(O)OR, -S(O)2R', or optionally substituted C1-6aliphatic; each Rzis independently halogen, -OR, -N(R)2, -N(R)C(O)(CH2)mR'', -N(R)C(S)(CH2)mR'', - N(R)C(O)N(R)R'', -C(O)R'', optionally substituted C1-6aliphatic, or optionally substituted C3-7carbocyclyl; LAis a covalent bond or an optionally substituted 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; each R'' is independently an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring, 3-to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; p is 1, 2, or 3; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, or 3.

[0034] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-1:or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-2:or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-3:or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-4:or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-5:or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-6:or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the present invention provides a compound of formula I-a, wherein the compound is a compound of formula I-a-7:or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the present invention provides a compound of formula I, whereinMBM is the MNK binding moiety, thereby forming a compound of formula I-b:or a pharmaceutically acceptable salt thereof, wherein: Y is a covalent bond, -N(R)-, -CH2N(R)-, -N(R)CH2-, -C(O)N(R)-, -N(R)C(O)-, -SO2N(R)-, or - N(R)S(O)2-; Ring Z is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ruis independently optionally substituted C1-6aliphatic, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two Ruare taken together to form an optionally substituted ring selected from a C3-7monocyclic carbocyclic ring, C4-10fused or bridged bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10- membered fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rvis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; Rwis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; each Rzis independently halogen, -OR, -N(R)2, -N(R)C(O)(CH2)mR'', -N(R)C(S)(CH2)mR'', - N(R)C(O)N(R)R'', -C(O)R'', optionally substituted C1-6aliphatic, or optionally substituted C3-7carbocyclyl; LAis a covalent bond or an optionally substituted 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; each R'' is independently an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; and z is 0, 1, 2, or 3.

[0042] In some embodiments, the present invention provides a compound of formula I-b, wherein the compound is a compound of formula I-b-1:or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present invention provides a compound of formula I-b, wherein the compound is a compound of formula I-b-2:or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the present invention provides a compound of formula I-b, wherein the compound is a compound of formula I-b-3:or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the present invention provides a compound of formula I-b, wherein the compound is a compound of formula I-b-4:or a pharmaceutically acceptable salt thereof.

[0046] As defined above and described herein, X1and X2are each independently a bond, - (CRxRx)p-, or -CRx=CRx-.

[0047] In some embodiments, X1is a bond. In some embodiments, X1is -(CRxRx)p-. In some embodiments, X1is -CRx=CRx-. In some embodiments, X2is a bond. In some embodiments, X2is -(CRxRx)n-. In some embodiments, X2is -CRx=CRx-.

[0048] In some embodiments, at least one of X1or X2is -(CRxRx)p-, or -CRx=CRx-. In some embodiments, at least one of X1or X2is -(CRxRx)p-. In some embodiments, at least one of X1or X2is -CRx=CRx-.

[0049] In some embodiments, X1and X2are -(CRxRx)p-, wherein p is 2. In some embodiments, X1and X2are -CH2CH2-.

[0050] In some embodiments, X1is selected from those depicted in Table 1 below.

[0051] In some embodiments, X2is selected from those depicted in Table 1 below.

[0052] As defined above and described herein, Y is a covalent bond, -N(R)-, -CH2N(R)-, - N(R)CH2-, -C(O)N(R)-, -N(R)C(O)-, -SO2N(R)-, or -N(R)S(O)2-.

[0053] In some embodiments, Y is a covalent bond. In some embodiments, Y is -N(R)-. In some embodiments, Y is -CH2N(R)-. In some embodiments, Y is -N(R)CH2-. In some embodiments, Y is -C(O)N(R)-. In some embodiments, Y is -N(R)C(O)-. In some embodiments, Y is -SO2N(R)-. In some embodiments, Y is -N(R)S(O)2-.

[0054] In some embodiments, Y is -NH-.

[0055] In some embodiments, Y is selected from those depicted in Table 1 below.

[0056] As defined above and described herein, Ring Y is a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0057] In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring Y is a 3- to 5-membered carbocyclic ring. In some embodiments, Ring Y is a 3- or 4-membered carbocyclic ring. In some embodiments, Ring Y is a 3- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 3- to 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 3- or 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0058] In some embodiments, Ring Y is cyclopropyl. In some embodiments, Ring Y is an aziridyl.

[0059] In some embodiments, Ring Y is selected from those depicted in Table 1 below.

[0060] As defined above and described herein, Ring Z is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0061] In some embodiments, Ring Z is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrimidine ring). In some embodiments, Ring Z is a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] In some embodiments, Ring Z is.

[0063] In some embodiments, Ring Z is selected from those depicted in Table 1 below.

[0064] As defined above and described herein, each Ru is independently optionally substituted C1-6aliphatic, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two Ruare taken together to form an optionally substituted ring selected from a C3-7monocyclic carbocyclic ring, C4-10fused or bridged bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, one or more Ru is an optionally substituted C1-6aliphatic. In some embodiments, one or more Ruis an optionally substituted phenyl. In some embodiments, one or more Ruis an optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments two Ruare taken together to form an optionally substituted C3-7monocyclic carbocyclic ring. In some embodiments two Ruare taken together to form an optionally substituted C4-10fused or bridged bicyclic carbocyclic ring. In some embodiments two Ruare taken together to form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments two Ruare taken together to form an optionally substituted 5- to 10-membered fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, one or more Ru is a C1-6aliphatic. In some embodiments, one or more Ruis a phenyl. In some embodiments, one or more Ruis a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments two Ruare taken together to form a C3-7monocyclic carbocyclic ring. In some embodiments two Ruare taken together to form a C4-10fused or bridged bicyclic carbocyclic ring. In some embodiments, two Ruare taken together to form a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments two Ruare taken together to form a 5- to 10-membered fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0067] In some embodiments, two Ru are taken together to form a cyclopentyl ring. In some embodiments, two Ruare taken together to form a cyclohexyl ring.

[0068] In some embodiments, Ru is selected from those depicted in Table 1 below.

[0069] As defined above and described herein, Rvis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl.

[0070] In some embodiments, Rvis optionally substituted C1-6alkyl or halogen. In some embodiments, Rvis hydrogen. In some embodiments, Rvis halogen. In some embodiments, Rvis cyano. In some embodiments, Rvis an optionally substituted C1-6aliphatic. In some embodiments, Rvis an optionally substituted C1-6alkyl. In some embodiments, Rvis an optionally substituted C3-6carbocyclyl. In some embodiments, Rvis a C1-6aliphatic. In some embodiments, Rvis a C1-6alkyl. In some embodiments, Rvis a C3-6carbocyclyl.

[0071] In some embodiments, Rvis methyl. In some embodiments, Rvis chloro. In some embodiments, Rvis CD3. In some embodiments, Rvis -CH2OH.

[0072] In some embodiments, Rvis selected from those depicted in Table 1 below.

[0073] As defined above and described herein, Rw is hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl.

[0074] In some embodiments, Rw is hydrogen. In some embodiments, Rw is halogen. In some embodiments, Rwis cyano. In some embodiments, Rwis an optionally substituted C1-6aliphatic. In some embodiments, Rwis an optionally substituted C1-6alkyl. In some embodiments, Rwis an optionally substituted C3-6carbocyclyl. In some embodiments, Rwis a C1-6aliphatic. In some embodiments, Rwis a C1-6alkyl. In some embodiments, Rwis a C3-6carbocyclyl.

[0075] In some embodiments, Rw is selected from those depicted in Table 1 below.

[0076] As defined above and described herein, each Rxis independently hydrogen, halogen, optionally substituted C1-6aliphatic, -N(R)C(O)R', or -N(R)S(O)2R', or two Rxare taken together to form a 3- to 7-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0077] In some embodiments, one or more Rxis hydrogen. In some embodiments, each Rxis hydrogen. In some embodiments, one or more Rxis halogen. In some embodiments, one or more Rxis an optionally substituted C1-6aliphatic. In some embodiments, one or more Rxis a C1-6aliphatic. In some embodiments, one or more Rxis -N(R)C(O)R'. In some embodiments, one or more Rxis -N(R)S(O)2R'. In some embodiments, two Rxare taken together to form a 3- to 7- membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, Rxis selected from those depicted in Table 1 below.

[0079] As defined above and described herein, each Ryis independently halogen, -C(O)OR, - S(O)2R', or optionally substituted C1-6aliphatic.

[0080] In some embodiments, one or more Ryis halogen. In some embodiments, one or more Ryis -C(O)OR. In some embodiments, one or more Ryis -S(O)2R'. In some embodiments, one or more Ryis an optionally substituted C1-6aliphatic. In some embodiments, one or more Ryis a C1-6aliphatic optionally substituted with -OH. In some embodiments, one or more Ryis a C1-6aliphatic.

[0081] In some embodiments, Ryis -CH2OH. In some embodiments, Ryis -C(O)OEt.

[0082] In some embodiments, Ryis selected from those depicted in Table 1 below.

[0083] As defined above and described herein, each Rzis independently halogen, -OR, -N(R)2, - N(R)C(O)(CH2)mR'', -N(R)C(S)(CH2)mR'', -N(R)C(O)N(R)R'', -C(O)R'', optionally substituted C1-6aliphatic, or optionally substituted C3-7carbocyclic.

[0084] In some embodiments, one or more Rzis halogen. In some embodiments, one or more Rzis -OR. In some embodiments, one or more Rzis -N(R)2. In some embodiments, one or more Rzis-N(H)R. In some embodiments, one or more Rz is -N(R)C(O)(CH2)mR''. In some embodiments,one or more Rzis -N(H)C(O)(CH2)mR''. In some embodiments, one or more Rzis - N(R)C(S)(CH2)mR''. In some embodiments, one or more Rzis -N(H)C(S)(CH2)mR''. In some embodiments, one or more Rzis -N(R)C(O)N(R)R''. In some embodiments, one or more Rzis - N(H)C(O)N(R)R''. In some embodiments, one or more Rzis -C(O)R''. In some embodiments, one or more Rzis an optionally substituted C1-6aliphatic. In some embodiments, one or more Rzis an optionally substituted C3-7carbocyclyl. In some embodiments, one or more Rzis a C1-6aliphatic. In some embodiments, one or more Rzis a C3-7carbocyclyl.

[0085] In some embodiments, Rzis -NH2.

[0086] In some embodiments, Rzis In some embodimentzs, R is

[0087] In some embodiments, Rzis selected from those depicted in Table 1 below.

[0088] As defined above and described herein, each R is independently hydrogen or an optionallysubstituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or optionally substituted C1-6aliphatic.

[0089] In some embodiments, one or more R is hydrogen. In some embodiments, one or more R is an optionally substituted C1-6aliphatic. In some embodiments, one or more R is an optionally substituted phenyl. In some embodiments, one or more R is an optionally substituted C3-7carbocyclic ring. In some embodiments, one or more R is an optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more R is an optionally substituted 3- to 7- membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, one or more R is a C1-6aliphatic. In some embodiments, one or more R is a phenyl. In some embodiments, one or more R is a C3-7carbocyclic ring. In some embodiments, one or more R is a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more Ris a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] In some embodiments, R is methyl. In some embodiments, R is ethyl.

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

[0093] As defined above and described herein, each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring.

[0094] In some embodiments, one or more R' is an optionally substituted C1-6aliphatic. In some embodiments, one or more R' is an optionally substituted C3-7carbocyclic ring.

[0095] In some embodiments, one or more R' is a C1-6aliphatic. In some embodiments, one or more R' is a C3-7carbocyclic ring.

[0096] In some embodiments, R' is selected from those depicted in Table 1 below.

[0097] As defined above and described herein, each R'' is independently an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, one or more R'' is an optionally substituted C1-6aliphatic. In some embodiments, one or more R'' is an optionally substituted C3-7monocyclic carbocyclic ring. In some embodiments, one or more R'' is an optionally substituted C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring. In some embodiments, one or more R'' is an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more R'' is an optionally substituted 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, one or more R'' is a C1-6aliphatic. In some embodiments, one or more R'' is a C3-7monocyclic carbocyclic ring (e.g., cyclopropyl). In some embodiments, one or more R'' is a C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring. In some embodiments, one or more R'' is a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more R''is a 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, R'' is selected from those depicted in Table 1 below.

[0101] As defined above and described herein, LAis a covalent bond or an optionally substituted 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-, -OC(O)NR-, or –NRC(O)O-.

[0102] In some embodiments, LAis a covalent bond. In some embodiments, LAis an optionally substituted 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-. 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-. In some embodiments, LAis an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-3hydrocarbon 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-. In some embodiments, LAis a bivalent, saturated or partially unsaturated, straight or branched C1-3hydrocarbon 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-.

[0103] In some embodiments, LAis -NH-. In some embodiments, LAis -O-. In some embodiments, LAis a -C(O)-.

[0104] In some embodiments, LAis selected from those depicted in Table 1 below.

[0105] As defined above and described herein, m is 0, 1, or 2.

[0106] In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0107] In some embodiments, m is selected from those depicted in Table 1 below.

[0108] As defined above and described herein, p is 1, 2, or 3.

[0109] In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0110] In some embodiments, p is selected from those depicted in Table 1 below.

[0111] As defined above and described herein, y is 0, 1, 2, 3, or 4.

[0112] In some embodiments, y is 0, 1, or 2. In some embodiments, y is 0 or 1. In some embodiments, y is 1 or 2. 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.

[0113] In some embodiments, y is selected from those depicted in Table 1 below.

[0114] As defined above and described herein, z is 0, 1, 2, or 3.

[0115] In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1. In some embodiments, z is 1 or 2. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0116] In some embodiments, z is selected from those depicted in Table 1 below.

[0117] In some embodiments, MBM IS

[0118] In some embodiments, MBM isIn some embodiments, MBM isIn some embodiments, MBM is

[0119] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moietythereby forming a compound of formula I-c:or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein: W1and W2are independently O, S or N-OR', where R' is lower alkyl; Y is -N(R5)-, -O-, -S-, -C(O)-, -S=O, -S(O)2-, or -CHR9-; R1is hydrogen, lower alkyl, cycloalkyl or heterocyclyl wherein any lower alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; n is 1, 2 or 3;R2and R3are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein any alkyl, aryl, aralkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, is optionally substituted with 1, 2 or 3 J groups; or R2and R3taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; R4aand R4bare each independently hydrogen, halogen, hydroxyl, thiol, hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl; R5is hydrogen, cyano, or lower alkyl; or R5and R8taken together with the atoms to which they are attached form a fused heterocyclyl optionally substituted with 1, 2 or 3 J groups; R6, R7and R8are each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; or R7and R8taken together with the atoms to which they are attached form a fused heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J groups; J is -SH, -SR9, -S(O)R9, -S(O)2R9, -S(O)NH2, -S(O)NR9R9, -NH2, -NR9R9, -COOH, -C(O)OR9, - C(O)R9, -C(O)-NH2, -C(O)-NR9R9, hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH2-C(O)- alkylene, NR9R9-C(O)-alkylene, -CHR9-C(O)-lower alkyl, -C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, -CHR9-C(O)-cycloalkyl, -C(O)-cycloalkyl, - CHR9-C(O)-aryl, -CHR9-aryl, -C(O)-aryl, -CHR9-C(O)-heterocycloalkyl, -C(O)- heterocycloalkyl, heterocyclylaminyl, or heterocyclyl; or any two J groups bound to the same carbon or hetero atom may be taken together to form oxo; andR9is hydrogen, lower alkyl or -OH, as defined and described in US9382248, the entirety of which is herein incorporated by reference.

[0120] In some embodiments, MBM isIn some

[0121] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moietythereby forming a compound of formula I-d:or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, pharmaceutically acceptable salt thereof, or a mixture of same, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein: A represents a group selected from:wherein one or more R3 substituents, independent from each other, is (are) present in any position of the A group; and wherein * indicates the point of attachment of said groups with the rest of the molecule; wherein one or more R3 substituents, independent from each other, is (are) present in any position of the A group; and wherein * indicates the point of attachment of said groups with the rest of the molecule; R1 represents a C1-C6-alkyl- group, said group being substituted with one or more -OH groups and optionally substituted with one or more substituents independently selected from: a halogen atom, a -CN, C1-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10- membered heterocycloalkyl-, aryl-, aryl- substituted with one or more R substituents, heteroaryl-, -C(=O)R', -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OR', -NH2, - NHR', -N(R')R'', -N(H)C(=O)H, -N(H)C(=O)R', -N(R')C(=O)H, -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, - N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', -N(H)C(=O)OR', -N(R')C(=O)OR', -N(H)S(=O)R', - N(R')S(=O)R', -N(H)S(=O)NH2, -N(H)S(=O)NHR', -N(H)S(=O)N(R')R'', -N(R')S(=O)NH2, - N(R')S(=O)NHR', -N(R')S(=O)N(R')R'', -N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', - OH, C1-C6-alkoxy-, -OC(=O)R', -OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, - S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', -S(=O)(=NR')R'', -S(=O)R', -S(=O)2R' group; R2 represents H; R3 represents a substituent selected from: a hydrogen atom, a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R', -C(=O)NH2, -C(=O)N(H)R', - C(=O)N(R')R'', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, - N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', - N(R')C(=O)N(R')R'', -N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', - N(R')S(=O)R', -N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-haloalkoxy-, - OC(=O)R', -SH, -S(=O)R', -S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', - S(=O)(=NR')R'' group; R4 represents a substituent selected from: a hydrogen atom, a halogen atom, a -CN, C1-C6-alkyl, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', - C(=O)OR', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, - N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', - N(R')C(=O)N(R')R'', -N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', - N(R')S(=O)R', -N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-alkoxy-, C1-C6- haloalkoxy-, -OC(=O)R', -OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl- S-, -S(=O)R', -S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', -S(=O)(=NR')R'' group; R represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OR', -NH2, -NHR', - N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', - N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', - N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', - OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, -S(=O)R', -S(=O)2R', -S(=O)2NH2, - S(=O)2NHR', -S(=O)2N(R')R'', -S(=O)(=NR')R''group; R' and R'' represent, independently from each other, a substituent selected from: C1-C6-alkyl-, C1- C6-haloalkyl-, as defined and described in US20140288069, the entirety of which is herein incorporated by reference. In some embodiments, MBM isIn some embodiments,

[0122] In certain embodiments, the present invention provides a compound of formula I, whereinMBM is the MNK binding moiety, thereby forming a compound of formula I-e;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, pharmaceutically acceptable salt thereof, or a mixture of same , wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein:represents a group selected from:wherein * indicates the point of attachment of said groups with the rest of the molecule; R1 represents a linear C1-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6- alkynyl-, C3-C10-cycloalkyl- ; aryl- optionally substituted one or more times, independently from each other, with an R substituent; aryl-C1-C6-alkyloxy- optionally substituted one or more times, independently from each other, with an R substituent; heteroaryl- optionally substituted one or more times, independently from each other, with an R substituent; -C(=O)NH2, - C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OH, -C(=O)OR', -NH2, -NHR', -N(R')R'', - N(H)C(=O)R', -N(R')C(=O)R', -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', - OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl-S- group; R2 represents a hydrogen atom; R3 represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R', -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', - NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', - N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', - N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', -SH, C1-C6-alkyl-S-, -S(=O)R', -S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', - S(=O)(=NR')R'' group; R4 represents a substituent selected from: a hydrogen atom, a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-optionally substituted one or more times, independently from each other, with an R substituent; heteroaryl- optionally substituted one or more times, independently from each other, with an R substituent; -C(=O)NH2, -C(=O)N(H)R', - C(=O)N(R')R'', -C(=O)OR', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, - N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', -N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, - N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1- C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', -OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl-S-, -S(=O)R', -S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', - S(=O)(=NR')R'' group; R represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C(=O)R', -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OR', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', - N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', - N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', - N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', - OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl-S-, -S(=O)R', -S(=O)2R', - S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', -S(=O)(=NR')R'' group; R' and R'' represent, independently from each other, a substituent selected from: a C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl group; R5 represents: either: a substituent selected from a C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl- , C2-C6-alkynyl-, C3-C10-cycloalkyl-, C3-C10-cycloalkyl-C1-C6-alkyl-, aryl-, -C(=O)NH2, - C(=O)N(H)R', -C(=O)N(R')R'', -S(=O)R', -S(=O)2R' group; or: together, with the nitrogen atom to which it is bound, and with a carbon atom of R1, form a 3- to 7-membered cyclic secondary amine group, which is optionally substituted with a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10- cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OH, -C(=O)OR', - NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)S(=O)R', -N(R')S(=O)R', - N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, - OC(=O)R', -OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl-S-, -S(=O)R', - S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'' group; n represents an integer of 0, 1, 2, 3, 4 or 5, as defined and described in US9409889, the entirety of which is herein incorporated by reference.

[0123] In some embodiments, MBM isIn some

[0124] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moietythereby forming a compound of formula I-f:or a stereoisomer, a tautomer, pharmaceutically acceptable salt thereof, or a mixture of same , wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein:represents a group selected from:wherein * indicates the point of attachment of said groups with the rest of the molecule; R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is optionally substituted with one or more substituents selected, independently from each other, from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalky-, 3- to 6-membered heterocycloalkyl which is connected as spiro; aryl- optionally substituted one or more times, independently from each other, with an R substituent; aryl-C1-C6-alkyloxy- optionally substituted one or more times, independently from each other, with an R substituent; heteroaryl- optionally substituted one or more times, independently from each other, with an R substituent; -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OH, - C(=O)OR', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -OH, C1-C6-alkoxy-, C1- C6-haloalkoxy-, -OC(=O)R', -OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6- alkyl-S- group; R2 represents a hydrogen atom; R3 represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R', -C(=O)NH2, -C(=O)N(H)R', -C(=O)N(R')R'', - NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', - N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', - N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-haloalkoxy-, C3-C6-cycloalkoxy-, C3-C6- cycloalkyl-C1-C3-alkoxy-, -OC(=O)R', -SH, -S(=O)R', -S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R'', -S(=O)(=NR')R'' group; R4 represents a substituent selected from: a hydrogen atom, a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl- optionally substituted one or more times, independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other, with an R substituent; -C(=O)NH2, -C(=O)N(H)R', - C(=O)N(R')R'', -C(=O)OR', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', - N(H)C(=O)-NH2, -N(H)C(=O)NHR', -N(H)C(=O)N(R')R'', -N(R')C(=O)-NH2, - N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', -N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, - N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1- C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', -OC(=O)-NH2, -OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl-S-, -S(=O)R', -S(=O)2R', -S(=O)2-NH2, -S(=O)2NHR', -S(=O)2N(R')R'', - S(=O)(=NR')R'' group; R represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C(=O)R', -C(=O)-NH2, -C(=O)N(H)R', -C(=O)N(R')R'', -C(=O)OR', -NH2, -NHR', -N(R')R'', -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)-NH2, -N(H)C(=O)NHR', - N(H)C(=O)N(R')R'', -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R'', - N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', - N(R')S(=O)2R', -N=S(=O)(R')R'', -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', - OC(=O)NH2,-OC(=O)NHR', -OC(=O)N(R')R'', -SH, C1-C6-alkyl-S-, -S(=O)R', -S(=O)2R', - S(=O)2-NH2, -S(=O)2NHR', -S(=O)2N(R')R'', -S(=O)(=NR')R'' group; R' and R'' represent, independently from each other, a substituent selected from: C1-C6-alkyl-, C1- C6-haloalkyl-; n represents an integer of 0, 1, 2 or 3, as defined and described in US9643974, the entirety of which is herein incorporated by reference.

[0125] In some embodiments, MBM isIn some embodiments, MBM isIn some embodiments, MBM is

[0126] In certain embodiments, the present invention provides a compound of formula I, whereinMBM is the MNK binding moiety thereby forming acompound of formula I-g:or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same , wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein: R1 represents a linear C2-C6-alkyl-, a linear C1-C6-alkyl-O-linear C1-C6-alkyl-, a branched C3-C6- alkyl-, a C3-C6-cycloalkyl, a linear C1-C6-alkyl-C3-C6-cycloalkyl- or a C3-C6-cycloalkyl-linear C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6- haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, heteroaryl- which is optionally substituted one or more times independently from each other with R, -C(=O)NH2, -C(=O)N(H)R',-C(=O)N(R')R", - C(=O)OH, -C(=O)OR', - NH2, -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(=O)R', - N(H)S(=O)R', -N(R')S(=O)R', - N(H)S(=O)2R', -N(R')S(=O)2R', -N=S(=O)(R')R", -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, - OC(=O)R', -OC(=O)NH2, -OC(=O)NHR', - OC(=O)N(R')R", -SH, d-Ce-alkyl-S-, -S(=O)R', - S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', - S(=O)2N(R')R" group ;represents agroup; wherein * indicates the point of attachment of said group with the rest of the molecule ; and R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl- , C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R', -C(=O)NH2, -C(=O)N(H)R',-C(=O)N(R')R", - NH2, -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", - N(H)C(=O)OR', - N(R')C(=O)OR', -N02, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', - N(R')S(=O)2R', - N=S(=O)(R')R", -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', -SH, C1-C6-alkyl- S-, -S(=O)R', -S(=O)2R', -S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R", - S(=O)(=NR')R" group; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, - C(=O)R', -C(=O)NH2, -C(=O)N(H)R',-C(=O)N(R')R", -C(=O)OR', -NH2, -NHR', - N(R')R", -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH2, -N(H)C(=O)NHR', - N(H)C(=O)N(R')R", -N(R')C(=O)NH2, -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", - N(H)C(=O)OR', -N(R')C(=O)OR', -NO2, -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O)2R', - N(R')S(=O)2R', -N=S(=O)(R')R", -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R', - OC(=O)NH2, -OC(=O)NHR', -OC(=O)N(R')R", -SH, C1-C6-alkyl-S-, -S(=O)R', -S(=O)2R', - S(=O)2NH2, -S(=O)2NHR', -S(=O)2N(R')R", - S(=O)(=NR')R"group ; R' and R" represent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1- C6-haloalkyl- ; n represents an integer of 0, 1 , 2, 3, 4 or 5, as defined and described in WO2013034570, the entirety of which is herein incorporated by reference.

[0127] In some embodiments, MBM isIn some

[0128] In certain embodiments, the present invention provides a compound of formula I, whereinMBM is the MNK binding moiety, thereby forming a compound of formula I-h:or pharmaceutically acceptable salt and prodrug thereof, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein: R1is H or C1-C4alkyl, wherein said C1-C4alkyl group can be optionally substituted with up to two groups, each independently selected from -OH, F, -OP(O)(OH)2and -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl moiety of said -OC(O)(C1-C6alkyl) substituent group can be optionally substituted with up to 2 groups, each independently selected from -N(R5)2, -C(O)N(R5)2and - S-(C1-C3alkyl); R2is H or -(C1-C3alkylene)-R4; R3represents up to 2 optional phenyl ring substituents, which are each independently selected from halo; R4is selected from -OH, -SH, -S-(C1-C3alkyl), -SO2(C1-C3alkyl) and - OP(O)(OH)2; and each occurrence of R5is H or C1-C6alkyl, or two R5groups that are attached to the same nitrogen atom, together with the common nitrogen atom to which they are attached, join to form a 4 to 7-membered heterocycloalkyl group, as defined and described in WO2014018449, the entirety of which is herein incorporated by reference.

[0129] In some embodiments, MBM isIn some embodiments, MBM is

[0130] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moiety, thereby forming a compound of formula I-i:or pharmaceutically acceptable salt or prodrug thereof, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, and wherein: X1, X2, and X3are independently N or C; X4and X5are independently N or CR4; wherein at least one of X1; X2, X3, X4, and X5is N; X7is N or CH; X8, is N or CH; is a single or double bond, as valency allows; R1is -C(O)R, wherein R is an optionally substituted heterocyclyl; R2, R3are independently -H, -F, -Cl, -CN, -CH3, -CF3, -CHF2, -C(O)NH2, OH, OC1-4alkyl, or-OCF3R7is -H, -F, -Cl,- CN, -CH3, -CF3, -CHF2, -OH, -OC1-4alkyl, or -OCF3; R6is hydrogen, or R6and R7are taken together to form a 5-6 membered fused heterocyclyl or 5- 6 membered fused heteroaryl; and each R4is independently hydrogen or C1-6alkyl, as defined and described in US9908886, the entirety of which is herein incorporated by reference.

[0131] In some embodiments, MBM is

[0132] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moiety, thereby forming a compound of formula I-j:or pharmaceutically acceptable salt thereof, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, as defined and described in Yang et. al. "Discovery of P11-2: A Potent First-in-Class MNK1-Targeting PROTAC Degrader for the Treatment of Cancer" J. Med. Chem.2025, 68, 10, 10092-10110, the entirety of which is herein incorporated by reference.

[0133] In some embodiments, when MBM is wherein LA, is as defined above and described in embodiments herein, the compound is not of the formula:, wherein n is 0, 1, 2, or 3.

[0134] In some embodiments, when MBM is wherein LA, is as defined above and described in embodiments herein, the compound is not of the formula:, wherein m is 0, 1, or 2.

[0135] In some embodiments, when MBM iswherein LA, is as defined above and described in embodiments herein, the compound is not of the formula:, wherein n is 0, 1, 2, 3 or 4.

[0136] In some embodiments, when MBM iswherein LA, is as defined above and described in embodiments herein, the compound is not of the formula:, wherein m is 0, 1, 2, 3, 4, or 5.

[0137] In some embodiments, when MBM is wherein LA, is as defined above and described in embodiments herein, the compound is not of the formula:, wherein:.

[0138] In some embodiments, when MBM is , wherein LA, is as defined above and described in embodiments herein, the compound is not:.

[0139] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moiety, thereby forming a compound of formula I-k:or pharmaceutically acceptable salt thereof, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, wherein: R1is -H, -F, or CN; R2isas defined and described in Jin et. al. "Using Imidazo[2,1-b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors" ACS Med Chem Lett.2022, 14, 1, 83-91, the entirety of which is herein incorporated by reference.

[0140] In certain embodiments, the present invention provides a compound of formula I, wherein MBM is the MNK binding moiety, thereby forming a compound of formula I-l:or pharmaceutically acceptable salt thereof, wherein LA, L and LBM are as defined above and described in embodiments herein, both singly and in combination, wherein:as defined and described in Jin et. al. "Using Imidazo[2,1-b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors" ACS Med Chem Lett.2022, 14, 1, 83-91, the entirety of which is herein incorporated by reference. Ligase Binding Moiety (LBM)

[0141] In some embodiments, LBM is an E3 ligase ligand well-known to one of ordinary skill in the art including those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO 2017 / 176708, US2017 / 0281784, WO 2017 / 161119, WO 2017 / 176957, WO 2017 / 176958, WO 2015 / 160845, US2015 / 0291562, WO 2016 / 197032, WO 2016 / 105518, US 2018 / 0009779, WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO2017 / 197036, US 2019 / 0076540, WO 2017 / 197046, US 2019 / 0076542, WO 2017 / 197051, US2019 / 0076539, WO 2017 / 197055, US 2019 / 0076541, and WO 2017 / 197056, the entirety of each of which is herein incorporated by reference.

[0142] As defined herein and described below, wherein a formula is depicted using square brackets, e.g.,, L is attached to a modifiable carbon, oxygen, or nitrogen atom within LBM including substitution or replacement of a defined group in LBM.

[0143] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is the cereblon E3 ubiquitin ligase binding moiety, thereby forming a compound of formula I-aa:or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rais independently oxo, halogen, optionally substituted C1-6aliphatic, -CN, -NO2, -ORaa, - SRaa, -N(Raa)2, -S(O)2Raa, -S(O)2N(Raa)2, -S(O)Raa, -C(O)Raa, -C(O)ORaa, -C(O)N(Raa)2, -C(O)N(Raa)ORaa, - C(Raa)2N(Raa)C(O)Raa, -C(Raa)2N(Raa)C(O)N(Raa)2, -OC(O)Raa, -OC(O)N(Raa)2, -N(Raa)C(O)ORaa, -N(R)C(O)Raa, -N(Raa)C(O)N(Raa)2, -N(Raa)S(O)2Raa, or –N(Raa)S(O)2Raa; 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 R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Raais independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, a 3- to 7-membered heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two Raagroups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0-1 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and a' is 0, 1, 2, 3 or 4.

[0144] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is the VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I- bb:or a pharmaceutically acceptable salt thereof, wherein: each R1is independently hydrogen, -C(O)R', or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; each R3is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; R4is hydrogen, halogen, or optionally substituted C1-6aliphatic;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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; and a is 0, 1, 2, 3, or 4.

[0145] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is the IAP / SMAC binding moietiesor, thereby forming a compound of formula I-cc or I-cc', respectively:or a pharmaceutically acceptable salt thereof, wherein: R5is optionally substituted C1-6aliphatic; R6is optionally substituted C1-6aliphatic; R7is an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, or a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R8is independently halogen or optionally substituted C1-6aliphatic, or two R8groups are taken together to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R7and an R8group are taken together to form an optionally substituted 7- to 8-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R9is Cy2or -C(O)N(R)Cy2; 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-; Cy2is an optionally substituted ring selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C3-7monocyclic carbocyclic ring, C4-10bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; b is 1 or 2; and c is 0, 1, 2, 3, or 4.

[0146] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is the IAP / SMAC binding moietiesthereby forming a compound of formula I-ddor I-dd', respectively:or a pharmaceutically acceptable salt thereof, wherein: R10is -OR or -N(R)2; R11is optionally substituted C1-6aliphatic; each R12is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; andd is 0, 1, 2, 3, 4, or 5.

[0147] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is the IAP / SMAC binding moiety, thereby forming a compound of formula I-ee:or a pharmaceutically acceptable salt thereof, wherein: Ring B is an optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R13is hydrogen or optionally substituted C1-6aliphatic; each R14and R15is independently optionally substituted C1-6aliphatic; each R16is independently hydrogen or optionally substituted C1-6aliphatic; each R17is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-;each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; e is 0, 1, 2, 3, 4, 5, or 6; f is 0, 1, 2, 3, 4, 5, or 6; and g is 01, 2, 3, 4, or 5.

[0148] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is the MDM2 binding moietiesorthereby forming a compound of formula I-ff or I- ff', respectively:or a pharmaceutically acceptable salt thereof, wherein: R18is hydrogen or optionally substituted C1-6aliphatic; each R19is independently optionally substituted C1-6aliphatic, or two R19are taken together to form an oxo; each R20, R21, and R22is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; h is 0, 1, 2, 3, 4, 5, or 6; and i, j, and k are each independently 0, 1, 2, 3, 4, or 5.

[0149] As defined above and described herein, Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0150] In some embodiments, Ring A is an optionally substituted phenyl. In some embodiments, Ring A is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0151] In some embodiments, Ring A is phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a phenyl. In some embodiments, Ring A is a 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0152] In some embodiments, Ring A isIn some embodiments, Ring A is

[0153] In some embodiments, Ring A is

[0154] In some embodiments, Ring A isIn some embodiments, Ring A is

[0155] In some embodiments, Ring A is selected from those depicted in Table 1 below.

[0156] As defined above and described herein, Ring B is an optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0157] In some embodiments, Ring B is an optionally substituted phenyl. In some embodiments, Ring B is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0158] In some embodiments, Ring B is a phenyl. In some embodiments, Ring B is a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0159] In some embodiments, Ring B is pyridyl or pyridonyl. In some embodiments, Ring B is pyridyl. In some embodiments, Ring B is pyridonyl.

[0160] In some embodiments,In some embodiments,

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

[0162] As defined above and described herein, each Ra is independently oxo, halogen, optionally substituted C1-6aliphatic, -CN, -NO2, -ORaa, -SRaa, -N(Raa)2, -S(O)2Raa, - S(O)2N(Raa)2,-S(O)Raa, -C(O)Raa, -C(O)ORaa, -C(O)N(Raa)2, -C(O)N(R)ORaa, - C(Raa)2N(Raa)C(O)Raa, -C(Raa)2N(Raa)C(O)N(Raa)2, -OC(O)Raa, -OC(O)N(Raa)2, - N(Raa)C(O)ORaa, -N(Raa)C(O)Raa, -N(Raa)C(O)N(Raa)2, -N(Raa)S(O)2Raa, or –N(Raa)S(O)2Raa.

[0163] In some embodiments, one or more Ra is oxo. In some embodiments, one or more Ra is halogen. In some embodiments, one or more Rais optionally substituted C1-6aliphatic. In some embodiments, one or more Rais -CN. In some embodiments, one or more Rais -NO2. In some embodiments, one or more Rais -ORaa. In some embodiments, one or more Rais -SRaa. In some embodiments, one or more Rais -N(Raa)2. In some embodiments, one or more Rais -S(O)2Raa. In some embodiments, one or more Rais -S(O)2N(Raa)2. In some embodiments, one or more Rais -S(O)Raa. In some embodiments, one or more Rais -C(O)Raa. In some embodiments, one or more Rais -C(O)ORaa. In some embodiments, one or more Rais -C(O)N(Raa)2. In some embodiments, one or more Rais -C(O)N(Raa)ORaa. In some embodiments, one or more Rais - C(Raa)2N(Raa)C(O)Raa. In some embodiments, one or more Rais -C(Raa)2N(Raa)C(O)N(Raa)2. In some embodiments, one or more Rais -OC(O)Raa. In some embodiments, one or more Rais -OC(O)N(Raa)2, -N(Raa)C(O)ORaa. In some embodiments, one or more Rais -N(Raa)C(O)Raa. In some embodiments, one or more Rais -N(Raa)C(O)N(Raa)2. In some embodiments, one or more Rais -N(Raa)S(O)2Raa. In some embodiments, one or more Rais –N(Raa)S(O)2Raa.

[0164] In some embodiments, Ra is selected from those depicted in Table 1 below.

[0165] As defined above and described herein, each Raais independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, a 3- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Raagroups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0-1 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0166] In some embodiments, each Raais independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, one or more Raais hydrogen. In some embodiments, one or more Raais optionally substituted C1-6aliphatic. In some embodiments, one or more Raais optionally substituted phenyl. In some embodiments, one or more Raais an optionally substituted C3-7carbocyclic ring. In some embodiments, one or more Raais an optionally substituted 3- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more Raais an optionally substituted 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Raagroups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- to 7- membered saturated, partially unsaturated, or heteroaryl ring having 0-1 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0167] As defined above and described herein, each R1is independently hydrogen, -C(O)R', or optionally substituted C1-6aliphatic.

[0168] In some embodiments, one or more of R1is hydrogen. In some embodiments, one or more of R1is -C(O)R'. In some embodiments, one or more of R1is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R1is a C1-6aliphatic.

[0169] In some embodiments, R1is selected from those depicted in Table 1 below.

[0170] As defined above and described herein, R2is optionally substituted C1-6aliphatic.

[0171] In some embodiments, R2is optionally substituted C1-6alkyl. In some embodiments, R2is a C1-6aliphatic.

[0172] In some embodiments, R2is t-butyl.

[0173] In some embodiments, R2is selected from those depicted in Table 1 below.

[0174] As defined above and described herein, each R3is independently halogen, -CN, -C(O)R', - C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic.

[0175] In some embodiments, one or more of R3is halogen. In some embodiments, one or more of R3is -CN. In some embodiments, one or more of R3is -C(O)R'. In some embodiments, one or more of R3is -C(O)N(R)2. In some embodiments, one or more of R3is -OR. In some embodiments, one or more of R3is -N(R)2. In some embodiments, one or more of R3is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R3is a C1-6aliphatic.

[0176] In some embodiments, R3is selected from those depicted in Table 1 below.

[0177] As defined above and described herein, R4is hydrogen, halogen, or optionally substituted C1-6aliphatic.

[0178] In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments, R4is an optionally substituted C1-6aliphatic. In some embodiments, R4is a C1-6aliphatic (e.g., methyl).

[0179] In some embodiments, R4is selected from those depicted in Table 1 below.

[0180] As defined above and described herein, R5is an optionally substituted C1-6aliphatic.

[0181] In some embodiments, R5is an optionally substituted C1-6alkyl. In some embodiments, R5is a C1-6aliphatic (e.g., methyl).

[0182] In some embodiments, R5is selected from those depicted in Table 1 below.

[0183] As defined above and described herein, R6is optionally substituted C1-6aliphatic.

[0184] In some embodiments, R6is optionally substituted C1-6alkyl. In some embodiments, R6is a C1-6aliphatic (e.g., methyl).

[0185] In some embodiments, R6is selected from those depicted in Table 1 below.

[0186] As defined above and described herein, R7is an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, or a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0187] In some embodiments, R7is an optionally substituted C1-6aliphatic. In some embodiments, R7is an optionally substituted C3-7monocyclic carbocyclic ring. In some embodiments, R7is an optionally substituted a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, R7is a C1-6aliphatic. In some embodiments, R7is a C3-7monocyclic carbocyclic ring. In some embodiments, R7is a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0189] In some embodiments, R7is t-butyl. In some embodiments, R7isIn some embodiments, R7is

[0190] In some embodiments, R7is selected from those depicted in Table 1 below.

[0191] As defined above and described herein, each R8is independently halogen or optionally substituted C1-6aliphatic, or two R8groups are taken together to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R7and an R8group are taken together to form an optionally substituted 7- to 8-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0192] In some embodiments, one or more of R8is halogen. In some embodiments, one or more of R8is an optionally substituted C1-6aliphatic. In some embodiments, two R8groups are taken together to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R8groups are taken together to form an optionally substituted phenyl. In some embodiments, two R8groups are taken together to form an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7and an R8group are taken together to form an optionally substituted 7- to 8- membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0193] In some embodiments, one or more of R8is a C1-6aliphatic. In some embodiments, two R8groups are taken together to form a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R8groups are taken together to form a phenyl. In some embodiments, two R8groups are taken together to form a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R7and an R8group are taken together to form a 7- to 8-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0194] In some embodiments, R7and an R8group are taken together to form an optionally substituted 1,5-diazocane ring. In some embodiments, R7and an R8group are taken together to form a 1,5-diazocane ring.

[0195] In some embodiments, R8is selected from those depicted in Table 1 below.

[0196] As defined above and described herein, R9is Cy2or -C(O)N(R)Cy2.

[0197] In some embodiments, R9is Cy2. In some embodiments, R9is -C(O)N(R)Cy2. In some embodiments, R9is -C(O)N(H)Cy2.

[0198] In some embodiments, R9is In s9ome embodiments, R is In so9me embodiments, R is

[0199] In some embodiments, R9is selected from those depicted in Table 1 below.

[0200] As defined above and described herein, R10is -OR or -N(R)2.

[0201] In some embodiments, R10is -OR. In some embodiments, R10is -N(R)2.

[0202] In some embodiments, R10is -OMe.

[0203] In some embodiments, R10is selected from those depicted in Table 1 below.

[0204] As defined above and described herein, R11is optionally substituted C1-6aliphatic.

[0205] In some embodiments, R11is optionally substituted C1-6alkyl. In some embodiments, R11is C1-6aliphatic.

[0206] In some embodiments, R11is i-Pr. In some embodiments, R11is -CH2C(H)(CH3)2.

[0207] In some embodiments, R11is selected from those depicted in Table 1 below.

[0208] As defined above and described herein, each R12is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic.

[0209] In some embodiments, one or more of R12is halogen. In some embodiments, one or more of R12is -CN. In some embodiments, one or more of R12is -C(O)R'. In some embodiments, oneor more of R12is -C(O)N(R)2. In some embodiments, one or more of R12is -OR. In some embodiments, one or more of R12is -N(R)2. In some embodiments, one or more of R12is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R12is a C1-6aliphatic.

[0210] In some embodiments, R12is selected from those depicted in Table 1 below.

[0211] As defined above and described herein, R13is hydrogen or optionally substituted C1-6aliphatic.

[0212] In some embodiments, R13is hydrogen. In some embodiments, R13is an optionally substituted C1-6aliphatic. In some embodiments, R13is a C1-6aliphatic.

[0213] In some embodiments, R13is selected from those depicted in Table 1 below.

[0214] As defined above and described herein, each R14and R15is independently optionally substituted C1-6aliphatic.

[0215] In some embodiments, one or more of R14is an optionally substituted C1-6alkyl. In some embodiments, one or more of R14is a C1-6aliphatic. In some embodiments, one or more R14is methyl.

[0216] In some embodiments, R14is selected from those depicted in Table 1 below.

[0217] In some embodiments, one or more of R15is an optionally substituted C1-6alkyl. In some embodiments, one or more of R15is a C1-6aliphatic. In some embodiments, one or more R15is methyl.

[0218] In some embodiments, R15is selected from those depicted in Table 1 below.

[0219] As defined above and described herein, each R16is independently hydrogen or optionally substituted C1-6aliphatic.

[0220] In some embodiments, one or more of R16is hydrogen. In some embodiments, one or more of R16is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R16is a C1-6aliphatic. In some embodiments, each R16is an optionally substituted C1-6aliphatic (e.g., methyl).

[0221] In some embodiments, R16is selected from those depicted in Table 1 below.

[0222] As defined above and described herein, each R17is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic.

[0223] In some embodiments, one or more of R17is halogen. In some embodiments, one or more of R17is -CN. In some embodiments, one or more of R17is -C(O)R'. In some embodiments, one or more of R17is -C(O)N(R)2. In some embodiments, one or more of R17is -OR. In someembodiments, one or more of R17is -N(R)2. In some embodiments, one or more of R17is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R17is a C1-6aliphatic.

[0224] In some embodiments, one or more of R17is fluoro.

[0225] In some embodiments, R17is selected from those depicted in Table 1 below.

[0226] As defined above and described herein, R18is hydrogen or optionally substituted C1-6aliphatic.

[0227] In some embodiments, R18is hydrogen. In some embodiments, R18is an optionally substituted C1-6aliphatic. In some embodiments, R18is a C1-6aliphatic.

[0228] In some embodiments, R18is selected from those depicted in Table 1 below.

[0229] As defined above and described herein, each R19is independently optionally substituted C1-6aliphatic, or two R19are taken together to form an oxo.

[0230] In some embodiments, one or more of R19is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R19is a C1-6aliphatic. In some embodiments, two R19are taken together to form an oxo.

[0231] In some embodiments, R19is selected from those depicted in Table 1 below.

[0232] As defined above and described herein, each R20, R21, and R22is independently halogen, - CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic.

[0233] In some embodiments, one or more of R20is halogen. In some embodiments, one or more of R20is -CN. In some embodiments, one or more of R20is -C(O)R'. In some embodiments, one or more of R20is -C(O)N(R)2. In some embodiments, one or more of R20is -OR. In some embodiments, one or more of R20is -N(R)2. In some embodiments, one or more of R20is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R20is a C1-6aliphatic.

[0234] In some embodiments, one or more of R20is -O(C1-6alkyl). In some embodiments, one or more of R20is -OMe. In some embodiments, one or more of R20is -O(i-Pr).

[0235] In some embodiments, R20is selected from those depicted in Table 1 below.

[0236] In some embodiments, one or more of R21is halogen. In some embodiments, one or more of R21is -CN. In some embodiments, one or more of R21is -C(O)R'. In some embodiments, one or more of R21is -C(O)N(R)2. In some embodiments, one or more of R21is -OR. In some embodiments, one or more of R21is -N(R)2. In some embodiments, one or more of R21is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R21is a C1-6aliphatic.

[0237] In some embodiments, one or more of R21is chloro.

[0238] In some embodiments, R21is selected from those depicted in Table 1 below.

[0239] In some embodiments, one or more of R22is halogen. In some embodiments, one or more of R22is -CN. In some embodiments, one or more of R22is -C(O)R'. In some embodiments, one or more of R22is -C(O)N(R)2. In some embodiments, one or more of R22is -OR. In some embodiments, one or more of R22is -N(R)2. In some embodiments, one or more of R22is an optionally substituted C1-6aliphatic. In some embodiments, one or more of R22is a C1-6aliphatic.

[0240] In some embodiments, one or more of R22is chloro.

[0241] In some embodiments, R22is selected from those depicted in Table 1 below.

[0242] As defined above and described herein, Cy2is an optionally substituted ring selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C3-7monocyclic carbocyclic ring, C4-10bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0243] In some embodiments, Cy2is an optionally substituted phenyl. In some embodiments, Cy2is an optionally substituted 9- to 10-membered bicyclic aryl ring. In some embodiments, Cy2is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted 9- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted C3-7monocyclic carbocyclic ring. In some embodiments, Cy2is an optionally substituted C4-10bicyclic carbocyclic ring. In some embodiments, Cy2is an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted 5- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0244] In some embodiments, Cy2is a phenyl. In some embodiments, Cy2is a 9- to 10-membered bicyclic aryl ring. In some embodiments, Cy2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is a 9- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is a C3-7monocyclic carbocyclic ring. In some embodiments, Cy2is a C4-10bicyclic carbocyclic ring. In some embodiments, Cy2is a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is a 5- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0245] In some embodiments, Cy2is In some embodiments, C2y is In some embodiments, C2y is

[0246] In some embodiments, Cy2is selected from those depicted in Table 1 below.

[0247] As defined above and described herein, a' is 0, 1, 2, 3, or 4.

[0248] In some embodiments, a' is 0 or 1. In some embodiments, a' is 1 or 2. 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.

[0249] In some embodiments, a' is selected from those depicted in Table 1 below.

[0250] As defined above and described herein, a is 0, 1, 2, 3, or 4.

[0251] In some embodiments, a is 0 or 1. In some embodiments, a is 1 or 2. 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.

[0252] In some embodiments, a is selected from those depicted in Table 1 below.

[0253] As defined above and described herein, b is 1 or 2.

[0254] In some embodiments, b is 1. In some embodiments, b is 2.

[0255] In some embodiments, b is selected from those depicted in Table 1 below.

[0256] As defined above and described herein, LB is a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-5hydrocarbon chain, wherein0-3 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-, -OC(O)NR-, or –NRC(O)O-.

[0257] In some embodiments, LB is a covalent bond. In some embodiments, LB is an optionally substituted 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-.In some embodiments, LBis 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-. In some embodiments, LBis an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-3hydrocarbon 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-. In some embodiments, LBis a bivalent, saturated or partially unsaturated, straight or branched C1-3hydrocarbon 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-.

[0258] In some embodiments, LB is -NH-. In some embodiments, LB is -O-. In some embodiments, LBis a -C(O)-.

[0259] In some embodiments, LB is selected from those depicted in Table 1 below.

[0260] As defined above and described herein, c is 0, 1, 2, 3, or 4.

[0261] In some embodiments, c is 0 or 1. In some embodiments, c is 1 or 2. 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.

[0262] In some embodiments, c is selected from those depicted in Table 1 below.

[0263] As defined above and described herein, d is 0, 1, 2, 3, 4, or 5.

[0264] In some embodiments, d is 0 or 1. In some embodiments, d is 1 or 2. 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. In some embodiments, d is 5.

[0265] In some embodiments, d is selected from those depicted in Table 1 below.

[0266] As defined above and described herein, e is 0, 1, 2, 3, 4, 5, or 6.

[0267] In some embodiments, e is 0 or 1 . In some embodiments, e is 1 or 2. In some embodiments, e is 0. In some embodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, e is 4. In some embodiments, e is 5. In some embodiments, e is 6.

[0268] In some embodiments, e is selected from those depicted in Table 1 below.

[0269] As defined above and described herein, f is 0, 1, 2, 3, 4, 5, or 6.

[0270] In some embodiments, f is 0 or 1. In some embodiments, f is 1 or 2. In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3. In some embodiments, f is 4. In some embodiments, f is 5. In some embodiments, f is 6.

[0271] In some embodiments, f is selected from those depicted in Table 1 below.

[0272] As defined above and described herein, g is 0 1, 2, 3, 4, or 5.

[0273] In some embodiments, g is 0 or 1. In some embodiments, g is 1 or 2. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5.

[0274] In some embodiments, g is selected from those depicted in Table 1 below.

[0275] As defined above and described herein, h is 0, 1, 2, 3, 4, 5, or 6.

[0276] In some embodiments, h is 0 or 1. In some embodiments, h is 1 or 2. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4. In some embodiments, h is 5. In some embodiments, h is 6.

[0277] In some embodiments, h is selected from those depicted in Table 1 below.

[0278] As defined above and described herein, i, j, and k are each independently 0, 1, 2, 3, 4, or 5.

[0279] In some embodiments, i is 0 or 1. In some embodiments, i is 1 or 2. In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, i is 2. In some embodiments, i is 3. In some embodiments, i is 4. In some embodiments, i is 5.

[0280] In some embodiments, i is selected from those depicted in Table 1 below.

[0281] In some embodiments, j is 0 or 1. In some embodiments, j is 1 or 2. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, j is 2. In some embodiments, j is 3. In some embodiments, j is 4. In some embodiments, j is 5.

[0282] In some embodiments, j is selected from those depicted in Table 1 below.

[0283] In some embodiments, k is 0 or 1. In some embodiments, k is 1 or 2. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5.

[0284] In some embodiments, k is selected from those depicted in Table 1 below.

[0285] In some embodiments, LBM isIn some embodiments, LBM is .

[0286] In some embodiments, LBM is,

[0287] In some embodiments, LBM isIn some embodiments, LBM

[0288] In some embodiments, LBM is. In some embodiments, LBM is

[0289] In some embodiments, LBM is

[0290] In some embodiments, LBM isIn some embodiments, LBM

[0291] In some embodiments, LBM is

[0292] In some embodiments, LBM isIn some embodiments, LBM

[0293] In some embodiments, LBM isIn some embodiments, LBM

[0294] In some embodiments, LBM isIn some embodiments,LBM isIn some embodiments, LBM isIn some embodiments, LBM is

[0295] In some embodiments, LBM is

[0296] In some embodiments, LBM is

[0297] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-aaa:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, Ring A, Ra, LB, a', and L is as defined above and described in embodiments herein, both singly and in combination.

[0298] In some embodiments, the present invention provides the compound of formula I-aaa wherein Ring A isto provide a compound of formula I-aaa-1:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, Ra, LB, a', and L is as defined above and described in embodiments herein, both singly and in combination.

[0299] In some embodiments, the present invention provides the compound of formula I-aaa wherein Ring A isto provide a compound of formula I-aaa-2:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, Ra, LB, a', and L is as defined above and described in embodiments herein, both singly and in combination.

[0300] In some embodiments, the present invention provides the compound of formula I-aaa wherein Ring A isto provide a compound of formula I-aaa-3:or a pharmaceutically acceptable salt thereof, wherein: Rvis an optionally substituted C1-6aliphatic or halogen; X3is -NH- or -O-; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0301] In some embodiments, the present invention provides the compound of formula I-aaa wherein Ring A isto provide a compound of formula I-aaa-4:or a pharmaceutically acceptable salt thereof, wherein: Rvis an optionally substituted C1-6aliphatic or halogenand n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0302] In some embodiments, the present invention provides the compound of formula I-aaa wherein Ring A isto provide a compound of formula I-aaa-5:or a pharmaceutically acceptable salt thereof, wherein: Rvis an optionally substituted C1-6aliphatic or halogen; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0303] In some embodiments, the present invention provides the compound of formula I-aaa wherein Ring A isto provide a compound of formula I-aaa-6:or a pharmaceutically acceptable salt thereof, wherein: Rvis an optionally substituted C1-6aliphatic or halogen; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0304] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-aa, to provide a compound of formula I-baa:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, ring A, Ra, LB, a', and L is as defined above and described in embodiments herein, both singly and in combination.

[0305] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-caa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4a, R4b, R6, R7, R8, Y, W1, W2, n, LA, L, LB, Ring A, Ra, and a', is as defined above and described in embodiments herein, both singly and in combination.

[0306] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-daa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, A, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0307] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-eaa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, R5, A, n, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0308] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-faa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, A, n, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0309] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-gaa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, A, n, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0310] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-haa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0311] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-iaa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R6, R7,X1, X2, X3, X4, X5, X7, X8, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0312] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-jaa:or a pharmaceutically acceptable salt thereof, wherein each of LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0313] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-kaa:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0314] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-aa, to provide a compound of formula I-laa:or a pharmaceutically acceptable salt thereof, wherein each of R2, LA, L, LB, Ring A, Ra, and a' is as defined above and described in embodiments herein, both singly and in combination.

[0315]

[0316] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-bb, to provide a compound of formula I-abb:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, R1, R2, R3, R4, LB, a, and L is 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-abb-1, I-abb-2, I-abb-3, or I-abb-4:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, LBand L is 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, wherein LBM isfrom formula I-bb, to provide a compound of formula I-abb-5:or a pharmaceutically acceptable salt thereof, wherein: Rvis an optionally substituted C1-6aliphatic or halogen; andn is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0319] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-bb, to provide a compound of formula I-abb-6:or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0320] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-bb, to provide a compound of formula I-bbb:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R1, R2, R3, R4, LB, a, and L is 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 LBM isfrom formula I-cc, to provide a compound of formula I-acc:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, y, z, LA, R5, R6, R7, R8, R9, LBc, b, and L is as defined above and described in embodiments herein, both singly and in combination.

[0322] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-cc', to provide a compound of formula I-acc':or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, y, z, LA, R5, R6, R7, R8, R9, LB, c, b, and L is as defined above and described in embodiments herein, both singly and in combination.

[0323] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-cc, to provide a compound of formula I-bcc:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R5, R6, R7, R8, R9, LBc, b, and L is as defined above and described in embodiments herein, both singly and in combination.

[0324] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-cc', to provide a compound of formula I-bcc':or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R5, R6, R7, R8, R9, LB, c, b, and L is as defined above and described in embodiments herein, both singly and in combination.

[0325] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-dd, to provide a compound of formula I-add:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, R10, R11, R12, LB, d, and L is as defined above and described in embodiments herein, both singly and in combination.

[0326] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-dd', to provide a compound of formula I-add':or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, R10, R11, R12, LB, d, and L is as defined above and described in embodiments herein, both singly and in combination.

[0327] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-dd, to provide a compound of formula I-bdd:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R10, R11, R12, LB, d, and L is as defined above and described in embodiments herein, both singly and in combination.

[0328] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-dd', to provide a compound of formula I-bdd':or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R10, R11, R12, LB, d, and L is as defined above and described in embodiments herein, both singly and in combination.

[0329] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-ee, to provide acompound of formula I-aee:I-aee or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, Ring B, R13, R14, R15, R16, R17, LB, e, f, g, and L is as defined above and described in embodiments herein, both singly and in combination.

[0330] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-ee, to provide acompound of formula I-bee:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, Ring B, R13, R14, R15, R16, R17, LB, e, f, g, and L is as defined above and described in embodiments herein, both singly and in combination.

[0331] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-ff, to provide a compound of formula I-aff:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, R18, R19, R20, R21, R22, LB, h, i, j, k, and L is as defined above and described in embodiments herein, both singly and in combination.

[0332] In some embodiments, the present invention provides the compound of formula I-a, wherein LBM isfrom formula I-ff', to provide a compound of formula I-aff':or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Ring Y, X1, X2, Y, Rw, Rv, Rz, Ry, LA, y, z, R18, R19, R20, R21, R22, LB, h, i, j, k, and L is as defined above and described in embodiments herein, both singly and in combination.

[0333] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-ff, to provide a compound of formula I-bff:or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R18, R19, R20, R21, R22, LB, h, i, j, k, and L is as defined above and described in embodiments herein, both singly and in combination.

[0334] In some embodiments, the present invention provides the compound of formula I-b, wherein LBM isfrom formula I-ff', to provide a compound of formula I-bff':or a pharmaceutically acceptable salt thereof, wherein each of Ring Z, Y, Rw, Rv, Rz, Ru, LA, z, R18, R19, R20, R21, R22, LB, h, i, j, k, and L is as defined above and described in embodiments herein, both singly and in combination. Linker (L)

[0335] As defined above and described herein, L is a bivalent moiety that connects MBM to LBM.

[0336] In some embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, or -N(R)SO2-; wherein: each –Cy– is independently an optionally substituted bivalent ring selected from phenylene, an 8- to 10-membered bicyclic arylene, a 3- to 7-membered carbocyclylene, a 4- to 10-membered bicyclic fused, bridged, or spirocyclic carbocyclylene, a 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0337] It will be appreciated that for compounds of the present disclosure, where R may be used in multiple instances in a single compound (i.e., in a linker, an E3 ubiquitin ligase binding moiety, and / or a MNK binding moiety), each occurrence of R throughout the compound is independently selected as defined and described herein.

[0338] In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, or -N(R)SO2-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-10hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-.

[0339] In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-; and 0-2 methylene units of L are independently replaced by -Cy-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -S-, - N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2- ; and 0-2 methylene units of L are independently replaced by -Cy-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-10hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-; and 0-2 methylene units of L are independently replaced by -Cy-.

[0340] In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-10hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-.

[0341] In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-; and 0-2 methylene units of L are independently replaced by -Cy-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-20hydrocarbon chain, wherein 0-6 methylene units of L areindependently replaced by -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-; and 0-2 methylene units of L are independently replaced by -Cy-. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-10hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-; and 0-2 methylene units of L are independently replaced by -Cy-.

[0342] In some embodiments, each –Cy– is independently an optionally substituted bivalent phenylene. In some embodiments, each –Cy– is independently an optionally substituted 8- to 10- membered bicyclic arylene. In some embodiments, each –Cy– is independently an optionally substituted 3- to 7-membered carbocyclylene. In some embodiments, each –Cy– is independently an optionally substituted 4- to 10-membered bicyclic fused, bridged, or spirocyclic carbocyclylene. In some embodiments, each –Cy– is independently an optionally substituted 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each –Cy– is independently an optionally substituted 5- to 10-membered bicyclic fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each –Cy– is independently an optionally substituted 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each –Cy– is independently an optionally substituted 8- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0343] 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.

[0344] In some embodiments, a -Cy- is a bivalent piperidine ring. In some embodiments, a -Cy- is a bivalent piperazine ring. In some embodiments, a -Cy- is a bivalent 2-azaspiro[3.3]heptane ring.

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

[0346] 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 someembodiments, 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.

[0347] In some embodiments, r is selected from those depicted in Table 1, below.

[0348] In some embodiments, L is -(CH2)1-10-. In some embodiments, L is -(CH2)1-10-O-. In some embodiments, L is -(CH2)1-10-NR-. In some embodiments, L is -(CH2)1-10-C(O)-. In some embodiments, L is -(CH2)1-10-Cy-. In some embodiments, L is -(CH2)1-10-NRCH2C(O)-. In some embodiments, L is -(CH2)1-10-CH2CH2OCH2C(O)-. In some embodiments, L is -O(CH2)1-10-. 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-Cy-. 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 -NR(CH2)1-10-. 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-Cy-. 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 -C(O)(CH2)1-10-. 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-Cy-. 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-NRC(O)CH2CH2NR-. In some embodiments, L is - NRCH2CH2C(O)NR(CH2)1-10-C(O)-. In some embodiments, L is -C(O)CH2NR(CH2)1-10-. 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-NRCH2C(O)-. In some embodiments, L is - C(O)CH2NR(CH2)1-10-OCH2C(O)-. 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- NRCH2C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2(CH2)1-10OCH2C(O)-. In some embodiments, L is -(OCH2CH2)1-10-. In some embodiments, L is -(OCH2CH2)1-10-O-. 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-Cy-. In some embodiments, L is -(OCH2CH2)1-10- NRCH2C(O)-. In some embodiments, L is -(OCH2CH2)1-10-OCH2C(O)-. In some embodiments,L is -C(O)CH2CH2(OCH2CH2)1-10-. 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)CH2OCH2CH2(OCH2CH2)1-10-. 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)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 -(CH2CH2O)1-10- CH2CH2O-. 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 -(CH2CH2O)1-10- CH2CH2C(O)-. 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 -(CH2CH2O)1-10-CH2CH2OCH2C(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 -(CH2CH2O)1-10-CH2CH2NRCH2C(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 -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 -Cy-(OCH2CH2)1-10-. 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 -Cy-(OCH2CH2)1-10- C(O)-. In some embodiments, L is -(CH2CH2O)1-10-Cy-. In some embodiments, L is - NR(CH2CH2O)1-10-Cy-. In some embodiments, L is -O(CH2CH2O)1-10-Cy-. In some embodiments, L is -C(O)(CH2CH2O)1-10-Cy-. In some embodiments, L is -C(O)-Cy-(OCH2CH2)1-10-. In some embodiments, L is -C(O)-Cy-(OCH2CH2)1-10-NR-. In some embodiments, L is -C(O)- Cy-(OCH2CH2)1-10-O-. In some embodiments, L is -C(O)-Cy-(OCH2CH2)1-10-C(O)-. In some embodiments, L is -(CH2CH2O)1-10-Cy-C(O)-. In some embodiments, L is -NR(CH2CH2O)1-10- Cy-C(O)-. In some embodiments, L is -O(CH2CH2O)1-10-Cy-C(O)-. In some embodiments, L is - C(O)(CH2CH2O)1-10-Cy-C(O)-. 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 -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 -C(O)CH2-Cy-C(O)-. In some embodiments, L is -C(O)-Cy-CH2C(O)-. 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 - 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 -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 someembodiments, L is -Cy-O-Cy-. In some embodiments, L is -Cy-O-Cy-CH2C(O)-. In some embodiments, L is -C(O)CH2-Cy-O-Cy-. In some embodiments, L is -Cy-O-Cy-CH2CH2O-. In some embodiments, L is -OCH2CH2-Cy-O-Cy-. In some embodiments, L is -O-CH2CH2-Cy-O- Cy-. In some embodiments, L is -C(O)CH2-Cy-O-Cy-. In some embodiments, L is -C(O)CH2- Cy-O-Cy-CH2C(O)-. In some embodiments, L is -C(O)CH2-Cy-O-Cy-CH2CH2OCH2C(O)-. In some embodiments, L is -C(O)CH2OCH2CH2-Cy-O-Cy-CH2C(O)-. In some embodiments, L is - Cy-O-Cy-C(O)-. In some embodiments, L is -C(O)-Cy-O-Cy-. In some embodiments, L is -Cy- O-Cy-NR-. In some embodiments, L is -NR-Cy-O-Cy-. In some embodiments, L is -OCH2CH2- Cy-O-Cy-NR-. In some embodiments, L is -NR-Cy-O-Cy-CH2CH2O-. In some embodiments, L is -NR-Cy-O-Cy-C(O)CH2-. In some embodiments, L is -C(O)-Cy-CH2NRCH2C(O)-. In some embodiments, L is -C(O)-Cy-. In some embodiments, L is -Cy-C(O)-. In some embodiments, L is -C(O)-Cy-(CH2CH2O)1-10-CH2CH2NR-. In some embodiments, L is -C(O)-Cy-(CH2CH2O)1-10- CH2CH2O-. In some embodiments, L is -C(O)-Cy-(CH2CH2O)1-10-CH2CH2C(O)-. In some embodiments, L is -NRCH2CH2-(OCH2CH2)1-10-Cy-C(O)-. In some embodiments, L is - OCH2CH2-(OCH2CH2)1-10-Cy-C(O)-. In some embodiments, L is -C(O)CH2CH2-(OCH2CH2)1-10- Cy-C(O)-. In some embodiments, L is -C(O)-Cy-(CH2)1-10-CH2CH2NR-. In some embodiments, L is -C(O)-Cy-(CH2)1-10-CH2CH2O-. In some embodiments, L is -C(O)-Cy-(CH2)1-10- CH2CH2C(O)-. In some embodiments, L is -NRCH2CH2-(CH2)1-10-Cy-C(O)-. In some embodiments, L is -OCH2CH2-(CH2)1-10-Cy-C(O)-. In some embodiments, L is -C(O)CH2CH2- (CH2)1-10-Cy-C(O)-.

[0349] In some embodiments, L is a covalent bond.

[0350] Without limitation, the point of attachment of L to MBM and LBM can be, for example when L isand LAand LBare covalent bonds, eitheror.

[0351] In some embodiments, L is

[0352] In some embodiments, L isIn some embodiments, L is

[0353] In some embodiments, L isTable 1: Exemplary CompoundsMNK Inhibitors

[0354] In some embodiments, the present disclosure provides compounds that are useful as MNK inhibitors. In some embodiments, the MNK inhibitor inhibits MKNK1 kinase (also known as MAP Kinase interacting Kinase, Mnkl). In some embodiments, the MNK inhibitor inhibits MKNK2 kinase (also known as MAP Kinase interacting Kinase, Mnk2).

[0355] In some embodiments, a compound of the present disclosure is a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.Table 2.General Methods of Providing the Present Compounds

[0356] 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.

[0357] In the Schemes below, where a particular protecting group, leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5thEdition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2ndEdition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.

[0358] 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-m ethoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxy carbonyl 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.

[0359] 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, di chloroacetyl, tri chloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0360] 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 protecting group that can thereafter be removed in situ or during a separate synthetic step.

[0361] In some embodiments, compounds of the present invention are generally prepared according to Scheme A set forth below:Scheme A: Synthesis of Compounds of Formula I

[0362] As depicted in Scheme A, above, amine Int-1 is coupled to acid Int-2 using a coupling reagent (e.g., EDCI or HATU) in the presence of a base (e.g., Hunig’s base) in a solvent to form a compound of formula I with a linker comprising an amide bond. The squiggly bond,represents the portion of the linker between LBM and the terminal amino group of Int-1 or the portion of the linker between MBM 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, DIG, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-CI, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU

[0363] In some embodiments, compounds of the present invention are generally prepared according to Scheme B set forth below:Scheme B: Synthesis of Compounds of Formula I

[0364] As depicted in Scheme B, above, acid Int-3 is coupled to amine Int-4 using a coupling reagent (e.g., EDCI or HATU) in the presence of a base (e.g., Hunig’s base) in a solvent to form a compound of formula I with a linker comprising an amide bond. The squiggly bond,represents the portion of the linker between LBM and the terminal carboxyl group of Int-3 or the portion of the linker between MBM 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.

[0365] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. “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. Compositions

[0366] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.

[0367] In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of formulae I, I-a, I-a-1, I-a-2, I-a-3, I-a-4, I-a-4, I-a-5, I-a-6, I- a-7, I-b, I-b-1, I-b-2, I-b-3, I-b-4, I-aa, I-bb, I-cc, I-cc’, I-dd, I-dd’, I-ee, I-ff, I-ff’, I-aaa, I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-baa, I-abb, I-abb-1, I-abb-2, I-abb-3, I-abb-4, I-abb-5,I-abb-6, I-bbb, I-acc, I-acc’, I-bcc, I-bcc’, I-add, I-add’, I-bdd, I-bdd’, I-aee, I-bee, I-aff, I-aff’, I- bff, and I-bff’).

[0368] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of formulae I, I-a, I-a-1, I-a-2, I-a-3, I-a-4, I-a-4, I-a-5, I-a-6, I-a-7, I-b, I-b-1, I-b-2, I-b-3, I-b-4, I-aa, I-bb, I-cc, I-cc’, I-dd, I-dd’, I-ee, I-ff, I-ff’, I-aaa, I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-baa, I-abb, I-abb- 1, I-abb-2, I-abb-3, I-abb-4, I-abb-5, I-abb-6, I-bbb, I-acc, I-acc’, I-bcc, I-bcc’, I-add, I-add’, I- bdd, I-bdd’, I-aee, I-bee, I-aff, I-aff’, I-bff, and I-bff’) and further comprises a pharmaceutically acceptable carrier.

[0369] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti- adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.

[0370] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0371] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predeterminedquantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0372] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example as described herein.

[0373] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition.Uses

[0374] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0375] In some embodiments, provided compounds are useful as MNK degraders or inhibitors.

[0376] In some embodiments, the present disclosure provides methods of degrading or inhibiting MNK, comprising contacting a provided compound with MNK. In some embodiments, contacting occurs in a cell. In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0377] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK.

[0378] In some embodiments, the present disclosure provides methods of degrading or inhibiting MNK in a patient or biological sample comprising administering to said patient, or contacting said biological sample, with a compound described herein (e.g., compounds of Formula I), or a pharmaceutical composition thereof.

[0379] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with MNK, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof.

[0380] In some embodiments, provided methods are for treating neuropathic pain. In some embodiments, the present disclosure provides a method of treating neuropathic pain, the method comprising administering a provided compound or composition thereof to a subject in need thereof.

[0381] Neuropathic pain typically develops over time and may benefit from therapies that interfere with pathways involved in its development and / or continuation. Disease or damage causing neuropathic pain may affect the central nervous system (CNS), the peripheral nervous system, or both (as opposed to causes of nociceptive pain, which affect the peripheral nervous system only). Common causes of neuropathic pain include spinal cord injury, multiple sclerosis, central nervous system ischemia, spinal nerve disease, diabetes, other metabolic disorders, herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders, physical trauma to a nerve trunk such as during surgery, peripheral ischemia, peripheral nerve lesions, nerve compression, chemotherapy or other drug-induced nerve damage, radiation injury, arthritis, autoimmune disease, and infection in an area near the affected nerves.

[0382] Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptors are specialized neurons that detect pain. Nociceptor sensitivity is not fixed; it can change over time. Some causes of neuropathic pain affect nociceptor sensitivity by inducing “peripheral sensitization.” Peripheral sensitization includes spontaneous pathological activity, abnormal excitability, heightened sensitivity to chemical stimuli, heightened sensitivity to thermal stimuli, heightened sensitivity to mechanical stimuli, and any combinations of these. Disruption of peripheral sensitization, either by reducing or preventing such peripheral sensitization in the first place or by reducing the degree of already-developed peripheral sensitization, may therefore treat neuropathic pain. Although the disclosure is not limited to one mechanism of action, MNK inhibitors as disclosed herein (e.g., compounds of Formula I) may disrupt peripheral sensitization.

[0383] MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). MNKs are a subfamily of Ser / Thr kinases, phylogenetically considered Ca2+ / calmodulin-dependent kinases (CaMKs). MNKs are activated through phosphorylation by the growth factor-stimulated Ras / extracellular signal -regulated kinase pathway and the stress-induced p38 pathway. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signal to the eukaryotic translation initiation factor (elF) 4E complex to regulate the sensitization of nociceptors.

[0384] In some embodiments, provided methods are for treating migraine. In some embodiments, the present disclosure provides a method of treating migraine, the method comprising administering a provided compound or composition thereof to a subject in need thereof.

[0385] In some embodiments, provided methods are for treating or preventing pain associated with rheumatoid arthritis. In some embodiments, the present disclosure provides a method of treating or preventing pain associated with rheumatoid arthritis, the method comprising administering a provided compound or composition thereof to a subject in need thereof.

[0386] In some embodiments, provided methods are for treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, nonalcoholic fatty liver disease (NAFLD), and Fragile X syndrome. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVED- 19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome, the method comprising administering a provided compound or composition thereof to a subject in need thereof.

[0387] In some embodiments, the compounds of the present invention provide methods for treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, undesiredcellular immune responses, or undesired cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, undesired cellular immune responses, or undesired cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and / or survival, undesired cellular immune responses, or undesired cellular inflammatory responses is mediated by MKNK-1, such as, for example,haematological tumours, solid tumours, and / or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and Small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and / or metastases thereof.

[0388] In some embodiments, the compounds of the present invention provide methods for the treatment or prophylaxis of cytokine related diseases, such as inflammatory diseases, allergies, or other conditions associated with proinflammatory cytokines.

[0389] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.EXAMPLESExample 1. Preparation of Compounds of the InventionScheme 1: Synthesis of Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)- 14-((6-((8"-methyI-1",5"-dioxo-1",5"-dihydro-2"H-dispiro[cyclopropane-1,1'-cyclohexane- 4',3"-imidazo[l,5-a]pyridin]-6"-yl)amino)pyrimidin-4-yl)amino)-3,6,9,12- tetraoxatetradecanamide (1-28)Step 1 : Synthesis of Intermediate 1-3To a solution of intermediate 1-1 (1 eq.) in DMF is added DIPEA (2 eq.) and intermediate 1-2 (1 eq.). The reaction mixture is allowed to stir overnight. The reaction is quenched by water, then extracted by EtOAc (3x). The combined organic layers are dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude product. The crude product is purified by Flash Silica-gel chromatography and the eluent is concentrated to give intermediate 1-3.Step 2: Synthesis of Intermediate 1-4To a solution of intermediate 1-3 (1 eq) in DCM is added TFA. The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under the pressure to give residue, which is purified by prep-HPLC The eluent is concentrated and lyophilized to get intermediate 1-4.Step 3: Synthesis of Intermediate 1-6

[0390] To a solution of intermediate 1-4 (1 eq) and intermediate 1-5 (1 eq.) in dioxane is added Pd2(dba)3(0.1 eq), 4A MS, Xantphos (0.2 eq.) and Cs2CO3(2 eq). The mixture is degassed and purged with N2(3x) and then the mixture is stirred at 80 °C for 12 hrs under N2atmosphere. The reaction mixture is filtered and concentrated in vacuo to give a residue, which is diluted with H2O (50 mL) and extracted with DCM (x3). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by prep- HPLC to give intermediate 1-6. Step 4: Synthesis of I-28

[0391] To a solution of intermediate 1-6 (1 eq) and intermediate 1-7 (1.5 eq) in DMF is added EDCI (3 eq), NMM (8 eq) and HOBt (1 eq). The mixture is stirred at 25°C for 1 hr. The reaction mixture is extracted with EtOAc (3x). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give I-28. Scheme 2: Synthesis of (2S,4R)-1-((S)-17-(tert-butyl)-1-((6-((8''-methyl-1'',5''-dioxo-1'',5''- dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''- yl)amino)pyrimidin-4-yl)amino)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-oyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (I-65)Step 1 : Synthesis of Intermediate 1-3To a solution of intermediate 1-1 (1 eq.) in DMF is added DIPEA (2 eq.) and intermediate 1-2 (1 eq.). The reaction mixture is allowed to stir overnight. The reaction is quenched by water, then extracted with EtOAc (3x). The combined organic layers are dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude product. The crude product is purified by Flash Silica-gel chromatography and the eluent is concentrated to give intermediate 1-3.Step 2: Synthesis of Intermediate 1-4To a solution of intermediate 1-3 (1 eq) in DCM is added TFA. The mixture is stirred at 25°C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a crude product, which is purified by prep-HPLC The eluent is concentrated and lyophilized to get intermediate 1-4.Step 3: Synthesis of 1-65

[0392] To a solution of intermediate 1-4 (1 eq) and intermediate 1-5 (1.5 eq) in DMF is added EDCI (3 eq), NMM (8 eq) and HOBt (1 eq). The mixture is stirred at 25°C for 1 hr. The reaction mixture is extracted with EtOAc (3x). The combined organic layers are washed with brine, driedover Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which is purified by prep-HPLC to give I-65. Scheme 3: Synthesis of 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(6- ((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''- imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)octanamide (I-31)Step 1: Synthesis of I-31

[0393] To a solution of intermediate 1-1 (1 eq) and intermediate 1-2 (1.5 eq) in DMF is added EDCI (3 eq), NMM (8 eq) and HOBt (1 eq). The mixture is stirred at 25°C for 1 hr. The reaction mixture is extracted with EtOAc (3x). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give I-31. Scheme 4: (2S,4R)-1-((S)-3,3-dimethyl-2-((7-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro- 2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''- yl)amino)pyrimidin-4-yl)amino)-7-oxoheptyl)amino)butanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0394] Compound I-66 is prepared as shown in the above scheme using suitable amide coupling conditions. Scheme 5: (2S,4R)-1-((S)-3,3-dimethyl-2-(8-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro- 2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''- yl)amino)pyrimidin-4-yl)amino)octanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

[0395] Compound I-2 is prepared as shown in the above scheme using suitable nitrogen alkylation and amide coupling conditions. Scheme 6: (2S,4R)-1-((S)-3,3-dimethyl-2-(3-(2-(2-((6-((8''-methyl-1'',5''-dioxo-1'',5''- dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)amino)-2-oxoethoxy)ethoxy)propanamido)butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0396] Compound I-67 is prepared as shown in the above scheme using suitable amide coupling conditions. Scheme 7: (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(3-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro- 2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''- yl)amino)pyrimidin-4-yl)amino)propanamido)hexanamido)butanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0397] Compound I-68 is prepared as shown in the above scheme using suitable nitrogen alkylation and amide coupling conditions. Scheme 8: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(6-((8''-methyl- 1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5- a]pyridin]-6''-yl)amino)pyrimidin-4-yl)heptanamide

[0398] Compound I-3 is prepared as shown in the above scheme using suitable oxygen alkylation and amide coupling conditions. Scheme 9: N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-8-((6-((8''-methyl-1'',5''- dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5- a]pyridin]-6''-yl)amino)pyrimidin-4-yl)amino)octanamide

[0399] Compound I-5 is prepared as shown in the above scheme using suitable nitrogen alkylation and amide coupling conditions. Scheme 10: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-3-((6- ((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'-cyclohexane-4',3''- imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)amino)propanamide

[0400] Compound I-6 is prepared as shown in the above scheme using suitable amide coupling conditions.Scheme 11: N-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxoethoxy)ethoxy)ethoxy)propyl)-3-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H- dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''- yl)amino)pyrimidin-4-yl)amino)propanamide

[0401] Compound I-69 is prepared as shown in the above scheme using suitable amide coupling conditions.

[0402] Examples 2-6 are further described in Yang et. al. "Discovery of P11-2: A Potent First-in- Class MNK1-Targeting PROTAC Degrader for the Treatment of Cancer" J. Med. Chem.2025, 68, 10, 10092-10110, the entirety of which is herein incorporated by reference. Example 2. MNK1 Biochemical Enzymatic Assay.

[0403] Final compounds are screened for MNK1 inhibition using the ADP-Glo kinase assay kit (Promega, catalogue No. V9101). All kinase reactions are performed in HEPES reaction buffer [15 mM HEPES (pH 7.4), 20 mM NaCl, 1 mM EGTA, 10 mM MgCl2, 0.1 mg / mL BGG, and 0.02% Tween 20]. The final MNK1 reaction mixture contains 10 nM recombinant MNK1 protein (Carna, catalogue No. 02-145), 100 µM substrate peptide (TATKSGSTTKNR, Genescript), 300µM ATP, and varying concentrations of compounds. All kinase reactions are conducted in 96-well plates with a final volume of 25 µL. Prior to ATP addition, the MNK1 enzyme is preincubated with the compound and substrate peptide for 5 min. After the addition of ATP, kinase reactions are incubated at room temperature for 40 min. Reactions are terminated by adding 25 µL of ADP-Glo reagent, followed by an additional incubation of 40 min. The final luminescent signal is generated by the addition of 50 µL of kinase detection reagent, with incubation for 40 min. The final DMSO concentration is 1%. Luminescent signals are detected using a Varioskan LUX multimode microplate reader. The IC50 values are calculated using GraphPad Prism 9.0 software. Data is shown in Tables 3A, 3B, 4A, 4B and 5. Example 3. Cell Culture and Cell Proliferation Assay.

[0404] MOLM-13, MDA-MB-231, and MM-1S cells are cultured in RPMI-1640 medium (Gibco) supplemented with 10% fetal bovine serum (FBS; Gibco) and 1% penicillin / streptomycin (Gibco). MV4-11 cells are cultured in IMDM (Gibco) with 10% FBS and 1% penicillin / streptomycin (Gibco). Cells are seeded in 96-well plates at densities of 1x104cells / well for MV4-11, 8x103cells / well for MOLM-13 and MDA-MB-231, and 4x103cells / well for MM-1S in 50 µL of medium. After overnight incubation, 50 µL of serially diluted compounds in the corresponding medium is added to each well. After MV4-11, MOLM-13, MDA-MB-231 and MM-1S cells are incubated for 72, 72, 96, and 120 h, respectively. The absorbance value of the cells at 450 nm is detected by CCK-8 colorimetry. The IC50 values are calculated using GraphPad Prism 9.0 software. Data is shown in Table 3A, 3B, 4A, 4B, 5 and 6. Example 4. Western Blot Analysis.

[0405] MV4-11 cells are seeded in six-well plates at a density of 1.5x106cells / well and treated with the compound at varying concentrations for 24 h. Briefly, cells are lysed with RIPA buffer plus containing 1X protease inhibitor cocktail, 1X PMSF and 1X Phosphatase Inhibitor cocktail (Meilunbio, MA0171). Following cell lysis, the lysates are centrifuged at 12,000 rpm for 10 min at 4°C, and protein concentrations are measured using a BCA assay (Enhanced BCA Protein Assay Kit, Beyotime Biotechnology). Equal amounts of protein are loaded onto a 10% SDS-PAGE gel (EpiZyme Biotechnology), separated, and transferred onto PVDF membranes (Millipore, 0.45 µm). Membranes are blocked with 5% nonfat milk in TBST for 2 h at room temperature, followed by incubation with primary antibodies MNK1 (ImmunoWay, YT2805), MNK2 (ImmunoWay,YT2808), P-eIF4E (Abcam, ab76256, / J-Actin (Proteintech, 66009-1-Ig); GAPDH, (Proteintech, 60004-1-Ig)) overnight at 4°C. After washing with TBST, the membranes are incubated with secondary antibodies (Goat Anti-Rabbit IgG HRP (1:5000, Proteintech)) for 1.5 h at room temperature. Protein bands are visualized using an ECL detection reagent (Proteintech, Wuhan, China) and quantified using ImageJ software. Data is shown in Table 3A, 3B, 4A, 4B, and 5. Also, see Yang et. al. J. Med. Chem.2025, 68, 10, 10092-10110 for results. Example 5. Cycle Assay and Cell Apoptosis.

[0406] MV4-11 cells are seeded at a density of 1.5x106cells per well in 6-well plates and incubated for 24 h, followed by treatment with compound at varying concentrations for an additional 24 h. For cell cycle analysis, MV4-11 cells are harvested, washed with cold PBS, and fixed in 70% ethanol at 4°C for 20 h. The cells are subsequently washed twice with cold PBS and stained using the Cell Cycle and Apoptosis Detection Kit (HY-K1071) following the manufacturer’s protocol. The cell cycle signals are analyzed by flow cytometry (Attune NxT, Thermo Fisher Scientific).

[0407] To measure apoptosis, MV4−11 cells are stained with Annexin V and propidium iodide (PI) via dual staining. After collection, cells are washed twice with cold PBS, resuspended in binding buffer, and stained using the Annexin V-FITC / PI Apoptosis Assay Kit (40302ES50) according to the manufacturer’s instructions. Apoptosis signals are detected using flow cytometry (Attune NxT, Thermo Fisher Scientific). See Yang et. al. J. Med. Chem.2025, 68, 10, 10092-10110 for results. Example 6. In Vivo Efficacy Studies in the MV4−11 Xenograft Model in Mice. Female NOD-PrkdcscidIl2rgem1 / Smoc mice (5 weeks old) are subcutaneously injected with MV4−11 cells (5x106cells in 0.1 mL of serum-free DMEM mixed 1:1 with Matrigel (Aspen Biosciences, 0827045)) into the right flank to establish tumors. Tumor volume is measured every other day using a caliper and calculated as follows: 0.5ab2, where a is the longest diameter and b is the shortest diameter. When the mean tumor size reached approximately 100 mm3, the mice are randomized and size-matched into the vehicle (n = 6 per group) and the compound groups (20 mg / kg). Compounds are freshly dissolved in a vehicle solution (2% DMSO and olive oil) and administered once daily via intraperitoneal injection for 16 days. All mice are sacrificed at the conclusion of the treatment, and tumors are collected and weighed. See Yang et. al. J. Med. Chem. 2025, 68, 10, 10092-10110 for results.Example 7. DIA-Based Quantitative Proteomics Assay. DIA-Based Quantitative Proteomics Assay. MV4−11 cells are seeded at a density of 1.5 × 106 cells per well in 6-well plates and incubated overnight before treatment with DMSO or 300 nM P11−2 for 24 h. Aliquots of proteins are mixed with 200 μL of 8 M urea in a Nanosep Centrifugal Devices (PALL). The device is centrifuged at 12,000 g at 20 °C for 20 min. All following centrifugation steps are performed by applying the same conditions allowing maximal concentration. Then, 200 μL of 8 M urea solution with 10 mM DTT are added, and the reduction reaction is kept for 2 h at 37 °C. The solution is removed by centrifugation, and 200 μL 8 M urea solution with 50 mM iodoacetamide (IAA) is added. The sample is incubated in the dark for 15 min at room temperature. The ultrafraction tube is washed with 200 μL of 8 M urea three times and 200 μL of 25 mM ammonium bicarbonate three times by centrifugation at 12,000 g for 20 min at room temperature. Then, 100 μL of 25 mM ammonium bicarbonate containing 0.01 μg / μL trypsin is added to each filter tube. The tubes are incubated at 37 °C for 12 h. The filter tubes are washed twice with 100 μL of 25 mM ammonium bicarbonate by centrifugation at 12,000 g for 10 min. The flow-through fractions are collected and lyophilized. All nano LC-MS / MS experiments are performed on an Orbitrap Astral (Thermo Scientific) equipped with a Vanquish Neo UHPLC system (Thermo Scientific). Peptides are loaded onto a 75 μm id × 2 cm trap column (Acclaim PepMap 100, Thermo Scientific), then separated onto a 75 μm id × 20 cm C18 column packed with reversed-phase silica (Reprosil-Pur 120 C18 -AQ, 1.9 μm, Dr. Maisch GmbH). Solvent A consisted of 0.1% formic acid in water solution, and Solvent B consisted of 80% acetonitrile and 0.1% formic acid. For proteomics, the peptides bound on the column are eluted with a 15 min linear gradient, with a flow rate of 400 nL / min. Data is acquired in data independent acquisition (DIA) mode with settings described below. The full MS resolution is 240,000 with a full scan range of 380−980 m / z when stated. The full MS AGC was set to 500%. Fragment ion scans are recorded at a resolution of 80,000 and a maxIT value of 2.5 ms.299 windows of 2-Th scanning from 380 to 980 m / z are used, and the isolated ions are fragmented using HCD with 25% NCE. The MS / MS data is analyzed for protein identification and quantification using PEAKS Online 11 as the default parameters. The local false discovery rate at PSM is 1.0% after searching against the Homo sapien protein database with a maximum of one missed cleavages. The following settings were selected: Oxidation (M), Acetylation (Protein N-term), and Deamidation (NQ), as well as fixedCarbamidomethylation of cysteine. See Yang et. al. J. Med. Chem.2025, 68, 10, 10092-10110 for results. Table 3A. Structure−Activity Relationship StudyTable 3B. Structure−Activity Relationship StudyTable 4A. Structure−Activity Relationship StudyTable 4B. Structure−Activity Relationship StudyTable 5. Structure−Activity Relationship StudyTable 6. Antiproliferative Activity of Selected Compounds against Different Cell Lines

Claims

CLAIMS 1. A compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: MBM is a MNK binding moiety; L is a bivalent moiety that connects MBM to LBM; and LBM is a ligase binding moiety.

2. The compound of claim 1, wherein MBM is an MNK binding moiety thereby forming a compound of formula I-a:or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described herein, and wherein: X1and X2are each independently a bond, -(CRxRx)p-, or -CRx=CRx-; Y is a covalent bond, -N(R)-, -CH2N(R)-, -N(R)CH2-, -C(O)N(R)-, -N(R)C(O)-, -SO2N(R)-, or - N(R)S(O)2-; Ring Y is a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring Z is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rvis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; Rwis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; each Rxis independently hydrogen, halogen, optionally substituted C1-6aliphatic, -N(R)C(O)R', or -N(R)S(O)2R', or two Rxare taken together to form a 3- to 7-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ryis independently halogen, -C(O)OR, -S(O)2R', or optionally substituted C1-6aliphatic; each Rzis independently halogen, -OR, -N(R)2, -N(R)C(O)(CH2)mR'', -N(R)C(S)(CH2)mR'', - N(R)C(O)N(R)R'', -C(O)R'', optionally substituted C1-6aliphatic, or optionally substituted C3-7carbocyclyl; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; each R'' is independently an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; p is 1, 2, or 3; y is 0, 1, 2, 3, or 4;z is 0, 1, 2, or 3; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O- , -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-; wherein: each –Cy– is independently an optionally substituted bivalent ring selected from phenylene, an 8- to 10-membered bicyclic arylene, a 3- to 7-membered carbocyclylene, a 4- to 10-membered bicyclic fused, bridged, or spirocyclic carbocyclylene, a 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10- membered bicyclic fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

3. The compound of claim 2, wherein X1and X2are each -(CRxRx)p-.

4. The compound of claim 2 or 3, wherein each Rxis hydrogen.

5. The compound of any one of claims 2-4, wherein Ring Y is a 3- to 5-membered carbocyclic ring.

6. The compound of any one of claims 2-5, wherein the compound is a compound of formula I-a-3:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 2-6, wherein each Ryis -C(O)OR or optionally substituted C1-6aliphatic.

8. The compound of any one of claims 2-7, wherein y is 0 or 1.

9. The compound of claim 8, wherein y is 0.

10. The compound of claim 1, wherein MBM is an MNK binding moiety thereby forming a compound of formula I-b:or a pharmaceutically acceptable salt thereof, wherein: Y is a covalent bond, -N(R)-, -CH2N(R)-, -N(R)CH2-, -C(O)N(R)-, -N(R)C(O)-, -SO2N(R)-, or - N(R)S(O)2-; Ring Z is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ruis independently optionally substituted C1-6aliphatic, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two Ruare taken together to form an optionally substituted ring selected from a C3-7monocyclic carbocyclic ring, C4-10fused or bridgedbicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10- membered fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rvis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; Rwis hydrogen, halogen, cyano, optionally substituted C1-6aliphatic, or optionally substituted C3-6carbocyclyl; each Rzis independently halogen, -OR, -N(R)2, -N(R)C(O)(CH2)mR”, -N(R)C(S)(CH2)mR”, - N(R)C(O)N(R)R”, -C(O)R”, optionally substituted C1-6aliphatic, or optionally substituted C3-7carbocyclyl; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; each R'' is independently an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, C4-10fused, bridged, or spirocyclic bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered fused, bridged, or spirocyclic bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, or 2; z is 0, 1, 2, or 3;L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O- , -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-; wherein: each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8- to 10-membered bicyclic arylene, a 3- to 7-membered carbocyclylene, a 4- to 10-membered bicyclic fused, bridged, or spirocyclic carbocyclylene, a 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10- membered bicyclic fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of any one of claims 2-10, wherein Y is -NH-.

12. The compound of any one of claims 2-11, wherein Ring Z is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

13. The compound of claim 12, wherein Ring Z is a pyrimidine ring.

14. The compound of any one of claims 2-13, wherein each Rzis -NH2.

15. The compound of any one of claims 2-14, wherein z is 1.

16. The compound of any one of claims 2-15, wherein Rwis hydrogen.

17. The compound of any one of claims 2-16, wherein Rvis optionally substituted C1-6alkyl or halogen.

18. The compound of claim 17, wherein Rvis -CH3, -CD3, or chloro.

19. The compound of any one of claims 10-18, wherein each Ruis independently optionally substituted C1-6aliphatic, optionally substituted phenyl, or optionally substituted 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

20. The compound of any one of claims 10-18, wherein two Ruare taken together to form a ring selected from a C3-7monocyclic carbocyclic ring, C4-10fused or bridged bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

21. The compound of any one of claims 1-20, wherein LBM is a cereblon E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-aa:or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rais independently oxo, halogen, optionally substituted C1-6aliphatic, -CN, -NO2, -ORaa, - SRaa, -N(Raa)2, -S(O)2Raa, -S(O)2N(Raa)2,-S(O)Raa, -C(O)Raa, -C(O)ORaa, - C(O)N(Raa)2, -C(O)N(Raa)ORaa, -C(Raa)2N(Raa)C(O)Raa, -C(Raa)2N(Raa)C(O)N(Raa)2, -OC(O)Raa, -OC(O)N(Raa)2, -N(Raa)C(O)ORaa, -N(R)C(O)Raa, -N(Raa)C(O)N(Raa)2, -N(Raa)S(O)2Raa, or –N(Raa)S(O)2Raa; 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 R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Raais independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, a 3- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two Raagroups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0-1 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and a' is 0, 1, 2, 3 or 4.

22. The compound of claim 21, wherein Ring A is an optionally substituted 9- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

23. The compound of claim 21, wherein Ring A is an optionally substituted phenyl.

24. The compound of any one of claims 21-23, wherein a' is 0.

25. The compound of any one of claims 1-24, wherein LBM is:.

26. The compound of any one of claims 1-20, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-bb:or a pharmaceutically acceptable salt thereof, wherein: each R1is independently hydrogen, -C(O)R', or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; each R3is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; R4is hydrogen, halogen, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; and a is 0, 1, 2, 3, or 4.

27. The compound of claim 26, wherein each R1is hydrogen.

28. The compound of claim 26 or 27, wherein R2is C1-6alkyl.

29. The compound of any one of claims 26-28, wherein R4is C1-6alkyl.

30. The compound of any one of claims 26-29, wherein a is 0.

31. The compound of any one of claims 1-20 and 26-30, wherein LBM is: ,32. The compound of any one of claims 1-20, wherein LBM is an IAP / SMAC binding moiety thereby forming a compound of formula I-cc or I-cc':or a pharmaceutically acceptable salt thereof, wherein: R5is optionally substituted C1-6aliphatic; R6is optionally substituted C1-6aliphatic; R7is an optionally substituted group selected from C1-6aliphatic, C3-7monocyclic carbocyclic ring, or a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R8is independently halogen or optionally substituted C1-6aliphatic, or two R8groups are taken together to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R7and an R8group are taken together to form an optionally substituted 7- to 8-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R9is Cy2or -C(O)N(R)Cy2; 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-, -OC(O)NR-, or –NRC(O)O-; Cy2is an optionally substituted ring selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C3-7monocyclic carbocyclic ring, C4-10bicyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; b is 1 or 2; and c is 0, 1, 2, 3, or 4.

33. The compound of claim 32, wherein R5is C1-6alkyl.

34. The compound of claim 32 or 33, wherein R6is C1-6alkyl.

35. The compound of any one of claims 32-34, wherein R7is C1-6alkyl.

36. The compound of any one of claims 32-35, wherein two R8groups are taken together to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

37. The compound of any one of claims 32-34, wherein R7and an R8group are taken together to form an optionally substituted 7- to 8-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

38. The compound of any one of claims 32-37, wherein R9is Cy2.

39. The compound of any one of claims 32-37, wherein R9is -C(O)N(H)Cy2.

40. The compound of any one of claims 32-39, wherein Cy2is an optionally substituted ring selected from a 9- to 10-membered bicyclic aryl ring and 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

41. The compound of any one of claims 32-40, wherein b is 1.

42. The compound of any one of claims 1-20 and 32-41, wherein LBM is:.

43. The compound of any one of claims 1-20, wherein LBM is an IAP / SMAC binding moiety thereby forming a compound of formula I-dd or I-dd':or a pharmaceutically acceptable salt thereof, wherein: R10is -OR or -N(R)2; R11is optionally substituted C1-6aliphatic; each R12is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; and d is 0, 1, 2, 3, 4, or 5.

44. The compound of claim 43, wherein R10is -OR.

45. The compound of claim 43 or 44, wherein R11is C1-6alkyl.

46. The compound of any one of claims 43-45, wherein d is 0.

47. The compound of any one of claims 1-20 or 43-46, wherein LBM is:

48. The compound of any one of claims 1-20, wherein LBM is an IAP / SMAC binding moiety thereby forming a compound of formula I-ee:or a pharmaceutically acceptable salt thereof, wherein: Ring B is an optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R13is hydrogen or optionally substituted C1-6aliphatic; each R14and R15is independently optionally substituted C1-6aliphatic; each R16is independently hydrogen or optionally substituted C1-6aliphatic; each R17is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclicheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; e is 0, 1, 2, 3, 4, 5, or 6; f is 0, 1, 2, 3, 4, 5, or 6; and g is 01, 2, 3, 4, or 5.

49. The compound of claim 48, wherein Ring B is optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

50. The compound of claim 48 or 49, wherein R13is hydrogen.

51. The compound of any one of claims 48-50, wherein each R14is independently C1-6alkyl.

52. The compound of any one of claims 48-51, wherein each R15is independently C1-6alkyl.

53. The compound of any one of claims 48-52, wherein each R16is independently C1-6alkyl.

54. The compound of any one of claims 48-53, wherein each R17is independently halogen.

55. The compound of any one of claims 1-20 or 48-54, wherein LBM is:

56. The compound of any one of claims 1-20, wherein LBM is MDM2 binding moiety thereby forming a compound of formula I-ff or I-ff':or a pharmaceutically acceptable salt thereof, wherein: R18is hydrogen or optionally substituted C1-6aliphatic; each R19is independently optionally substituted C1-6aliphatic, or two R19are taken together to form an oxo; each R20, R21, and R22is independently halogen, -CN, -C(O)R', -C(O)N(R)2, -OR, -N(R)2, or optionally substituted C1-6aliphatic; 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-, -OC(O)NR-, or –NRC(O)O-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7carbocyclic ring, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R' is independently optionally substituted C1-6aliphatic or an optionally substituted C3-7carbocyclic ring; h is 0, 1, 2, 3, 4, 5, or 6; and i, j, and k are each independently 0, 1, 2, 3, 4, or 5.

57. The compound of claim 56, wherein R18is hydrogen.

58. The compound of claim 56 or 57, wherein two R19are taken together to form an oxo.

59. The compound of any one of claims 56-58, wherein each R20is independently -OR.

60. The compound of any one of claims 56-59, wherein each R21and R22is independently halogen.

61. The compound of any one of claims 56-60, wherein i, j, and k are each independently 0, 1, or 2.

62. The compound of any one of claims 1-20 or 56-61, wherein LBM is:.

63. The compound of any one of claims 2-62, wherein LAis a covalent bond.

64. The compound of any one of claims 2-62, wherein LAis -NH-, -O-, or -C(O)-.

65. The compound of any one of claims 2-64, wherein LBis a covalent bond.

66. The compound of any one of claims 2-64, wherein LBis -NH-, -O-, or -C(O)-.

67. The compound of any one of claims 1-66, wherein L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-.

68. The compound of any one of claims 1-66, wherein L is a bivalent, saturated or partially unsaturated, straight or branched C1-30hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-; and 0-2 methylene units of L are independently replaced by -Cy-.

69. The compound of any one of claims 1-66, wherein L is a bivalent, saturated or partially unsaturated, straight or branched C1-30 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-.

70. The compound of any one of claims 1-66, wherein L is a bivalent, saturated or partially unsaturated, straight or branched C1-10hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -O-, -N(R)-, -C(O)-, -C(O)N(R)-, or -N(R)C(O)-; and 0-2 methylene units of L are independently replaced by -Cy-.

71. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

72. A compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

73. A pharmaceutical composition comprising a compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.