KRAS-targeting covalent-induced drug conjugates comprising a tubulin inhibitor payload

Abstract

The present disclosure provides covalent-induced drug conjugates comprising a KRASG12C binding moiety and a tubulin inhibitor payload moiety, as well as compositions and methods of use thereof.

Description

KRAS-TARGETING COVALENT-INDUCED DRUG CONJUGATES COMPRISING A TUBULIN INHIBITOR PAYLOADCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 696,692, filed September 19, 2024; the contents of which is herein incorporated by reference.BACKGROUND

[0002] In 2024, over 2 million new cancer diagnoses are expected in the US, and an estimated 1680 people are predicted to die from cancer each day in the US. Cancer Facts & Figures 2024, Atlanta: American Cancer Society; 2024. Current treatments for cancer largely rely on chemotherapy using cytotoxic agents. Patients taking these cytotoxic agents, however, often experience serious side effects related to off-target effects of the drugs on non-cancerous cells. Therapies that specifically target cancer cells while minimally affecting non-cancer cells are desirable.SUMMARY

[0003] The present disclosure provides bifunctional compounds comprising a KRASG12Cbinding moiety and a tubulin inhibitor payload moiety. As described further herein, provided compounds act as covalent-induced drug conjugates, whereby a cytotoxic payload (e g., a tubulin inhibitor payload moiety) is specifically delivered to a cell expressing an oncogenic protein (e.g., KRASG12C). Upon binding to KRASG12C, the tubulin inhibitor payload moiety is released and thereby is allowed to engage with targets within the cell.

[0004] In some embodiments, the present disclosure provides compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein L1, X, Rx, Ry, Rz, KBM, and TPM are as defined herein.BRIEF DESCRIPTION OF THE DRAWING

[0005] FIG. 1A is a schematic showing a proposed mechanism of payload release from a covalent-induced drug conjugate.

[0006] FIG. IB is a schematic showing a proposed mechanism of payload release from a covalent-induced drug conjugate comprising a self-immolative or degradable linker.DETAILED DESCRIPTIONCompounds and Definitions

[0007] 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 organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0008] 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, atropisomeric, 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.

[0009] 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.

[0010] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19(1977).

[0011] 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., Cue). 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 1-2 aliphatic 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.

[0012] 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, Ci-s, 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-).

[0013] 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.

[0014] 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.

[0015] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., Ce-u), 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.

[0016] 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-C8 hydrocarbon, or an optionally substituted C5-C10 bicyclic 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 carboncarbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0017] 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 7t electrons shared in a cyclic array; and having, in addition tocarbon 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.

[0018] 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.

[0019] 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-, orpolycyclic, 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)).

[0020] 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) moi eties, as herein defined.

[0021] 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.

[0022] 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 bythis 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.

[0023] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CH2)o 4R0; (CH2)o 4OR0; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(Cthjo4SRC; -(Ckhjo4Ph, which may be substituted with R°; -(CH2)o40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o40(CH2)o 1 -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O 4N(RO)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; - C(S)R°; -(CH2)O4C(O)OR°; -(CH2)O4C(O)SR°; -(CH2)O4C(O)OSiRo3; -(CH2)o4OC(O)R°; - OC(0)(CH2)o 4SR0; -(CH2)O4SC(O)RO; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; - SC(S)SR°, -(CH2)O4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)o4SSR°; -(CH2)0 4S(O)2R°; -(CH2)o4S(O)2OR°; -(CH2)o4OS(O)2RO; - S(O)2NR°2; -(CH2)O4S(O)R°; -N(R°)S(O)2NRO2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; - (CH2)O4P(O)2R°; (CH2)O4P(O)RO2; (CH2)O 4P(O)(ORO)2; (CH2)O4OP(O)R°2; (CH2)O4OP(O)(OR°)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or - (Ci^i straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2PI1, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0024] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o 2R*,-(haloR*), -(CH2)0 2OH, -(CH2)o-2OR*, -(CH2)O2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)02C(O)R*, -(CH2)O 2C(O)OH, -(CH2)O 2C(O)OR*, -(CH2)O 2SR’, -(CH2)O-2SH, -(CH2)O 2NH2, - (CH2)0 2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR*. -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, - CH2Ph, -0(CH2)o-iPh, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0025] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R’2))2-3O- or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: O(CR*2)23O- wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] 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 C 1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R;, -NR‘:2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf,C(O)CH2C(O)Rt, -S(O)2RT, -S(O)2NRT2, -C(S)NRT2, -C(NH)NR‘:'2, or -N(RT)S(O)2RT; wherein each R is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-7-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.

[0028] 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 C i 4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3-7- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, 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 a subject 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.

[0030] In some embodiments, a bond is denoted byIn such cases, it is understood to denote either an “R” or “S” stereoisomer, but the particular isomer was not determined.Covalent-Induced Drug Conjugates

[0031] In some embodiments, the present disclosure provides covalent-induced drug conjugates (CIDCs), as described further herein. Provided CIDCs are bifunctional compounds that deliver a cytotoxic payload specifically to cancer cells expressing an oncogenic protein. Such CIDCs comprise (i) a protein binding moiety, typically targeting an oncogenic protein capable of covalently interacting with the protein binding moiety, such as through a reactive cysteine residue; (ii) a payload moiety; and (iii) a linking moiety connecting the protein binding moiety to the payload moiety. Exemplary schemes are shown in FIG. lAand FIG. IB. First, the protein bindingmoiety (“R”) binds the oncogenic protein (“Target”), which bears a reactive cysteine residue. Then, the reactive cysteine residue covalently binds an a,P-unsaturated carbonyl moiety (or other suitable Michael acceptor) of the CIDC, triggering cleavage of the linking moiety and release of the activated payload moiety (“Payload”).

[0032] CIDCs have the potential to reduce off-target side effects, because the cytotoxic payload is inactivated when it is part of the CIDC and is not released until the CIDC covalently binds an oncogenic target, meaning the payload is activated only upon delivery to a cancer cell expressing a particular oncogenic protein. Like antibody-drug conjugates (ADCs), the CIDC delivery mechanism allows for specific targeting of cancer cells; however, unlike ADCs, which target extracellular surface markers, CIDCs can also exploit intracellular proteins for precise payload delivery. Additionally, CIDCs are small molecules, in contrast to large-molecule ADCs, which makes CIDCs potentially amenable for oral administration.

[0033] The present disclosure, in particular, relates to CIDCs comprising a KRASG12Cprotein binding moiety and a tubulin inhibitor payload moiety.Provided Compounds

[0034] In some embodiments, the present disclosure provides a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:KBM is a KRASG12Cbinding moiety;Rxis hydrogen, halogen, cyano, or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ryis hydrogen, halogen, cyano, or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rzis independently hydrogen, halogen, or optionally substituted C1-6 aliphatic;X is a covalent bond, -O-, -N(RW)-, or -S-;Rwis hydrogen or optionally substituted C1-6 aliphatic;L1is a covalent bond or a linking moiety; andTPM is a tubulin inhibitor payload moiety.

[0035] In some embodiments, the present disclosure provides a compound of Formula I-a:or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, X, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0036] In some embodiments, the present disclosure provides a compound of Formula I-b:I-b or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lais a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-;each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0037] In some embodiments, the present disclosure provides a compound of Formula I-c:I-C or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lais a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, oraromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0038] In some embodiments, the present disclosure provides a compound of Formula I-d:I-d or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0039] In some embodiments, the present disclosure provides a compound of Formula I-e:I-eor a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] In some embodiments, the present disclosure provides a compound of Formula I-f:I-f or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0041] In some embodiments, the present disclosure provides a compound of Formula I-g:I-g or a pharmaceutically acceptable salt thereof, wherein KBM, L1, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0042] In some embodiments, the present disclosure provides a compound of Formula I-h:I-h or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h, Rzis not hydrogen.

[0043] In some embodiments, the present disclosure provides a compound of Formula I-h-1 :I-h-1or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-1, Rzis not hydrogen.

[0044] In some embodiments, the present disclosure provides a compound of Formula I-h-2:or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-2, Rzis not hydrogen.

[0045] In some embodiments of any Formulae described herein, Rxis hydrogen, halogen, cyano, or optionally substituted C1-6 aliphatic. In some embodiments, Rxis hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, Rxis hydrogen or optionally substituted C1-6 alkyl. In some embodiments, Rxis an optionally substituted group selected from C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rxis an optionally substituted group selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rxis hydrogen. In some embodiments, Rxis halogen (e.g., fluoro). In some embodiments, Rxis cyano. In some embodiments, Rxis optionally substituted C1-6 aliphatic. In some embodiments, Rxis C1-6 aliphatic optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Rxis C1-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Rxis C1-6 alkyl. In some embodiments, Rxis -CH3. In some embodiments, Rxis C1-6 aliphatic. In some embodiments, Rxis optionally substituted C1-6 alkyl. In some embodiments, Rxis C1-6 alkyl. In some embodiments, Rxis optionally substituted C3-7 cycloaliphatic. In some embodiments, RxisC3-7 cycloaliphatic. In some embodiments, Rxis optionally substituted C3-7 cycloalkyl. In some embodiments, Rxis C3-7 cycloalkyl. In some embodiments, Rxis optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rxis optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rxis optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rxis -CH2C(CH3)2N(H)CH3.

[0046] In some embodiments of any Formulae described herein, Ryis hydrogen, halogen, cyano, or optionally substituted C1-6 aliphatic. In some embodiments, Ryis hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, Ryis hydrogen or optionally substituted C1-6 alkyl. In some embodiments, Ryis an optionally substituted group selected from C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis an optionally substituted group selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis hydrogen. In some embodiments, Ryis halogen (e.g., fluoro). In some embodiments, Ryis cyano. In some embodiments, Ryis optionally substituted C1-6 aliphatic. In some embodiments, Ryis C1-6 aliphatic optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ryis C1-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ryis C1-6 alkyl. In some embodiments, Ryis -CH3. In some embodiments, Ryis C1-6 aliphatic. In some embodiments, Ryis optionally substituted C1-6 alkyl. In some embodiments, Ryis C1-6 alkyl. In some embodiments, Ryis optionally substituted C3-7 cycloaliphatic. In some embodiments, Ryis C3-7 cycloaliphatic. In some embodiments, Ryis optionally substituted C3-7 cycloalkyl. In some embodiments, Ryis C3-7 cycloalkyl. In some embodiments, Ryis optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Tn some embodiments, Ryis optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis -CH3, -CH2CH3, -CF3, -CH2N(CH3)2, - CH2CH2N(H)CH3, or -CH2C(CH3)2N(H)CH3.

[0047] In some embodiments of any Formulae described herein, each Rzis independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each Rzis independently hydrogen or C1-6 aliphatic. In some embodiments, each Rzis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rzis independently hydrogen or C1-6 alkyl. In some embodiments, each Rzis hydrogen. In some embodiments, one Rzis hydrogen and the other Rzis optionally substituted C1-6 alkyl. In some embodiments, one Rzis hydrogen and the other Rzis C1-6 alkyl. In some embodiments, a Rzis hydrogen. In some embodiments, a Rzis halogen (e.g., fluoro). In some embodiments, a Rzis optionally substituted C1-6 aliphatic. In some embodiments, a Rzis C1-6 aliphatic optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), - NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rzis C1-6 aliphatic. In some embodiments, a Rzis optionally substituted C1-6 alkyl. In some embodiments, a Rzis C1-6 alkyl. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more halogen atoms. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more fluorine atoms. In some embodiments, a Rzis CF3. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), -NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rzis C1-6 alkyl.In some embodiments, a Rzis hydrogen, -CH3,. In some embodiments, one Rzis hydrogen, and one Rzis optionally substituted C1-6 aliphatic.

[0048] In some embodiments of any Formulae described herein, X is -O- or -N(RW)-. In some embodiments, X is -O-. In some embodiments, X is -N(RW)-. In some embodiments, X is -N(H)- . In some embodiments, X is -N(CHs)-. In some embodiments, X is -S-. In some embodiments, X is a covalent bond. It will be appreciated that, in some embodiments, when X is a covalent bond, -iJ-TPM is a sufficient leaving group to result in release of the tubulin inhibitor payload upon binding of the compound to KRASG12C.

[0049] In some embodiments of any Formulae described herein, Rwis hydrogen. In some embodiments, Rwis optionally substituted C1-6 aliphatic. In some embodiments, Rwis C1-6 aliphatic. In some embodiments, Rwis optionally substituted C1-6 alkyl. In some embodiments, Rwis C1-6 alkyl (e.g., methyl).

[0050] In some embodiments of any Formulae described herein, L1is a covalent bond. In some embodiments, L1is a linking moiety.

[0051] In some embodiments of any Formulae described herein, L1is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S- , -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SC>2-, or -Cy-, wherein each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multi cyclic, 3- to 16-membered bivalent ring system, wherein thering system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0052] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-.

[0053] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -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 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-io hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -S02-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)- , -N=N-, -O-N=, =N-O-, -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 1-2 methylene units are optionally and independently replaced by -Cy-.

[0054] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O- , -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-.

[0055] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N- , -O-N=, =N-O-, -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 1-2 methylene units are optionally and independently replaced by -Cy-.

[0056] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O- , -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or - Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, - N(R)C(O)O-, -OC(O)N(R)-, or -Cy-.

[0057] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units areoptionally and independently replaced by -Cy- In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-io hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units are optionally and independently replaced by -Cy-.0

[0058] In some embodiments of any Formulae described herein, L1isR, wherein Laand R are as defined above for Formula I-b and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-b.

[0059] In some embodiments of any Formulae described herein, L1isLais as defined above for Formula 1-c and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-c.

[0060] In some embodiments of any Formulae described herein, L1isAVCy-LaA>e, whereinLais as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0061] In some embodiments of any Formulae described herein,, wherein Laand R are as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.R

[0062] In some embodiments of any Formulae described herein, L1is O , wherein Lband R are as defined above for Formula I-d and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-d.

[0063] In some embodiments of any Formulae described herein, L1is, whereinLbis as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0064] In some embodiments of any Formulae described herein, L1is R , wherein Lbis as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached toTPM.

[0065] In some embodiments of any Formulae described herein, L1is O

[0066] In some embodiments of any Formulae described herein, L1is selected from: a covalentwherein R is as defined herein; each Lcis independently an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain; the bond labeled^ is attached to X; and the bond labeled B is attached to TPM.

[0067] In some embodiments of any Formulae described herein, L1is selected from:wherein R is as defined herein; each Lcis independently an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain; the bond labeled^ is attached to X; and the bond labeled B is attached to TPM.

[0068] In some embodiments of any Formulae described herein, L1is selected from:optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain.

[0069] In some embodiments of any Formulae described herein, L1is selected from: a covalentwherein the bond labeled A is attached to X; and the bond labeled B is attached to TPM.In some embodiments of any Formulae described herein, L1is selected from: a covalent bond,and the bond labeled B is attached to TPM. o

[0070] In some embodiments of any Formulae described herein, L1isRwherein Lband R are as defined above for Formula I-e and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-e., V LbY O y

[0071] In some embodiments of any Formulae described herein, L1is O , wherein Lband R are as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-f.

[0072] In some embodiments of any Formulae described herein, L1is selected from: a covalent, wherein R is as defined herein; each Lcis independently an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0073] In some embodiments of any Formulae described herein, L1is selected from: a covalentX; and the bond labeled B is attached to TPM.

[0074] In some embodiments of any Formulae described herein, Lais a covalent bond.

[0075] In some embodiments of any Formulae described herein, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent,straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1 -2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0076] In some embodiments of any Formulae described herein, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0077] In some embodiments of any Formulae described herein, Lbis a covalent bond.

[0078] In some embodiments of any Formulae described herein, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -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)-, -S02-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0079] In some embodiments of any Formulae described herein, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0080] In some embodiments of any Formulae described herein, Lcis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain. In some embodiments, Lcis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-3 hydrocarbon chain. In some embodiments, Lcis optionally substituted C1-6 alkylene. In some embodiments, Lcis optionally substituted C1-3 alkylene. In some embodiments, Lcis C1-6 alkylene. In some embodiments, Lcis C1-3 alkylene. In some embodiments, Lcis -CH2- . In some embodiments, Lcis -CH2CH2-. In some embodiments, Lcis -CH2CH2CH2-.

[0081] In some embodiments of any Formulae described herein, each R is independently hydrogen or an optionally substituted group selected from C1-6 alkyl, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic and C3-7 monocyclic carbocyclyl. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more halogen, -OH, -O(C1-6 alkyl), -NH2, - N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each R is independently hydrogen or Ci- 6 alkyl optionally substituted with one or more halogen, -OH, -O(C1-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, each R is independently hydrogen or C1-6 alkyl. In some embodiments, each R is hydrogen. In some embodiments, a R is hydrogen. In some embodiments, a R is optionally substituted C1-6 aliphatic. In some embodiments, a R is C1-6 aliphatic optionally substituted with one or more halogen, -OH, -O(C1-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, an R is -CH2CH2N(CH3)2. In some embodiments, a R is optionally substituted C1-6 alkyl. In some embodiments, a R is C1-6 alkyl optionallysubstituted with one or more halogen, -OH, -O(C1-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, a R is C1-6 alkyl (e.g., methyl). In some embodiments, an R is isopropyl. In some embodiments, an R is methyl. In some embodiments, a R is optionally substituted phenyl. In some embodiments, a R is optionally substituted C3-7 monocyclic carbocyclyl. In some embodiments, a R is optionally substituted C3-7 cycloalkyl (e.g., cyclopropyl). In some embodiments, a R is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a R is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments of any Formulae described herein, each Cy is independently an optionally substituted, mono- or multi cyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, phenylene, a bicyclic C9-10 arylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10- membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, phenylene, a monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 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 bivalent ring system selected from a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, a bicyclic C9-10 arylene, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments of any Formulae described herein, a Cy is an optionally substituted monocyclic C3-7 carbocyclylene. In some embodiments, a Cy is an optionally substituted bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Cy is bivalent bicyclo[l.l.l]pentane. In some embodiments, a Cy is an optionally substituted phenylene. In some embodiments, a Cy is an optionally substituted bicyclic C9-10 arylene. In some embodiments, a Cy is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a bivalent pyrrolidine). In some embodiments, a Cy is an optionally substituted bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Cy is an optionally substituted monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is bivalent tetrazole. In some embodiments, a Cy is an optionally substituted bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0084] In some embodiments of any Formulae described herein, -X-L1- forms a self- immolative or degradable linking moiety, such that upon binding of the compound to KRASG12C, the tubulin inhibitor payload is released from the compound. It will be appreciated therefore that, in some embodiments, when both X and L1are a covalent bond, TPM is a sufficient leaving group to result in release of the tubulin inhibitor payload upon binding of the compound to KRASG12C.KRA^12CBinding Moie ty

[0085] As described and defined herein, KBM is a KRASG12Cbinding moiety, i.e., a moiety capable of binding KRASG12Cprotein. Typically, a KBM is considered to be capable of binding a KRASG12Cprotein if it specifically (or preferentially) associates with the KRASG12Cprotein when contacted with KRASG12Cprotein in the presence of at least one other protein. In some embodiments, a KBM is considered to be capable of binding KRASG12Cprotein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a KBM is considered capable of binding a KRASG12Cprotein if it binds to it with measurable affinity (e.g.,a binding constant of less than about 10 μM, less than about 1 μM, less than about 100 nM, less than about 10 nM, or less).

[0086] In some embodiments, the present disclosure provides a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: each R1is independently hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R2is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R2are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring;R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R4is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R4are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring;R5is hydrogen, -OR6,, -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R6is an optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy1and Cy2are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L2is a covalent bond or -N(R’)(CH2)m-;L3is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

[0087] In some embodiments, the present disclosure provides a compound of Formula Il-aII-a or a pharmaceutically acceptable salt thereof, wherein L1, L2, L3, R3, R\ Rx, Ry, Rz, X, Ring A, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination.

[0088] In some embodiments, the present disclosure provides a compound of Formula Il-bIl-b or a pharmaceutically acceptable salt thereof, wherein L1, R3, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein:Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.

[0089] In some embodiments, the present disclosure provides a compound of Formula II-cII-c or a pharmaceutically acceptable salt thereof, wherein L1, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein:Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene; andR33is hydrogen, a halogen, or an optionally substituted C1-6 aliphatic.

[0090] In some embodiments, the present disclosure provides a compound of Formula Il-d:Il-d or a pharmaceutically acceptable salt thereof, wherein L1, R3, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein: each R7is independently optionally substituted C1-6 aliphatic, or two R7are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R7moieties are attached; and nl is 0, 1, 2, 3, 4, 5, or 6.

[0091] In some embodiments, the present disclosure provides a compound of Formula II’:IF or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: each R1is independently hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3is hydrogen or C1-6 aliphatic; each R4is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R4are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring;v°^^Cy1R5is hydrogen, -OR6, , -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R6is an optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy1and Cy2are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L2is a covalent bond or -N(R’)(CH2)m-;L3is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclyl ene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

[0092] In some embodiments, the present disclosure provides a compound of Formula II’-a or II’-b:II’-air-b or a pharmaceutically acceptable salt thereof, wherein L1, R3, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein:Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.

[0093] In some embodiments, the present disclosure provides a compound of Formula II’-c orFormula Il’-d:II’ -d or a pharmaceutically acceptable salt thereof, wherein L1, R3, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II’ and described in classes and subclasses herein, both singly and in combination, and wherein: each R7is independently optionally substituted C1-6 aliphatic; and nl’ is 0, 1, 2, 3, 4, 5, or 6.

[0094] In some embodiments, the present disclosure provides a compound of Formula III:Ill or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:R8is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R9is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R10is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R11is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L4is a covalent bond or -N(R’)(CH2)m-;L5is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring B is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

[0095] In some embodiments, the present disclosure provides a compound of Formula Ill-a:or a pharmaceutically acceptable salt thereof, wherein L1, R9, R10, R11, Rx, Ry, Rz, X, and TPM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination, and wherein:Ring B is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.

[0096] In some embodiments, the present disclosure provides a compound of Formula Ill-b:111-b or a pharmaceutically acceptable salt thereof, wherein L1, R9, R10, R11, Rx, Ry, Rz, X, and TPM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination, and wherein: each R12is independently optionally substituted C1-6 aliphatic, or two R12are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R12moieties are attached; and n2 is 0, 1, 2, 3, 4, 5, or 6.

[0097] In some embodiments, the present disclosure provides a compound of Formula IV:IV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:R13is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R14is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R15is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R16is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R17is independently hydrogen or optionally substituted C1-6 aliphatic; each R18is independently hydrogen or optionally substituted C1-6 aliphatic, or two R18groups are taken together to form an oxo; each R19is independently hydrogen or optionally substituted C1-6 aliphatic; each R20is independently hydrogen or optionally substituted Ci.6 aliphatic; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic; q is 1 or 2; and p is 1 or 2.

[0098] In some embodiments, the present disclosure provides a compound of Formula IV-a:IV-a or a pharmaceutically acceptable salt thereof, wherein L1, R13, R14, R15, R16, Rx, Ry, Rz, X, and TPM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0099] In some embodiments, the present disclosure provides a compound of Formula V:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:R21is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Cy4is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy5is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L6is a covalent bond or -(CH2)mN(R’)-; m is 0, 1, or 2; andRing D is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, the present disclosure provides a compound of Formula V-a:V-a or a pharmaceutically acceptable salt thereof, wherein Cy4, Cy5, L1, R21, Rx, Ry, Rz, X, and TPM are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0101] In some embodiments, the present disclosure provides a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:Ring E is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L7is a covalent bond or -(CH2)mN(R’)-; m is 0, 1, or 2;R23is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R24is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Cy6is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring F is an optionally substituted 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andCy7is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, the present disclosure provides a compound of Formula Vl-a:Vl-a or a pharmaceutically acceptable salt thereof, wherein Cy6, Cy7, L1, Rx, Ry, Rz, X, Ring F, and TPM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination, and wherein:Ring E is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.

[0103] In some embodiments, the present disclosure provides a compound of Formula Vl-b:VI -b or a pharmaceutically acceptable salt thereof, wherein Cy6, Cy7, L1, Rx, Ry, Rz, X, Ring F, and TPM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination, and wherein: each R25is independently optionally substituted C1-6 aliphatic, or two R25are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R25moieties are attached; and n3 is 0, 1, 2, 3, 4, 5, or 6.

[0104] In some embodiments, the present disclosure provides a compound of Formula VII:VII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:Y is CR27or N;R26is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R27is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R28is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R29is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R30is hydrogen, -OR31,-O(Ci-4 alkylene)Cy9, or an optionally substituted3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R31is optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy8and Cy9are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L8is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring G is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring H is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 0, 1, or 2.

[0105] In some embodiments, the present disclosure provides a compound of Formula Vll-a:Vll-a or a pharmaceutically acceptable salt thereof, wherein L1, R28, R29, R30, Rx, Ry, Rz, X, Y, Ring H, and TPM are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination, and wherein:Ring G is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.

[0106] In some embodiments, the present disclosure provides a compound of Formula VIII:VIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:Y is CR27or N;R26is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R27is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R28is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R29is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R30is hydrogen, -OR31,, -O(Ci-4 alkylene)Cy9, or an optionally substituted3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R31is optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy8and Cy9are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic; each R32is independently optionally substituted C1-6 aliphatic, or two R32are taken together to form an optionally substituted 4- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R32moieties are attached;Ring J is an optionally substituted monocyclic 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0, 1, 2, 3, 4, 5, or 6.

[0107] In some embodiments of any Formulae described herein, each R1is independently hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, each R1is hydrogen. In some embodiments, an R1is a hydrogen. In some embodiments, an R1is a halogen. In some embodiments, an R1is -OR’. In some embodiments, an R1is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, an R1is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl). In some embodiments, each R1is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, each R1is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl).

[0108] In some embodiments of any Formulae described herein, each R2is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R2are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring. In some embodiments, each R2is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, each R2is hydrogen. In some embodiments, an R2is hydrogen. In some embodiments, an R2is -OR’. In some embodiments, an R2is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, an R2is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3- 7 cycloalkyl). In some embodiments, two R2are taken together to form an oxo. In some embodiments, two R2are taken together to form an optionally substituted C3-7 cycloaliphatic ring (e.g., optionally substituted C3-7 cycloalkyl ring).

[0109] In some embodiments of any Formulae described herein, R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R3is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -O(Ci-6alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0110] In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, Ci- 6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R3is a substituted phenyl. In some embodiments, R3is phenyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0111] In some embodiments, R3is phenyl substituted with one or more of the following groups: halogen, C1-6 aliphatic, C1-6 haloaliphatic, or -NH2. In some embodiments, R3is

[0112] In some embodiments, R3is an optionally substituted naphthyl. In some embodiments, R3is a naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R3is a substituted naphthyl. In some embodiments, R3a is naphthyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R3is a naphthyl optionally substituted with -CH3.

[0113] In some embodiments, R3is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R3is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0114] In some embodiments, R3is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R3is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0115] In some embodiments,, wherein R33is as defined herein for FormulaII-c and described in classes and subclasses herein, both singly and in combination. In some embodiments,embodiments,

[0116] In some embodiments of any Formulae described herein, R3is an optionally substituted ring selected from:XX

[0117] In some embodiments, R3is not Cl

[0118] In some embodiments of any Formulae described herein, R33is hydrogen, a halogen, or an optionally substituted C1-6 aliphatic. In some embodiments, R33is hydrogen. In some embodiments, R33is halogen (e.g. Cl). In some embodiments, R33is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, R33is methyl. In some embodiments, R33is not Cl.

[0119] In some embodiments of any Formulae described herein, R3is hydrogen or C1-6 aliphatic. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-6 aliphatic.

[0120] In some embodiments of any Formulae described herein, each R4is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R4are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring. In some embodiments, each R4is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, each R4is hydrogen. In some embodiments an R4is hydrogen. In some embodiments, an R4is an optionally substituted C1-6aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, an R4is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl). In some embodiments, each R4is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, each R4is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl). In some embodiments, two R4are taken together to form an oxo. In some embodiments, two R4are taken together to form an optionally substituted C3-7 cycloaliphatic ring (e.g., optionally substituted C3-7 cycloalkyl ring).

[0121] In some embodiments of any Formulae described herein, R5is hydrogen, -OR6,, -O(Ci-4alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is -OR ,, -O(Ci-4 alkylene)Cy , or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R?is hydrogen. In some embodiments, R5is -OR6. In some embodiments, R5is. In some embodiments,R5is -O(Ci-4 alkylene)Cy2. In some embodiments, R5is -OCIbCy2. In some embodiments, R5is an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is an optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., azetidinyl optionally substituted with -N(CI-6 alkyl)2).

[0122] In some embodiments, R5is selected from:

[0123] In some embodiments,some embodiments,

[0124] In some embodiments of any Formulae described herein, R6is an optionally substituted C1-6 aliphatic or an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is an optionally substituted C1-6 aliphatic. In some embodiments, R6is an optionally substituted C1-6 alkyl. In some embodiments, R6is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur optionally substituted with C1-6 alkyl. In some embodiments, R6is monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with C1-6 alkyl.

[0125] In some embodiments of any Formulae described herein, Cy1and Cy2are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0126] In some embodiments, Cy1is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl.

[0127] In some embodiments, Cy1is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted bicyclic 6- to 8-membered bridged heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0128] In some embodiments, Cy2is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl. In some embodiments, Cy2is an optionally substituted pyrrolidinyl.

[0129] In some embodiments, Cy2is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is a bicyclic 6- to 8- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl.

[0130] In some embodiments, Cy2is. In some embodiments, Cy2is. In some embodiments,embodiments,

[0131] In some embodiments of any Formulae described herein, L2is a covalent bond or - N(R’)(CH2)m-. In some embodiments, L2is a covalent bond. In some embodiments, L2is -N(R’)(CH2)m-. In some embodiments, L2is -N(H)(CH2)m-. In some embodiments, L2is - N(CH3)(CH2)m-. In some embodiments, L2is -N(R’)-. In some embodiments, L2is -N(R’)CH2-

[0132] In some embodiments of any Formulae described herein, L3is a covalent bond or - (CH2)mN(R’)-. In some embodiments, L3is a covalent bond. In some embodiments, L3is - (CH2)mN(R’)-. In some embodiments, L3is -(CH2)mN(H)-. In some embodiments, L3is - (CH2)mN(CH3)-. In some embodiments, L3is -N(R’)-. In some embodiments, L3is -CH2N(R’)-.

[0133] In some embodiments of any Formulae described herein, Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0134] In some embodiments, Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring A is an optionally substituted bivalent monocyclic C3-7 carbocyclylene. In some embodiments, Ring A is an optionally substituted bivalent bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene.

[0135] In some embodiments of any Formulae described herein, Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0136] In some embodiments, Ring A is an optionally substituted bivalent monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted monocyclic 4- to 6- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted monocyclic 3- to 7- membered heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring A is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring A is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more C1-6 alkyl or -CH2CN). In some embodiments, Ring A is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] In some embodiments, Ring A is an optionally substituted bivalent bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0138] In some embodiments of any Formulae described herein, Ring A is optionally substituted

[0139] In some embodiments of any Formulae described herein, Ringwherein R7and nl are as defined herein for Formula Il-d and described in classes and subclasses herein, both singly and in combination.

[0140] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:

[0141] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:

[0142] In some embodiments of any Formulae described herein, Ring A is selected from:

[0143] In some embodiments of any Formulae described herein, Ring A is selected from:

[0145] In some embodiments of any Formulae described herein, Ring A is:some embodiments, Ring A is:

[0146] In some embodiments of any Formulae described herein, each m is independently 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0147] In some embodiments of any Formulae described herein, each R7is independently optionally substituted C1-6 aliphatic, or two R7are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R7moieties are attached. In some embodiments, each R7is independently optionally substituted C1-6 aliphatic. In some embodiments, each R7is independently optionally substituted C1-6 alkyl. In some embodiments, a R7is optionally substituted C1-6 aliphatic. In some embodiments, a R7is optionally substituted C1-6 alkyl. In some embodiments, a R7is C1-6 alkyl optionally substituted with -CN. In some embodiments, a R7is -CH3 or -CH2CN. In some embodiments, two R7are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / orspirofused with the ring to which the R7moieties are attached. In some embodiments, two R7are taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R7moieties are attached.

[0148] In some embodiments of any Formulae described herein, nl is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, nl is 0. In some embodiments, nl is 1. In some embodiments, nl is 2. In some embodiments, nl is 3. In some embodiments, nl is 4. In some embodiments, nl is 5. In some embodiments, nl is 6.

[0149] In some embodiments of any Formulae described herein, each R7is independently optionally substituted C1-6 aliphatic. In some embodiments, a R7is C1-6 aliphatic. In some embodiments, a R7is optionally substituted C1-6 alkyl. In some embodiments, a R7is C1-6 alkyl optionally substituted with -CN. In some embodiments, a R7is C1-6 alkyl. In some embodiments, a R7is -CH3. In some embodiments, a R7is -CH2CN. In some embodiments, a R7is -CH3 or - CH2CN.

[0150] In some embodiments of any Formulae described herein, nl’ is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, nl’ is 0. In some embodiments, nl’ is 1. In some embodiments, nl’ is 2. In some embodiments, nl’ is 3. In some embodiments, nl’ is 4. In some embodiments, nl’ is 5. In some embodiments, nl’ is 6.

[0151] In some embodiments of any Formulae described herein, R8is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R8is hydrogen. In some embodiments, R8is a halogen. In some embodiments, R8is -OR’. In some embodiments, R8is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, R8is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl). In some embodiments, R8is not H.

[0152] In some embodiments of any Formulae described herein, R9is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R9is hydrogen. In some embodiments, R9is a halogen. In some embodiments, R9is F or Cl. In some embodiments, R9is F. In some embodiments, R9is -OR’. In some embodiments, R9is an optionally substituted C1-6 aliphatic or an optionally substituted C3-7 cycloaliphatic. In some embodiments, R9is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, R9is an optionally substituted C3-7 cycloaliphatic (e.g., optionallysubstituted C3-7 cycloalkyl). In some embodiments, R9is not a halogen. In some embodiments, R9is not F.

[0153] In some embodiments of any Formulae described herein, R10is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R10is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R10is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0154] In some embodiments, R10is an optionally substituted phenyl. In some embodiments, R10is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, Ci- 6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R10is a substituted phenyl. In some embodiments, R10is a phenyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0155] In some embodiments, R10is an optionally substituted naphthyl. In some embodiments, R10is a naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R10is a substituted naphthyl. In some embodiments, R10is a naphthyl substituted with one or more halogen, -CN, - OH, -O(Ci-6alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R10is a naphthyl optionally substituted with -CH3.

[0156] In some embodiments, R10is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R10is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or morehalogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. Tn some embodiments, R10is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R10is a 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0157] In some embodiments, R10is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R10is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R10is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R10is 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0158] In some embodiments,some embodiments,some embodiments,

[0159] In some embodiments, R10is not a phenyl. In some embodiments, R10is not aOH substituted phenyl. In some embodiments, R10is not

[0160] In some embodiments of any Formulae described herein, R11is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0161] In some embodiments, R11is an optionally substituted phenyl. In some embodiments, R11is a phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0162] In some embodiments, R11is an optionally substituted naphthyl. In some embodiments, R11is a naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0163] In some embodiments, R11is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R11is an optionally substituted 6-membered monocyclic heteroaryl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R11is a pyridyl or pyrimidyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0164] In some embodiments, R11is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R11is a 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0165] In some embodiments,some embodiments,

[0166] In some embodiments, R11is not an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R11is not an optionally substituted pyridyl. In some embodiments,

[0167] In some embodiments of any Formulae described herein, L4is a covalent bond or - N(R’)(CH2)m-. In some embodiments, L4is a covalent bond. In some embodiments, L4is - N(R’)(CH2)m-. In some embodiments, L4is -N(H)(CH2)m-. In some embodiments, L4is -N(CH3)(CH2)m-. In some embodiments, L4is -N(R’)-. In some embodiments, L4is -N(R’)CH2-. In some embodiments, L4is not a covalent bond.

[0168] In some embodiments of any Formulae described herein, L5is a covalent bond or - (CH2)mN(R’)-. In some embodiments, L5is a covalent bond. In some embodiments, I? is - (CH2) m N(R’)-. In some embodiments, L5is -(CH2)mN(H)-. In some embodiments, L5is - (CH2)mN(CH3)-. In some embodiments, L5is -N(R’)-. In some embodiments, L5is -CH2N(R’)-. In some embodiments, L5is not a covalent bond.

[0169] In some embodiments of any Formulae described herein, Ring B is an optionally substituted bivalent ring selected from a monocyclic C3.7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0170] In some embodiments, Ring B is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring B is an optionally substituted bivalent monocyclic C3.7 carbocyclylene. In some embodiments, Ring B is an optionally substituted bivalent bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene.

[0171] In some embodiments, Ring B is selected from a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0172] In some embodiments, Ring B is an optionally substituted bivalent monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted monocyclic 4- to 6- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted monocyclic 3- to 7- membered heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionallysubstituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring B is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring B is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more C1-6 alkyl or -CH2CN). In some embodiments, Ring B is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0173] In some embodiments, Ring B is an optionally substituted bivalent bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0174] In some embodiments of any Formulae described herein, Ring B is optionally substituted

[0175] In some embodiments of any Formulae described herein, Ringwherein R12and n2 are as defined herein for Formula Ill-b and described in classes and subclasses herein, both singly and in combination.

[0176] In some embodiments, Ring, whereindepicts a bond to L5. In some embodiments, Ring B is, whereindepicts a bond to L5.

[0177] In some embodiments, Ring B is not an optionally substituted bivalent monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is not, whereindepicts a bond toL5.

[0178] In some embodiments of any Formulae described herein, each R12is independently optionally substituted Cue aliphatic, or two R12are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R12moieties are attached. In some embodiments, each R12is independently optionally substituted Ci- 6 aliphatic. In some embodiments, each R12is independently optionally substituted C1-6 alkyl. In some embodiments, each R12is methyl. In some embodiments, a R12is optionally substituted C1-6 aliphatic. In some embodiments, a R12is optionally substituted C1-6 alkyl. In some embodiments, aR12is C1-6 alkyl optionally substituted with -CN. In some embodiments, aR12is -CH3 or-CFBCN. In some embodiments, two R12are taken together to form an optionally substituted 3- to 7- membered ring that is fused, bridged, and / or spirofused with the ring to which the R12moieties are attached. In some embodiments, two R12are taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R12moieties are attached.

[0179] In some embodiments of any Formulae described herein, n2 is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6.

[0180] In some embodiments of any Formulae described herein, R13is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R13is hydrogen. In some embodiments, R13is a halogen. In some embodiments, R13is F. In some embodiments, R13is -OR’. In some embodiments, R13is an optionally substituted Ci- 6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, R13is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted an optionally substituted C3-7 cycloalkyl).

[0181] In some embodiments of any Formulae described herein, R14is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R14is hydrogen. In some embodiments, R14is a halogen. In some embodiments, R14is F. In some embodiments, R14is -OR’. In some embodiments, R14is an optionally substituted Ci- 6 aliphatic (e.g., an optionally substituted C1-6 alkyl or optionally substituted C2-6 alkynyl). In some embodiments, R14is. In some embodiments, R14is CN. In some embodiments, R14is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0182] In some embodiments of any Formulae described herein, R15is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0183] In some embodiments of any Formulae described herein, R13is an optionally substituted phenyl. In some embodiments, R13is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R13is substituted phenyl. In some embodiments, R13is phenyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0184] In some embodiments of any Formulae described herein, R15is an optionally substituted naphthyl. In some embodiments, R15is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R15is substituted naphthyl. In some embodiments, R15is naphthyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R15is naphthyl optionally substituted with -CH3.

[0185] In some embodiments of any Formulae described herein, R15is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R15is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R13is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R15is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0186] In some embodiments of any Formulae described herein, R15is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R15is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R15is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R15is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, - CN, -OH, -O(Ci-6alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0187] In some embodiments,some embodiments,some embodiments,

[0188] In some embodiments of any Formulae described herein, R16is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments R16is hydrogen. In some embodiments R16is a halogen. In some embodiments R16is F. In some embodiments R16is Cl. In some embodiments R16is -OR’. In some embodiments R16is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments R16is an optionally substituted C3-7 cycloaliphatic (e g., an optionally substituted C3- 7 cycloalkyl).

[0189] In some embodiments of any Formulae described herein, each R17is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each R17is hydrogen. In some embodiments, an R17is a hydrogen. In some embodiments R17is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl).

[0190] In some embodiments of any Formulae described herein, each R18is independently hydrogen or optionally substituted C1-6 aliphatic, or two R18groups are taken together to form an oxo. In some embodiments, an R18is a hydrogen or an optionally substituted C1-6 aliphatic. In some embodiments, an R18is a hydrogen. In some embodiments, each R18is a hydrogen. In some embodiments, an R18is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, each R18is an optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, two R18groups are taken together to form an oxo.

[0191] In some embodiments of any Formulae described herein, each R19is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, an R19is a hydrogen. In some embodiments, each R19is a hydrogen. In some embodiments, an R19is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, each R19is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl).

[0192] In some embodiments of any Formulae described herein, each R20is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each R20is a hydrogen. In some embodiments, an R20is a hydrogen. In some embodiments, an R20is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, each R20is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl).

[0193] In some embodiments of any Formulae described herein, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2.

[0194] In some embodiments of any Formulae described herein, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0195] In some embodiments of any Formulae described herein, R21is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R21is hydrogen. In some embodiments, R21is a halogen. In some embodiments, R21is F. In some embodiments, R21is -OR’. In some embodiments, R21is an optionally substituted Ci. 6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, R21is methyl. In some embodiments, R21is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0196] In some embodiments of any Formulae described herein, Cy4is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy4is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy4is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0197] In some embodiments, Cy4is an optionally substituted phenyl. In some embodiments, Cy4is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy4is substituted phenyl. In some embodiments, Cy4is phenyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0198] In some embodiments, Cy4is an optionally substituted naphthyl. In some embodiments, Cy4is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, Cy4is substituted naphthyl. In some embodiments, Cy4is naphthyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, Cy4is naphthyl optionally substituted with -CH3.

[0199] In some embodiments, Cy4is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Cy4is 5- to 6-membered monocyclic heteroaryl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy4is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy4is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0200] In some embodiments, Cy4is an optionally substituted, 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy4is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy4is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy4is 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0201] In some embodiments,

[0202] In some embodiments of any Formulae described herein, Cy5is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy3is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclicheteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0203] In some embodiments, Cy5is an optionally substituted phenyl. In some embodiments, Cy5is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy5is substituted phenyl. In some embodiments, Cy5is phenyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0204] In some embodiments, Cy5is an optionally substituted naphthyl. In some embodiments, Cy5is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e g., -CH3), or C1-6 haloaliphatic. In some embodiments, Cy5is substituted naphthyl. In some embodiments, Cy5is naphthyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, Cy5is naphthyl optionally substituted with -CH3.

[0205] In some embodiments, Cy5is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy5is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy5is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy3is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0206] In some embodiments, Cy5is an optionally substituted, 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy5is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy5is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy5is 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0207] In some embodiments,

[0208] In some embodiments of any Formulae described herein, L6is a covalent bond or - (CH2) m N(R’)-. In some embodiments, L6is a covalent bond. In some embodiments, L6is - (CH2)mN(R’)-.

[0209] In some embodiments of any Formulae described herein, Ring D is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0210] In some embodiments, Ring D is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring D is an optionally substituted bivalent monocyclic C3-7 carbocyclylene. In some embodiments, Ring D is an optionally substituted bivalent bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene.

[0211] In some embodiments, Ring D is an optionally substituted bivalent ring selected a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0212] In some embodiments, Ring D is an optionally substituted bivalent monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted monocyclic 4- to 6- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted monocyclic 3- to 7- membered heterocyclylene having at least one nitrogen and optionally one additional heteroatomindependently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring D is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring D is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more C1-6 alkyl or -CH2CN). In some embodiments, Ring D is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0213] In some embodiments, Ring D is an optionally substituted bivalent bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0214] In some embodiments, Ring

[0215] In some embodiments of any Formulae described herein, Ring E is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0216] In some embodiments, Ring E is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring E is an optionally substituted bivalent monocyclic C3-7 carbocyclylene. In some embodiments, Ring E is an optionally substituted bivalent bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene.

[0217] In some embodiments, Ring E is an optionally substituted bivalent ring selected a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0218] In some embodiments, Ring E is an optionally substituted bivalent monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is an optionally substituted monocyclic 4- to 6- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is an optionally substituted monocyclic 3- to 7- membered heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is an optionally substituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring E is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring E is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more C1-6 alkyl or -CH2CN). In some embodiments, Ring E is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0219] In some embodiments, Ring E is an optionally substituted bivalent bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is an optionallysubstituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0220] In some embodiments of any Formulae described herein, Ring E is optionally substituted Y '®A

[0221] In some embodiments of any Formulae described herein, Ringwherein R23and n3 are as defined herein for Formula Vl-b and described in classes and subclasses herein, both singly and in combination.

[0222] In some embodiments, Ring

[0223] In some embodiments of any Formulae described herein, L7is a covalent bond or -(CH2)tnN(R’)-. In some embodiments, L7is a covalent bond. In some embodiments, L7is - (CH2)mN(R’)-.

[0224] In some embodiments of any Formulae described herein, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0225] In some embodiments of any Formulae described herein, R23is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R23is hydrogen. In some embodiments, R23is a halogen. In some embodiments, R23is F. In some embodiments, R23is -OR’. In some embodiments, R23is an optionally substituted Ci. 6 aliphatic (e g., an optionally substituted C1-6 alkyl). In some embodiments, R23is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0226] In some embodiments of any Formulae described herein, R24is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In someembodiments, R24is hydrogen. In some embodiments, R24is a halogen. In some embodiments, R24is F. In some embodiments, R24is -OR’. In some embodiments, R24is an optionally substituted Ci- 6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, R24is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0227] In some embodiments of any Formulae described herein, Cy6is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0228] In some embodiments, Cy6is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy6is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy6is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl.

[0229] In some embodiments, Cy6is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy6is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy6is an optionally substituted bicyclic 6- to 8-membered bridged heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0230] In some embodiments, Cy6is selected from:some

[0231] In some embodiments of any Formulae described herein, Ring F is an optionally substituted 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring F is an optionally substituted 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring F is an optionally substituted 6- membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring F is, whereindepicts a bond to Cy7.

[0232] In some embodiments of any Formulae described herein, Cy7is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0233] In some embodiments, Cy7is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy7is a substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0234] In some embodiments, Cy7is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy7is a substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with one or more halogen, -CN, -OH, - O(Ci-6alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0235] In some embodiments, Cy7is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy7is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0236] In some embodiments, Cy7is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is an optionally substituted 9- to 10-membered bicyclic heteroaryl having1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy7is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy7is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0237] In some embodiments,

[0238] In some embodiments of any Formulae described herein, each R25is independently optionally substituted C1-6 aliphatic, or two R23are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R25moieties are attached. In some embodiments, each R25is independently optionally substituted Ci- 6 aliphatic. In some embodiments, each R25is independently optionally substituted C1-6 alkyl. In some embodiments, each R25is methyl. In some embodiments, a R23is optionally substituted C1-6 aliphatic. In some embodiments, a R25is optionally substituted C1-6 alkyl. In some embodiments, R23is methyl. In some embodiments, a R23is C1-6 alkyl optionally substituted with -CN. In some embodiments, a R25is -CH3 or -CH2CN. In some embodiments, two R25are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R23moieties are attached. In some embodiments, two R23are taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R23moieties are attached.

[0239] In some embodiments of any Formulae described herein, n3 is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n3 is 0. In some embodiments, n3 is 1. In some embodiments, n3 is 2. In some embodiments, n3 is 3. In some embodiments, n3 is 4. In some embodiments, n3 is 5. In some embodiments, n3 is 6.

[0240] In some embodiments of any Formulae described herein, Y is CR27or N. In some embodiments, Y is CR27. In some embodiments, Y is N.

[0241] In some embodiments of any Formulae described herein, R26is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In someembodiments, R26is hydrogen. In some embodiments, R26is a halogen. In some embodiments, R26is -OR’. In some embodiments, R26is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, R26is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0242] In some embodiments of any Formulae described herein, R27is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R27is hydrogen. In some embodiments, R27is a halogen. In some embodiments, R27is a Cl. In some embodiments, R27is -OR’. In some embodiments, R27is an optionally substituted C1-6 aliphatic (e.g., an optionally substituted C1-6 alkyl). In some embodiments, R27is an optionally substituted C3-7 cycloaliphatic (an optionally substituted C3-7 cycloalkyl).

[0243] In some embodiments of any Formulae described herein, R28is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R28is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R28is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0244] In some embodiments, R28is an optionally substituted phenyl. In some embodiments, R28is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, Ci- 6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R28is substituted phenyl. In some embodiments, R28is phenyl substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0245] In some embodiments, R28is an optionally substituted naphthyl. In some embodiments, R28is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2,C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R28is a substituted naphthyl. In some embodiments, R28is a naphthyl substituted with one or more halogen, -CN, - OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R3is a naphthyl optionally substituted with -CH3.

[0246] In some embodiments, R28is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R28is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R28is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R28is 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0247] In some embodiments, R28is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R28is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R28is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R28is 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0248] In some embodiments,some embodiments,.

[0249] In some embodiments of any Formulae described herein, R29is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R29is hydrogen. In some embodiments, R29is a halogen. In some embodiments, R29is F. In some embodiments, R29is -OR’. In some embodiments, R29is an optionally substituted Ci. 6 aliphatic (an optionally substituted C1-6 alkyl). In some embodiments, R29is an optionally substituted C3-7 cycloaliphatic (an optionally substituted C3-7 cycloalkyl).

[0250] In some embodiments of any Formulae described herein, R30is hydrogen, -OR31,, -O(Ci-4 alkylene)Cy9, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R30is hydrogen. In some embodiments, R30is -OR31,, -O(Ci-4 alkylene)Cy9, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R30is -OR31,. In some embodiments, R30is -O(Ci-4 alkylene)Cy9. In some embodiments, R30is -OCFFCy9. In some embodiments, R30is an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R30is an optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., azetidinyl optionally substituted with -N(CI-6 alkyl k).

[0251] In some embodiments of any Formulae described herein, R31is optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R31is an optionally substituted C1-6 aliphatic. In some embodiments, R31is an optionally substituted C1-6 alkyl. In some embodiments, R31is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R31is optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R31is monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with C1-6 alkyl. In some embodiments, R31is monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with C1-6 alkyl.

[0252] In some embodiments of any Formulae described herein, Cy8and Cy9are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0253] In some embodiments, Cy8is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy8is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy8is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl.

[0254] In some embodiments, Cy8is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy8is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy8is an optionally substituted bicyclic 6- to 8-membered bridged heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0255] In some embodiments, Cy9is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy9is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy9is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl. In some embodiments, Cy9is an optionally substituted pyrrolidinyl.

[0256] In some embodiments, Cy9is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy9is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy9is a bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or C1-6 alkyl.

[0257] In some embodiments of any Formulae described herein, L8is a covalent bond or - (CH2) m N(R’)-. In some embodiments, L8is a covalent bond. In some embodiments, L8is - (CH2)mN(R’)-.

[0258] In some embodiments of any Formulae described herein, Ring G is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclyl ene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0259] In some embodiments, Ring G is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring G is an optionally substituted bivalent monocyclic C3-7 carbocyclylene. In some embodiments, Ring G is an optionally substituted bivalent bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene.

[0260] In some embodiments, Ring G is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0261] In some embodiments, Ring G is an optionally substituted bivalent monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is an optionally substituted monocyclic 4- to 6- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is an optionally substituted monocyclic 3- to 7- membered heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is an optionally substituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring G is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring A is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more C1-6 alkyl or -CH2CN). In some embodiments, Ring G is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0262] In some embodiments, Ring G is an optionally substituted bivalent bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is an optionally substituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0263] In some embodiments of any Formulae described herein, Ring G is optionally

[0264] In some embodiments, Ring G is, whereindenotes a bond to L8anddenotes a bond to Ring H. In some embodiments, Ring G is, whereindenotes a bond toL8anddenotes a bond to Ring H.

[0265] In some embodiments of any Formulae described herein, Ring H is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring H is an optionallysubstituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring H is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0266] In some embodiments, Ring H, taken with the ring to which it is fused, is

[0267] In some embodiments of any Formulae described herein, each R32is independently optionally substituted C1-6 aliphatic, or two R32are taken together to form an optionally substituted 4- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R32moieties are attached. In some embodiments, each R32is an optionally substituted C1-6 aliphatic. In some embodiments, an R32is an optionally substituted C1-6 alkyl. In some embodiments, an R32is an optionally substituted C1-6 alkyl. In some embodiments, R32is methyl. In some embodiments, aR32is C1-6 alkyl optionally substituted with -CN. In some embodiments, aR32is -CH3 or-CFfcCN. In some embodiments, two R32are taken together to form an optionally substituted 4- to 7- membered ring that is fused, bridged, and / or spirofused with the ring to which the R32moieties are attached.

[0268] In some embodiments of any Formulae described herein, Ring J is an optionally substituted monocyclic 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring J is an optionally substituted monocyclic 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0269] In some embodiments, Ring I, taken with the rings to which it is fused, is. In some embodiments, Ring J, taken with the rings to which it is fused, is. In some embodiments, Ring J, taken with the rings to which it is fused, is

[0270] In some embodiments of any Formulae described herein, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0271] In some embodiments of any Formulae described herein, each R’ is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each R’ is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl. In some embodiments, a R’ is hydrogen. In some embodiments, a R’ is optionally substituted C1-6 aliphatic. In some embodiments, a R’ is optionally substituted C1-6 alkyl. In some embodiments, a R’ is C1-6 alkyl. In some embodiments, a R’ is C1-6 haloalkyl.

[0272] In some embodiments of any Formulae described herein, a moiety, embodiments, when L2is -N(R’)(CH2)m-, then L3is a covalent bond. In some embodiments, whenL3is -(CH2)mN(R’)-, then L2is a covalent bond. In some embodiments, when Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, then L3is -(CH2)mN(R’)-.

[0273] In some embodiments of any Formulae described herein, a moietyembodiments, when L4is -N(R’)(CH2)m-, then L5is a covalent bond. In some embodiments, whenL5is -(CH2)mN(R’)-, then L4is a covalent bond. In some embodiments, when Ring B is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4- 10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then L5is -(CH2)mN(R’)-.

[0275] In some embodiments of any Formulae described herein, a moiety

[0276] In some embodiments of any Formulae described herein, a moiety(i.e., L6is a covalent bond). In some embodiments, when Ring D is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then L6is -(CH2)mN(R’)-.

[0277] In some embodiments of any Formulae described herein, a moiety

[0278] In some embodiments of any Formulae described herein, a moietyis(i.e., L7is a covalent bond). In some embodiments, when Ring E is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then L7is -(CH2)mN(R’)-.

[0280] In some embodiments of any Formulae described herein, a moietyis(i.e., L8is a covalent bond). In some embodiments, when Ring G is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then L8is -(CH2)mN(R’)-.

[0281] In some embodiments of any Formulae described herein, a moietyselected from:

[0282] In some embodiments of any Formulae described herein, KBM is:

[0283] In some embodiments of any Formulae described herein, KBM is:

[0284] In some embodiments of any Formulae described herein, KBM is:

[0285] In some embodiments of any Formulae described herein, KBM is:

[0286] In some embodiments of any Formulae described herein, KBM is:

[0287] In some embodiments of any Formulae described herein, KBM is:

[0288] In some embodiments of any Formulae described herein, KBM is:

[0289] In some embodiments of any Formulae described herein, KBM is:

[0290] In some embodiments of any Formulae described herein, KBM is:

[0291] In some embodiments of any Formulae described herein, KBM is:

[0292] In some embodiments of any Formulae described herein, KBM is:

[0293] In some embodiments of any Formulae described herein, KBM is:

[0294] In some embodiments of any Formulae described herein, KBM is:

[0295] In some embodiments of any Formulae described herein, KBM is:

[0296] In some embodiments of any Formulae described herein, KBM is:

[0297] In some embodiments of any Formulae described herein, KBM is:

[0298] In some embodiments of any Formulae described herein, KBM is:

[0299] In some embodiments of any Formulae described herein, KBM is:

[0300] In some embodiments of any Formulae described herein, KBM is:wherein L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0301] In some embodiments of any Formulae described herein, KBM is:wherein L2, L3, R3, R5, and Ring A are as defined herein for Formula Il-a and described in classes and subclasses herein, both singly and in combination.

[0302] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, and Ring A are as defined herein for Formula Il-b and described in classes and subclasses herein, both singly and in combination.

[0303] In some embodiments of any Formulae described herein, KBM is:wherein L2, L3, R1, R3, R3, R4, R5, and Ring A are as defined herein for Formula II’ and described in classes and subclasses herein, both singly and in combination.

[0304] In some embodiments of any Formulae described herein, KBM is:wherein L2, L3, R3, R5, and Ring A are as defined herein for Formula II’-a and Il’-b and described in classes and subclasses herein, both singly and in combination.

[0305] In some embodiments of any Formulae described herein, KBM is:wherein L2, L3, R3, R5, and Ring A are as defined herein for Formula II’-a and Il’-b and described in classes and subclasses herein, both singly and in combination.

[0306] In some embodiments of any Formulae described herein, KBM is:wherein L2, L3, R3, R5, and Ring A are as defined herein for Formula II’-a and Il’-b and described in classes and subclasses herein, both singly and in combination.

[0307] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, and Ring A are as defined herein for Formula II’-a and IF-b and described in classes and subclasses herein, both singly and in combination.

[0308] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, and Ring A are as defined herein for Formula II’-a and II’-b and described in classes and subclasses herein, both singly and in combination.

[0309] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, and Ring A are as defined herein for Formula IF -a and IF-b and described in classes and subclasses herein, both singly and in combination.

[0310] In some embodiments of any Formulae described herein, KBM is:wherein R33, R5, and Ring A are as defined herein for Formula II-c and described in classes and subclasses herein, both singly and in combination.

[0311] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, R7, and nl are as defined herein for Formula Il-d and described in classes and subclasses herein, both singly and in combination.

[0312] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, R7, and nl ’ are as defined herein for Formula II’-c and II’-d and described in classes and subclasses herein, both singly and in combination.

[0313] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, R7, and nl’ are as defined herein for Formula II’-c and II’-d and described in classes and subclasses herein, both singly and in combination.

[0314] In some embodiments of any Formulae described herein, KBM is:wherein R3, R5, R7, and nl’ are as defined herein for Formula II’-c and II’-d and described in classes and subclasses herein, both singly and in combination.

[0315] In some embodiments of any Formulae described herein, KBM is:wherein L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination.

[0316] In some embodiments of any Formulae described herein, KBM is:wherein R9, R10, R11, and Ring B are as defined herein for Formula III-a and described in classes and subclasses herein, both singly and in combination.

[0317] In some embodiments of any Formulae described herein, KBM is:wherein R9, R10, R11, R12, and n2 are as defined herein for Formula Ill-b and described in classes and subclasses herein, both singly and in combination.

[0318] In some embodiments of any Formulae described herein, KBM is:wherein R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0319] In some embodiments of any Formulae described herein, KBM is:wherein R13, R14, R15, and R16are as defined herein for Formula IV-a and described in classes and subclasses herein, both singly and in combination.

[0320] In some embodiments of any Formulae described herein, KBM is:wherein L6, Cy4, Cy5, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination.

[0321] In some embodiments of any Formulae described herein, KBM is:wherein Cy4, Cy5, and R21are as defined herein for Formula V-a and described in classes and subclasses herein, both singly and in combination.

[0322] In some embodiments of any Formulae described herein, KBM is:wherein L7, Cy6, Cy7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination.

[0323] In some embodiments of any Formulae described herein, KBM is:wherein Cy6, Cy7, Ring E, and Ring F are as defined herein for Formula Vl-a and described in classes and subclasses herein, both singly and in combination.

[0324] In some embodiments of any Formulae described herein, KBM is:wherein Cy6, Cy7, R25, n3 and Ring F are as defined herein for Formula VT-b and described in classes and subclasses herein, both singly and in combination.

[0325] In some embodiments of any Formulae described herein, KBM is:wherein Y, L8, R26, R28, R29, R30, Ring H, and Ring G are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination.

[0326] In some embodiments of any Formulae described herein, KBM is:wherein Y, R28, R29, R30, Ring H, and Ring G are as defined herein for Formula Vll-a and described in classes and subclasses herein, both singly and in combination.

[0327] In some embodiments of any Formulae described herein, KBM is:wherein Y, R26, R28, R29, R30, R32, Ring J, and n are as defined herein for Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0328] In some embodiments, KBM is a KRASG12Cbinding moiety (e.g., a moiety that binds and / or inhibits KRASG12C). The present disclosure encompasses the recognition that i) KRASG12Cinhibitor compounds generally comprise an a,P-unsaturated carbonyl moiety (or other suitable Michael acceptor) at a suitable position to interact with a cysteine of KRASG12C, and ii) a KRASG12Cbinding moiety in the CIDCs described herein can be made by installing a linking moiety bound to a tubulin inhibitor payload moiety, as defined herein (e.g.,such suitable position where an a,P-unsaturated carbonyl moiety is located on a KRASG12Cinhibitor compound. In some embodiments, a KBM is a KRASG12Cbinding moiety (e.g., without an a,P-unsaturated carbonyl moiety) of a KRASG12Cinhibitor selected from sotorasib, adagrasib, divarasib, opnurasib, garsorasib, MRTX-1257, BI-0474, ASP2453, BBO- 8520, AZD4625, LY3537982, ARS-1620, and AZD4747. In some embodiments, KBM is a KRASG12Cbinding moiety (e.g., without an a,P-unsaturated carbonyl moiety) of a KRASG12Cinhibitor described in WO2018 / 119183; WO2018 / 217651; WO2019 / 051291; WO2020 / 259432; WO2019 / 241157; WO2021 / 104431; W02020 / 156285; CN112225734; WO2021 / 027943; CN112390796; W02021 / 037018; WO2021 / 043322; WO2021 / 063346; CN112574199;CN112778302; CN112920183; WO2021 / 118877; CN113004269; WO2021 / 124222;W02021 / 120890; WO2021 / 121371; WO2021 / 143693; WO2021 / 249563; WO2022 / 135591; CN113754653; CN114380827; WO2022 / 111527; WO2022 / 135546; CN114685460;CN114874234; W02023 / 045960; WO2023 / 066371; WO2023 / 072297; CN116120315;CN116199703; CN116217592; WO2023 / 196959; WO2023 / 199180; WO2023 / 226902;WO2013 / 155223; WO2014 / 143659; WO2014 / 152588; WO2014 / 160200; WO2015 / 054572;WO20 16 / 044772; WO2016 / 049524; WO2016 / 164675; WO2016 / 168540; W02017 / 058805;WO2017 / 015562; WO2017 / 058728; WO2017 / 058768; WO2017 / 058792; W02017 / 058805;W02017 / 058807; W02017 / 058902; WO2017 / 058915; WO2017 / 087528; W02017 / 100546;W02017 / 201161; WO2018 / 064510; WO2018 / 068017; WO2018 / 119183; W02018 / 140512;W02018 / 140513; W02018 / 140514; WO2018 / 140598; WO2018 / 140599; WO2018 / 140600;WO2018 / 143315; WO2018 / 206539; WO2018 / 218070; WO2018 / 218071; WO2019 / 099524;W02019 / 110751; W02019 / 141250; W02019 / 150305; WO2019 / 155399; WO2019 / 213516;WO2019 / 213526; WO2019 / 217307; WO2019 / 217691; WO2019 / 232419; W02020 / 050890;W02020 / 035031; W02020 / 047192; W02020 / 081282; W02020 / 086739; W02020 / 106640;W02020 / 113071; WO2021 / 055728; W02021 / 058018; WO2021 / 086833; WO2022 / 083569;WO2022 / 087375; WO2022 / 087371; WO2022 / 093856; WO2022 / 109487; WO2022 / 109485;WO2022 / 119748; WO2022 / 152233; WO2022 / 221528; WO2022 / 232318; WO2022 / 232320;WO2022 / 269508; WO2022 / 269525; WO2023 / 225252; WO2023 / 133181; W02023 / 004102;WO2023 / 283213; WO2023 / 284730; WO2023 / 287896; WO2023 / 284537; WO2023 / 283933;W02023 / 001141; W02023 / 018809; W02023 / 018699; W02023 / 034290; W02023 / 030495;W02023 / 030517; W02024 / 050640; W02023 / 039240; WO2023 / 049697; WO2023 / 046135;WO2023 / 056421; WO2023 / 057985; WO2023 / 064857; W02023 / 081840; WO2023 / 086341;WO2023 / 086383; WO2023 / 097227; WO2023 / 101928; WO2023 / 099623; WO2023 / 099612;WO2023 / 099592; WO2023 / 105491; WO2023 / 114733; WO2023 / 125627; WO2023 / 133183;W02023 / 141300; WO2023 / 150284; WO2023 / 154766; WO2023 / 152255; WO2023 / 159086;WO2023 / 159087; WO2023 / 173014; WO2023 / 172737; WO2023 / 183755; WO2023 / 179703;WO2023 / 183585; WO2023 / 205719; WO2023 / 212548; WO2023 / 212549; WO2023 / 215801;WO2023 / 213269; WO2023 / 219941; WO2023 / 220421; WO2023 / 225302; W02023 / 230190;WO2023 / 240263; WO2023 / 240189; WO2023 / 240188; WO2023 / 244604; WO2023 / 244599;WO2023 / 244615; WO2023 / 244713; WO2023 / 246777; W02024 / 008610; W02024 / 008068;W02024 / 009191; W02024 / 008179; W02024 / 008834; W02024 / 015262; W02024 / 015731;W02024 / 030647; W02024 / 030633; W02024 / 036270; W02024 / 032703; W02024 / 032704;W02024 / 032702; W02024 / 040109; W02024 / 040131; WO2024 / 041621; WO2024 / 041573;WO2024 / 047135; WO2024 / 054926; WO2024 / 051721; WO2024 / 054647; WO2024 / 064353;WO2024 / 076674; W02024 / 076670; WO2024 / 085661; WO2024 / 083168; WO2024 / 083246;W02024 / 091409; WO2024 / 097559; W02024 / 103010; WO2024 / 107686; WO2024 / 112654;WO2024 / 120419; WO2024 / 153116; WO2024 / 155706; WO2024 / 153119; WO2024 / 158778;WO2024 / 159471; WO2024 / 159470; WO2024 / 173842; WO2024 / 178304; WO2024 / 178313;WO2024 / 179546; WO2024 / 192424; WO2024 / 197503; WO2024 / 206747; WO2024 / 206766;WO2024 / 209339; WO2024 / 213979; WO2024 / 215754; WO2024 / 220532; WO2024 / 220645;WO2024 / 218686; WO2024 / 227091; WO2024 / 229317; WO2024 / 229442; WO2024 / 229444;WO2024 / 229447; WO2024 / 230734; WO2024 / 233776; WO2024 / 236452; WO2024 / 238343;WO2024 / 238633; WO2024 / 235286; WO2024 / 243025; WO2024 / 241248; WO2024 / 246099;WO2024 / 259169; WO2024 / 255795; W02025 / 006704; W02025 / 007000; W02025 / 006962;W02025 / 006720; W02025 / 123007; WO2025 / 122619; WO2025 / 123318; WO2025 / 124415;WO2025 / 137519; WO2025 / 151765; WO2025 / 151738; WO2025 / 151594; WO2025 / 153038;WO2025 / 163494; WO2025 / 165972; WO2025 / 170938; WO2025 / 171055; WO2025 / 168072;WO2025 / 179058; WO2025 / 184572; and WO2025 / 188668.Tubulin Inhibitor Payload Moiety

[0329] As described and defined herein, TPM is a tubulin inhibitor payload moiety, i.e., a moiety capable of binding and / or inhibiting tubulin protein. Typically, a TPM is considered to be capable of binding a tubulin protein if it specifically (or preferentially) associates with the tubulin protein when contacted with tubulin protein in the presence of at least one other protein or DNA. In some embodiments, a TPM is considered to be capable of binding tubulin protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a TPM is considered capable of binding a tubulin protein if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 μM, less than about 1 μM, less than about 100 nM, less than about 10 nM, or less). In some embodiments, a TPM is considered to be capable of inhibiting a tubulin protein if it inhibits it with measurable affinity (e.g., an IC50 of less than about 10 μM, less than about 1 μM, less than about 100 nM, less than about 10 nM, or less).

[0330] In some embodiments, the present disclosure provides a compound of Formula IX:IX or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Rais independently halogen, -OR33, -N(Raa)2, or optionally substituted C1-6 aliphatic; each Rbis independently halogen, -ORaa, -NCR^X or optionally substituted C1-6 aliphatic;Rcand Rdare each independently hydrogen, halogen, or optionally substituted C1-6 aliphatic; each Raais independently hydrogen or optionally substituted C1-6 aliphatic; a is 0, 1, 2, 3, 4, or 5; and b is 0, 1, 2, 3, 4, or 5.

[0331] In some embodiments, the present disclosure provides a compound of Formula IX-a:IX-a or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rx, Ry, Rz, X, a, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0332] In some embodiments, the present disclosure provides a compound of Formula IX-b:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Rx, Ry, Rz, X, b, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination; and a is 0, 1, 2, 3, or 4.

[0333] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0334] In some embodiments of any Formulae described herein, TPM is:wherein Raand a are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0335] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0336] In some embodiments of any Formulae described herein, each Rais independently halogen, -OR33, -N(Raa)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rais independently -ORaaor -N(Raa)2. In some embodiments, each Rais independently -ORaa(e.g., - O(Ci-6alkyl), e.g., -OCH3). In some embodiments, Rais -OH. In some embodiments, Rais -OCH3. In some embodiments, a Rais halogen. In some embodiments, a Rais -ORaa(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rais -N(Raa)2. In some embodiments, a Rais -N(H)(Raa). In some embodiments, a Rais optionally substituted C1-6 aliphatic. In some embodiments, a Rais C1-6 aliphatic. In some embodiments, a Rais optionally substituted C1-6 alkyl. In some embodiments, a Rais C1-6 alkyl. In some embodiments, Rais the point of attachment to the rest of the molecule.

[0337] In some embodiments of any Formulae described herein, each Rbis independently halogen, -OR33, -N(R33)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rbis independently -OR33or -N(R33)2. In some embodiments, each Rbis independently -OR33(e.g., - O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rbis halogen. In some embodiments, a Rbis -OR33(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rbis -N(R33)2. In some embodiments, a Rbis -N(H)(R33). In some embodiments, a Rbis optionally substituted C1-6 aliphatic. In some embodiments, a Rbis C1-6 aliphatic. In some embodiments, a Rbis optionally substituted C1-6 alkyl. In some embodiments, a Rbis C1-6 alkyl.

[0338] In some embodiments of any Formulae described herein, a moietyis

[0339] In some embodiments of any Formulae described herein, Rcis hydrogen, halogen, or optionally substituted C1-6 alkyl. In some embodiments, Rcis hydrogen. In some embodiments, Rcis halogen. In some embodiments, Reis optionally substituted C1-6 aliphatic. In some embodiments, Rcis C1-6 aliphatic. In some embodiments, Rcis optionally substituted C1-6 alkyl. In some embodiments, Rcis C1-6 alkyl.

[0340] In some embodiments of any Formulae described herein, Rdis hydrogen, halogen, or optionally substituted C1-6 alkyl. In some embodiments, Rdis hydrogen. In some embodiments, Rdis halogen. In some embodiments, Rdis optionally substituted C1-6 aliphatic. In some embodiments, Rdis C1-6 aliphatic. In some embodiments, Rdis optionally substituted C1-6 alkyl. In some embodiments, Rdis C1-6 alkyl.

[0341] In some embodiments of any Formulae described herein, each R33is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Raais hydrogen. In some embodiments, each Raais independently optionally substituted C1-6 aliphatic. In some embodiments, each R33is independently C1-6 aliphatic. In some embodiments, each Raais independently optionally substituted C1-6 alkyl. In some embodiments, each R33is independently C1-6 alkyl. In some embodiments, a Raais hydrogen. In some embodiments, a Raais optionally substituted C1-6 aliphatic. In some embodiments, a R33is C1-6 aliphatic. In some embodiments, a R33is optionally substituted C1-6 alkyl. In some embodiments, a R33is C1-6 alkyl (e g., methyl).

[0342] In some embodiments of any Formulae described herein, a is 0, 1, 2, or 3. In some embodiments, a is 0, 1, or 2. In some embodiments, a is 1, 2, or 3. In some embodiments, a is 0 or1. In some embodiments, a is 1 or 2. In some embodiments, a is 2 or 3. 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. In some embodiments, a is 5.

[0343] In some embodiments of any Formulae described herein, b is 0, 1, 2, or 3. In some embodiments, b is 0, 1, or 2. In some embodiments, b is 1, 2, or 3. In some embodiments, b is 0 or1 . In some embodiments, b is 1 or 2. In some embodiments, b is 2 or 3. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4. In some embodiments, b is 5.

[0344] In some embodiments, the present disclosure provides a compound of Formula X:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 aliphatic, or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rfis independently halogen or optionally substituted C1-6 aliphatic, each Rgis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 aliphatic; each Rbbis independently hydrogen or optionally substituted C1-6 aliphatic; e is 0, 1, 2, 3, 4, or 5; f is 0, 1, 2, or 3; and g is 0, 1, 2, 3, 4, or 5.

[0345] In some embodiments, the present disclosure provides a compound of Formula X-a:X-a or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, Ring Z, e, f, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0346] In some embodiments, the present disclosure provides a compound of Formula X-b:X-b or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, e, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination; and f is 0 or 1.

[0347] In some embodiments, the present disclosure provides a compound of Formula X-c:X-c or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, e, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination; and f is 0 or 1.

[0348] In some embodiments, the present disclosure provides a compound of Formula X-d:X-d or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rx, Ry, Rz, X, e, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0349] In some embodiments, the present disclosure provides a compound of Formula X-e:or a pharmaceutically acceptable salt thereof, wherein L1, Re, R1, Rx, Ry, Rz, X, Ring Z, f, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, or 3.

[0350] In some embodiments, the present disclosure provides a compound of Formula X-f:or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rg, Rx, Ry, Rz, X, Ring Z, f, g, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, 3, or 4.

[0351] In some embodiments, the present disclosure provides a compound of Formula X-g:or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, Ring Z, f, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, or 3.

[0352] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, R8, Ring Z, e, f, and g are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0353] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Ring Z, e, and f are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0354] In some embodiments of any Formulae described herein, TPM is:wherein Re, R4, e, and f are as defined in Formula X-b and described in classes and subclasses herein, both singly and in combination.

[0355] In some embodiments of any Formulae described herein, TPM is:wherein Re, R1, e, and f are as defined in Formula X-c and described in classes and subclasses herein, both singly and in combination.

[0356] In some embodiments of any Formulae described herein, TPM is:wherein Reand e are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0357] In some embodiments of any Formulae described herein, TPM is:wherein Re, R4, e, and f are as defined in Formula X-e and described in classes and subclasses herein, both singly and in combination.

[0358] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0359] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0360] In some embodiments of any Formulae described herein, Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a oxazole, isoxazole, or triazole. In some embodiments, Ring Z is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0361] In some embodiments of any Formulae described herein, Ring Z is selected from:wherein each ring is substituted with / instances of R1.

[0362] In some embodiments of any Formulae described herein, Ring Z substituted with / instances of Rfis selected from:

[0363] In some embodiments of any Formulae described herein, each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 aliphatic. In some embodiments, each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 alkyl. In some embodiments, each Reis independently -ORbbor -N(Rbb)2. In some embodiments, each Reis independently -ORbb(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, Reis -OCH3. In some embodiments, a Reis halogen. In some embodiments, a Reis -ORbb(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Reis -N(Rbb)2. In some embodiments, a Reis -N(H)(Rbb). In some embodiments, a Reis optionally substituted C1-6 aliphatic. In some embodiments, a Reis Ci- 6 aliphatic. In some embodiments, a Reis optionally substituted C1-6 alkyl. In some embodiments, a Reis C1-6 alkyl. In some embodiments, each Reis independently -ORbb(e.g., -O(C1-6 alkyl), e.g., -OCH3), or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Reis independently -ORbb(e.g., -O(C1-6 alkyl), e.g., -OCH3), or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted imidazole ring. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Reis the point of attachment to the rest of the molecule. In some embodiments, the ring formed by taking two Retogether is the point of attachment to the rest of the molecule.

[0364] In some embodiments of any Formulae described herein, each Rfis independently halogen or optionally substituted C1-6 alkyl. In some embodiments, each Rfis independently halogen. In some embodiments, each R1is independently optionally substituted C1-6 aliphatic. Insome embodiments, each Rfis independently C1-6 aliphatic. In some embodiments, each R1is independently optionally substituted C1-6 alkyl. In some embodiments, each Rfis independently C1-6 alkyl. In some embodiments, a Rfis halogen. In some embodiments, a Rfis optionally substituted C1-6 aliphatic. In some embodiments, a R1is C1-6 aliphatic. In some embodiments, a Rfis optionally substituted C1-6 alkyl. In some embodiments, a Rfis C1-6 alkyl.

[0365] In some embodiments of any Formulae described herein, each Rsis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rgis independently -ORbbor -N(Rbb)2. In some embodiments, each Rgis independently -ORbb(e.g., - O(Ci-6alkyl), e.g., -OCH3). In some embodiments, a Rgis halogen. In some embodiments, a Rgis -ORbb(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rgis -N(Rbb)2. In some embodiments, a Rsis -N(H)(Rbb). In some embodiments, a Rsis optionally substituted C1-6 aliphatic. In some embodiments, a Rgis C1-6 aliphatic. In some embodiments, a Rgis optionally substituted C1-6 alkyl. In some embodiments, a Rgis C1-6 alkyl.

[0366] In some embodiments of any Formulae described herein, a moietyis

[0367] In some embodiments of any Formulae described herein, each Rbbis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rbbis hydrogen. In some embodiments, each Rbbis independently optionally substituted C1-6 aliphatic. In some embodiments, each Rbbis independently C1-6 aliphatic. In some embodiments, each Rbbis independently optionally substituted C1-6 alkyl. In some embodiments, each Rbbis independently C1-6 alkyl. In some embodiments, a Rbbis hydrogen. In some embodiments, a Rbbis optionally substituted C1-6 aliphatic. In some embodiments, a Rbbis C1-6 aliphatic. In some embodiments, a Rbbis optionally substituted C1-6 alkyl. In some embodiments, a Rbbis C1-6 alkyl (e.g., methyl).

[0368] In some embodiments of any Formulae described herein, e is 0, 1, 2, 3, or 4. In some embodiments, e is 0, 1, 2, or 3. In some embodiments, e is 0, 1, or 2. In some embodiments, e is 1, 2, or 3. In some embodiments, e is 0 or 1. In some embodiments, e is 1 or 2. In some embodiments,e is 2 or 3. In some embodiments, e is 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.

[0369] In some embodiments of any Formulae described herein, f is 0, 1, or 2. In some embodiments, f is 0 or 1. In some embodiments, f is 1 or 2. In some embodiments, f is 2 or 3. In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3.

[0370] In some embodiments of any Formulae described herein, g is 0, 1, 2, or 3. In some embodiments, g is 0, 1, or 2. In some embodiments, g is 1, 2, or 3. In some embodiments, g is 0 or 1. In some embodiments, g is 1 or 2. In some embodiments, g is 2 or 3. 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.

[0371] In some embodiments, the present disclosure provides a compound of Formula XI:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z’ is NH, O, or S; each Rhis independently halogen, -ORce, -N(Rec)2, or optionally substituted C1-6 aliphatic;Rjis hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted phenyl; each Rkis independently halogen, -ORce, -N(RCC)2, or optionally substituted C1-6 aliphatic; each Rccis independently hydrogen or optionally substituted C1-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

[0372] In some embodiments, the present disclosure provides a compound of Formula Xl-a:Xl-a or a pharmaceutically acceptable salt thereof, wherein L1, Rh, Rj, Rx, Ry, Rz, X, h, and KBM are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0373] In some embodiments, the present disclosure provides a compound of Formula Xl-b:Xl-b or a pharmaceutically acceptable salt thereof, wherein L1, Rh, Rj, Rk, Rx, Ry, Rz, X, h, k, and KBM are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0374] In some embodiments of any Formulae described herein, TPM is:wherein Rh, RJ, Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0375] In some embodiments, the present disclosure provides a compound of Formula XI’ :xr or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination; and wherein: each Rhis independently halogen, -ORCC, -N(R“)2, or optionally substituted C1-6 aliphatic; each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted C1-6 aliphatic; each Recis independently hydrogen or optionally substituted C1-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

[0376] In some embodiments, the present disclosure provides a compound of Formula XI’-a:XI’-a or a pharmaceutically acceptable salt thereof, wherein L1, Rh, Rx, Ry, Rz, X, h, and KBM are as defined in Formula XF and described in classes and subclasses herein, both singly and in combination.

[0377] In some embodiments of any Formulae described herein, TPM is:wherein Rhand h are as defined in Formula XI’ and described in classes and subclasses herein, both singly and in combination.

[0378] In some embodiments of any Formulae described herein, TPM is:wherein Rk, Rh, k, and h are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.

[0379] In some embodiments of any Formulae described herein, TPM is:wherein Rh, Rj, and h are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0380] In some embodiments of any Formulae described herein, TPM is:wherein Rh, R'. Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0381] In some embodiments of any Formulae described herein, Z1is NH. In some embodiments, Z1is O. In some embodiments, Z1is S. In some embodiments, Z1is the point of attachment to the rest of the molecule.

[0382] In some embodiments of any Formulae described herein, each Rhis independently halogen, -ORce, -N(Rec)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rhis independently -ORCCor -N(Rec)2. In some embodiments, each Rhis independently -ORCC(e.g., - O(Ci-6alkyl), e.g., -OCH3). In some embodiments, a Rhis halogen. In some embodiments, a Rhis -ORce(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, Rhis -OCH3. In some embodiments, a Rhis -N(RCC)2. In some embodiments, a Rhis -N(H)(RCC). In some embodiments, a Rhis optionally substituted C1-6 aliphatic. In some embodiments, a Rhis C1-6 aliphatic. In some embodiments, a Rhis optionally substituted C1-6 alkyl. In some embodiments, Rhis methyl. In some embodiments, a Rhis C1-6 alkyl. In some embodiments, Rhis the point of attachment to the rest of the molecule.

[0383] In some embodiments of any Formulae described herein, R' is hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted phenyl. In some embodiments, R' is optionally substituted C1-6 aliphatic or optionally substituted phenyl. In some embodiments, R' is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, R' is hydrogen. In some embodiments, R) is halogen. In some embodiments, R> is optionally substituted C1-6 aliphatic. In some embodiments, R1is C1-6 aliphatic. In some embodiments, R' is optionally substituted C1-6 alkyl. In some embodiments, Rjis C1-6 alkyl (e.g., methyl). In some embodiments, R' is methyl. In some embodiments, R> is optionally substituted phenyl (e.g., phenyl optionally substituted with one or more halogen, -OH, -O(C1-6 alkyl), or C1-6 alkyl). In some embodiments, Rj is phenyl.

[0384] In some embodiments of any Formulae described herein, each Rkis independently halogen, -OR“, -N(RCC)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rkis independently -ORCCor -N(RCC)2. In some embodiments, each Rkis independently -ORCC(e.g., - O(C1-6 alkyl), e.g., -OCH3). In some embodiments, Rkis -OCH3. In some embodiments, a Rkis halogen. In some embodiments, a Rkis -ORCC(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rkis -N(RCC)2. In some embodiments, a Rkis -N(H)(RCC). In some embodiments, a Rkis optionally substituted C1-6 aliphatic. In some embodiments, a Rkis C1-6 aliphatic. In some embodiments, a Rkis optionally substituted C1-6 alkyl. In some embodiments, a Rkis C1-6 alkyl.

[0385] In some embodiments of any Formulae described herein, a moietyis

[0386] In some embodiments of any Formulae described herein, each Rccis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rccis hydrogen. In some embodiments, each Rceis independently optionally substituted C1-6 aliphatic. In some embodiments, each Rccis independently C1-6 aliphatic. In some embodiments, each Rccis independently optionally substituted C1-6 alkyl. In some embodiments, each Rccis independently C1-6 alkyl. In some embodiments, a Rccis hydrogen. In some embodiments, a Recis optionally substituted C1-6 aliphatic. In some embodiments, a Rccis C1-6 aliphatic. In some embodiments, a Recis optionally substituted C1-6 alkyl. In some embodiments, a Rccis C1-6 alkyl (e.g., methyl).

[0387] In some embodiments of any Formulae described herein, h is 0, 1, 2, or 3. In some embodiments, h is 0, 1, or 2. In some embodiments, h is 0 or 1. In some embodiments, h is 1 or 2. In some embodiments, h is 2 or 3. 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.

[0388] In some embodiments of any Formulae described herein, k is 0, 1, 2, or 3. In some embodiments, k is 0, 1, or 2. In some embodiments, k is 1, 2, or 3. In some embodiments, k is 0 or 1. In some embodiments, k is 1 or 2. In some embodiments, k is 2 or 3. 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.

[0389] In some embodiments, the present disclosure provides a compound of Formula XII:XIIor a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z2is CH or N;Ring Y is phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Q is -CH2- or -C(O)-;W is -CH2-, -CHOH-, -C(O)-, -NH-, or -O-;Rmis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6 aliphatic; each Rnis independently halogen or optionally substituted C1-6 aliphatic; each Rpis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6 aliphatic; each Rddis independently hydrogen or optionally substituted C1-6 aliphatic; n4 is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

[0390] In some embodiments, the present disclosure provides a compound of Formula Xll-a:XH-a or a pharmaceutically acceptable salt thereof, wherein L1, Rm, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0391] In some embodiments, the present disclosure provides a compound of Formula Xll-b:Xll-b or a pharmaceutically acceptable salt thereof, wherein L1, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0392] In some embodiments, the present disclosure provides a compound of Formula XII-c:XII-c or a pharmaceutically acceptable salt thereof, wherein L1, Rm, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0393] In some embodiments of any Formulae described herein, TPM is:wherein Rm, Rn, Rp, Q, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0394] In some embodiments of any Formulae described herein, TPM is:wherein Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0395] In some embodiments of any Formulae described herein, TPM is:wherein Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0396] In some embodiments of any Formulae described herein, TPM is:wherein Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0397] In some embodiments of any Formulae described herein, Z2is CH. In some embodiments, Z2is N.

[0398] In some embodiments of any Formulae described herein, Ring Y is phenyl or a 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is phenyl. In some embodiments, Ring Y is a 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, Ring Y is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a furan, thiophene, pyrrole, or isoxazole). In some embodiments, Ring Y is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine). In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring Y is a 5- to 6- membered carbocyclic ring. In some embodiments, Ring Y is a 5-membered carbocyclic ring. In some embodiments, Ring Y is a 6-membered carbocyclic ring. In some embodiments, Ring Y is a C3-7 cycloalkyl ring. In some embodiments, Ring Y is a C5-6 cycloalkyl ring. In some embodiments, Ring Y is a C5 cycloalkyl ring. In some embodiments, Ring Y is a Ce cycloalkyl ring. In some embodiments, Ring Y is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0399] In some embodiments of any Formulae described herein, Q is -CH2-. In some embodiments, Q is -C(O)-.

[0400] In some embodiments of any Formulae described herein, W is -CH2-. In some embodiments, W is -CHOH-. In some embodiments, W is -C(O)-. In some embodiments, W is - NH-. In some embodiments, W is -O-. In some embodiments, W is the point of attachment to the rest of the molecule.

[0401] In some embodiments of any Formulae described herein, Q is -C(O)- and W is -NH-. In some embodiments, Q is -CH2- and W is -CH2. In some embodiments, Q is -CH2- and W is - C(O)-. In some embodiments, Q is -CH2- and W is -CHOH-. In some embodiments, Q is -CH2- and W is -O-.

[0402] In some embodiments of any Formulae described herein, Rmis hydrogen, halogen, - ORdd, -N(Rdd)2, or optionally substituted C1-6 alkyl. In some embodiments, Rmis halogen, -N(Rdd)2, or optionally substituted C1-6 aliphatic. In some embodiments, Rmis halogen, -N(Rdd)2, or C1-6 alkyl. In some embodiments, Rmis hydrogen. In some embodiments, Rmis halogen. In some embodiments, Rmis -ORdd(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, Rmis - N(Rdd)2. In some embodiments, Rmis -N(H)(Rdd) (e.g., -NH(CI-6 alkyl), e.g., -N(H)CH3). In some embodiments, Rmis -N(H)CH3. In some embodiments, Rmis optionally substituted C1-6 aliphatic.In some embodiments, Rmis C1-6 aliphatic. In some embodiments, Rmis optionally substituted Ci. 6 alkyl. In some embodiments, Rmis C1-6 alkyl. In some embodiments, Rmis the point of attachment to the rest of the molecule.

[0403] In some embodiments of any Formulae described herein, each Rnis independently halogen or optionally substituted C1-6 alkyl. In some embodiments, a Rnis halogen. In some embodiments, a R11is optionally substituted C1-6 aliphatic. In some embodiments, a R11is C1-6 aliphatic. In some embodiments, a Rnis optionally substituted C1-6 alkyl. In some embodiments, a Rnis C1-6 alkyl.

[0404] In some embodiments of any Formulae described herein, each Rpis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rpis independently -ORddor -N(Rdd)2. In some embodiments, each Rpis independently -ORdd(e.g., - O(Ci.6 alkyl), e.g., -OCH3). In some embodiments, a Rpis halogen. In some embodiments, a Rpis -ORdd(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, Rpis -OCH3. In some embodiments, a Rpis -N(Rdd)2. In some embodiments, a Rpis -N(H)(Rdd). In some embodiments, a Rpis optionally substituted C1-6 aliphatic. In some embodiments, a Rpis C1-6 aliphatic. In some embodiments, a Rpis optionally substituted C1-6 alkyl. In some embodiments, a Rpis C1-6 alkyl.

[0405] In some embodiments of any Formulae described herein, each Rddis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rddis hydrogen. In some embodiments, each Rddis independently optionally substituted C1-6 aliphatic. In some embodiments, each Rddis independently C1-6 aliphatic. In some embodiments, each Rddis independently optionally substituted C1-6 alkyl. In some embodiments, each Rddis independently C1-6 alkyl. In some embodiments, a Rddis hydrogen. In some embodiments, a Rddis optionally substituted C1-6 aliphatic. In some embodiments, a Rddis C1-6 aliphatic. In some embodiments, a Rddis optionally substituted C1-6 alkyl. In some embodiments, a Rddis C1-6 alkyl (e.g., methyl).

[0406] In some embodiments of any Formulae described herein, n4 is 0, 1, 2, or 3. In some embodiments, n4 is 0, 1, or 2. In some embodiments, n4 is 1, 2, or 3. In some embodiments, n4 is 0 or 1. In some embodiments, n4 is 1 or 2. In some embodiments, n4 is 2 or 3. In some embodiments, n4 is 0. In some embodiments, n4 is 1. In some embodiments, n4 is 2. In some embodiments, n4 is 3. In some embodiments, n4 is 4. In some embodiments, n4 is 5.

[0407] In some embodiments of any Formulae described herein, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2.In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1 . In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0408] In some embodiments, the present disclosure provides a compound of Formula XIII:XIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rqis independently halogen, -ORCC, -N(RCC)2, or optionally substituted C1-6 aliphatic; each Rris independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 aliphatic; each Rsis independently halogen or optionally substituted C1-6 aliphatic;Rlis -N(Ree)(Ci-4 alkylene)CN; each Reeis independently hydrogen or optionally substituted C1-6 aliphatic; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, or 4; and s is 0, 1, or 2.

[0409] In some embodiments, the present disclosure provides a compound of Formula Xlll-a:or a pharmaceutically acceptable salt thereof, wherein L1, Rq, Rr, R\ Rx, Ry, Rz, X, q, r, and KBM are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0410] In some embodiments, the present disclosure provides a compound of Formula XIILb:XIILb or a pharmaceutically acceptable salt thereof, wherein L1, Rq, Rr, Rs, Rl, Rx, Ry, Rz, X, q, r, s, and KBM are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination; and q is 0, 1, 2, 3, or 4.

[0411] In some embodiments of any Formulae described herein, TPM is:wherein Rq, Rr, Rs, R\ Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0412] In some embodiments of any Formulae described herein, TPM is:wherein Rq, Rr, Rl, q, and r are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0413] In some embodiments of any Formulae described herein, TPM is:wherein Rq, Rr, Rs, Rl, q, r, and s are as defined in Formula XIILb and described in classes and subclasses herein, both singly and in combination.

[0414] In some embodiments of any Formulae described herein, Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring X is an oxadiazole (e.g., a 1,2,5-oxadiazole). In some embodiments,Ring

[0415] In some embodiments of any Formulae described herein, each Rqis independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rqis independently -OReeor -N(Ree)2. In some embodiments, each Rqis independently -ORee(e.g., - O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rqis halogen. In some embodiments, a Rqis -ORee(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rqis -N(Ree)2. In some embodiments, a Rqis -N(H)(Ree). In some embodiments, a Rqis optionally substituted C1-6 aliphatic. In some embodiments, a Rqis C1-6 aliphatic. In some embodiments, a Rqis optionally substituted C1-6 alkyl. In some embodiments, a Rqis C1-6 alkyl. In some embodiments, a Rqis the point of attachment to the rest of the molecule.

[0416] In some embodiments of any Formulae described herein, each Rris independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rris independently -OReeor -N(Ree)2. In some embodiments, each Rris independently -ORee(e.g., - O(Ci-6alkyl), e.g., -OCH3). In some embodiments, a Rris halogen. In some embodiments, a Rris -ORee(e.g., -O(C1-6 alkyl), e.g., -OCH3). In some embodiments, a Rris -N(Ree)2. In some embodiments, a Rris -N(H)(Ree). In some embodiments, a Rris optionally substituted C1-6 aliphatic. In some embodiments, a Rris C1-6 aliphatic. In some embodiments, a Rris optionally substituted C1-6 alkyl. In some embodiments, a Rris C1-6 alkyl.

[0417] In some embodiments of any Formulae described herein, each Rsis independently halogen or optionally substituted C1-6 alkyl. In some embodiments, a Rsis halogen. In some embodiments, a Rsis optionally substituted C1-6 aliphatic. In some embodiments, a Rsis C1-6 aliphatic. In some embodiments, a Rsis optionally substituted C1-6 alkyl. In some embodiments, a Rsis C1-6 alkyl.

[0418] In some embodiments of any Formulae described herein, Rlis -N(H)(CI-4 alkylene)CN. In some embodiments, R‘ is -N(Ree)(Ci-2 alkylene)CN. In some embodiments, Rlis -N(H)(CI-2 alkylene)CN. In some embodiments, R‘ is -N(Ree)CH2CH2CN. In some embodiments, Rlis - N(H)CH2CH2CN.

[0419] In some embodiments of any Formulae described herein, each Reeis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Reeis hydrogen. In some embodiments, each Reeis independently optionally substituted C1-6 aliphatic. In some embodiments, each Reeis independently C1-6 aliphatic. In some embodiments, each Reeis independently optionally substituted C1-6 alkyl. In some embodiments, each Reeis independently C1-6 alkyl. In some embodiments, a Reeis hydrogen. In some embodiments, a Reeis optionally substituted C1-6 aliphatic. In some embodiments, a Reeis C1-6 aliphatic. In some embodiments, a Reeis optionally substituted C1-6 alkyl. In some embodiments, a Reeis C1-6 alkyl (e.g., methyl).

[0420] In some embodiments of any Formulae described herein, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.

[0421] In some embodiments of any Formulae described herein, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. 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.

[0422] In some embodiments of any Formulae described herein, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0423] In some embodiments, the present disclosure provides a compound of Formula XIV:XIV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;M is a covalent bond or C1-4 alkylene; each Ruis independently halogen, -ORff, -N(Rff)2, or optionally substituted C1-6 aliphatic; each Rvis independently halogen, -ORff, -N(Rff)2, or optionally substituted C1-6 aliphatic; each Rffis independently hydrogen or optionally substituted C1-6 aliphatic;Rggis hydrogen or optionally substituted C1-6 aliphatic; u is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, 3, or 4.

[0424] In some embodiments, the present disclosure provides a compound of Formula XlV-a:XlV-a or a pharmaceutically acceptable salt thereof, wherein L1, Ru, Rv, Rx, Ry, Rz, Rff, X, u, v, and KBM are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0425] In some embodiments, the present disclosure provides a compound of Formula XlV-b:XlV-b or a pharmaceutically acceptable salt thereof, wherein L1, M, Ru, Rv, Rx, Ry, Rz, Rfl, Rgg, X, u, v, and KBM are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0426] In some embodiments, the present disclosure provides a compound of Formula XIV-c:XIV-c or a pharmaceutically acceptable salt thereof, wherein L1, Ru, Rv, Rx, Ry, Rz, R11, X, u, v, and KBM are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0427] In some embodiments of any Formulae described herein, TPM is:wherein M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0428] In some embodiments of any Formulae described herein, TPM is:wherein Ru, Rv, Rfl, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0429] In some embodiments of any Formulae described herein, TPM is:wherein M, Ru, Rv, Rff, Rgs, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0430] In some embodiments of any Formulae described herein, TPM is:wherein Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0431] In some embodiments of any Formulae described herein, M is a covalent bond. In some embodiments, M is Ci-4 alkylene. In some embodiments, M is C1-2 alkylene. In some embodiments, M is -CH2-.

[0432] In some embodiments, a moiety

[0433] In some embodiments of any Formulae described herein, each Ruis independently halogen, -ORff, -N(Rff)2, or optionally substituted C1-6 alkyl. In some embodiments, each Ruis independently -ORffor -N(Rff)2. In some embodiments, each Ruis independently -ORff(e.g., - O(Ci-6alkyl) or -OH). In some embodiments, a Ruis halogen. In some embodiments, a Ruis -ORff(e.g., -O(C1-6 alkyl) or -OH). In some embodiments, a Ruis -N(Rff)2. In some embodiments, a Ruis -N(H)(Rff). In some embodiments, a Ruis optionally substituted C1-6 aliphatic. In some embodiments, a Ruis C1-6 aliphatic. In some embodiments, a Ruis optionally substituted C1-6 alkyl. In some embodiments, a Ruis C1-6 alkyl. In some embodiments, a Ruis the point of attachment to the rest of the molecule.

[0434] In some embodiments of any Formulae described herein, each Rvis independently halogen, -ORff, -N(Rft)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rvis independently -ORflor -N(Rff)2. In some embodiments, each Rvis independently -ORfl(e.g., - O(C1-6 alkyl), e.g., -OCH3). In some embodiments, aRvis halogen. In some embodiments, a Rvis -ORff(e.g., -O(Ci-6alkyl), e.g., -OCH3). In some embodiments, a Rvis -N(Rff)2. In some embodiments, a Rvis -N(H)(Rff). In some embodiments, a Rvis optionally substituted C1-6 aliphatic. In some embodiments, a Rvis C1-6 aliphatic. In some embodiments, a Rvis optionally substituted C1-6 alkyl. In some embodiments, a Rvis C1-6 alkyl.

[0435] In some embodiments of any Formulae described herein, each Rffis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rffis hydrogen. In some embodiments, each Rffis independently optionally substituted C1-6 aliphatic. In some embodiments, each Rffis independently C1-6 aliphatic. In some embodiments, each Rffis independently optionally substituted C1-6 alkyl. In some embodiments, each Rffis independently C1-6 alkyl. In some embodiments, a Rflis hydrogen. In some embodiments, a Rflis optionally substituted C1-6 aliphatic. In some embodiments, a Rffis C1-6 aliphatic. In some embodiments, a Rffis optionally substituted C1-6 alkyl. In some embodiments, a Rffis C1-6 alkyl (e.g., methyl).

[0436] In some embodiments of any Formulae described herein, Rggis hydrogen or optionally substituted C1-6 alkyl. In some embodiments, Rggis hydrogen. In some embodiments, Rggis optionally substituted C1-6 aliphatic. In some embodiments, Rggis C1-6 aliphatic. In some embodiments, Rggis optionally substituted C1-6 alkyl. In some embodiments, Rggis C1-6 alkyl.

[0437] In some embodiments of any Formulae described herein, u is 0, 1, 2, or 3. In some embodiments, u is 0, 1, or 2. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 0 or1 . In some embodiments, u is 1 or 2. In some embodiments, u is 2 or 3. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

[0438] In some embodiments of any Formulae described herein, v is 0, 1, 2, or 3. In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0 or 1. In some embodiments, v is 1 or 2. In some embodiments, v is 2 or 3. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4.

[0439] In some embodiments, TPM is a tubulin inhibitor payload moiety (e.g., a moiety that binds and / or inhibits tubulin). In some embodiments, TPM is a tubulin inhibitor payload moiety targeting the colchicine binding site. The present invention encompasses the recognition that a tubulin inhibitor payload moiety in the CIDCs described herein can be made by installing a linking moiety bound to a KRASO1Cbinding moiety, as defined herein (any suitable position on a tubulin inhibitor compound. In some embodiments, TPM is a tubulin inhibitor (e.g., a radical of such inhibitor compound) selected from ABT-751, avanbulin, BNC105P, cabazitaxel, colchicine, combretastatin A-4, combretastatin A-l , docetaxel, dolastatin 10, EAPB0203, EAPB02303, EAPB0503, epothilone A, eribulin, fosbretabulin, ixabepilone, KX2-361, lisavanbulin, monomethyl auristatin E, A-acetylcolchicinol, ombrabulin, Oxi4503, paclitaxel, plinabulin, tesetaxel, sabizabulin, verubulin, vinblastine, and vincristine. In some embodiments, TPM is a tubulin inhibitor (e.g., a radical of such inhibitor compound) described in Hawesh, M. Biomolecules 2022, 12, 1843; Weng, H., et al., Future Med. Chem. 2023, 15(1), 73- 95; Beale, T. M., et al., ACS Med. Chem. Lett. 2012, 3, 177-181; Liou, J.-P., et al., J. Med. Chem. 2004, 47, 2897-2905; Patinote, C , et al., Eur. J. Med. Chem. 2021, 212, 113031; Pochampally, S., et al., ACS Pharmacol. Transl. Sci. 2023, 6, 526-45; Prota, A. E., et al., J. Mol. Biol. 2014, 426, 1848-60; Sun, C.-M., et al., Bioorg. Med. Chem. Lett. 2007, 17, 1078-81; Zhou, J. et al., Eur. J. Med. Chem. 2013, 68, 222-32; WO1996 / 030355; WO1998 / 045301; WO 1999 / 002514; W02002 / 056872; US2003 / 0195244; W02004 / 054498; W02005 / 054199; US2005 / 0065595; WO20 12 / 027481; and WO2012 / 106522.

[0440] In some embodiments, TPM is a means for binding tubulin. In some embodiments, TPM is a means for inhibiting tubulin. In some embodiments, TPM is a means for inhibiting tubulin at the colchicine binding site.Exemplary Compounds of the Disclosure

[0441] In some embodiments, the present disclosure provides a compound of Formula XV:XV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0442] In some embodiments, the present disclosure provides a compound of Formula XV-a:XV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ra, Rh, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0443] In some embodiments, the present disclosure provides a compound of Formula XVI:XVI or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, R1, Rg, Ring Z, e, f, and g are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0444] In some embodiments, the present disclosure provides a compound of Formula XVI-a:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0445] In some embodiments, the present disclosure provides a compound of Formula XVI-b:XVI-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0446] In some embodiments, the present disclosure provides a compound of Formula XVII:XVII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rh, Rj, Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0447] In some embodiments, the present disclosure provides a compound of Formula XVII- a:XVII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes andsubclasses herein, both singly and in combination; and Rh, R>, Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0448] In some embodiments, the present disclosure provides a compound of Formula XVIII:XVIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Q, Rm, Rn, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0449] In some embodiments, the present disclosure provides a compound of Formula XVIII- a:XVIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0450] In some embodiments, the present disclosure provides a compound of Formula XVIII- b:XVIII-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0451] In some embodiments, the present disclosure provides a compound of Formula XIX:XIX or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R5, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, Rl, Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0452] In some embodiments, the present disclosure provides a compound of Formula XlX-a:XlX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Xlll-b and described in classes and subclasses herein, both singly and in combination.

[0453] In some embodiments, the present disclosure provides a compound of Formula XX:XX or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0454] In some embodiments, the present disclosure provides a compound of Formula XX-a:XX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XlV-b and described in classes and subclasses herein, both singly and in combination.

[0455] In some embodiments, the present disclosure provides a compound of Formula XX-b:XX-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R2, R3, R4, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0456] In some embodiments, the present disclosure provides a compound of Formula XXI:XXIor a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Ra, Rh, Rc, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0457] In some embodiments, the present disclosure provides a compound of Formula XXI-a:XXI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, I?, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0458] In some embodiments, the present disclosure provides a compound of Formula XXII:XXII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Re, R1, R8, Ring Z, e, f, and g are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0459] In some embodiments, the present disclosure provides a compound of Formula XXII- a:XXII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0460] In some embodiments, the present disclosure provides a compound of Formula XXII- b:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Re, R1, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0461] In some embodiments, the present disclosure provides a compound of Formula XXIII:XXIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0462] In some embodiments, the present disclosure provides a compound of Formula XXIII- a:XXIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Rh, Rj, Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0463] In some embodiments, the present disclosure provides a compound of Formula XXIV:XXIV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Q, Rm, Rn, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0464] In some embodiments, the present disclosure provides a compound of Formula XXIV- a:XXIV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0465] In some embodiments, the present disclosure provides a compound of Formula XXIV- b:XXIV-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0466] In some embodiments, the present disclosure provides a compound of Formula XXV:XXV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0467] In some embodiments, the present disclosure provides a compound of Formula XXV- a:XXV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Xlll-b and described in classes and subclasses herein, both singly and in combination.

[0468] In some embodiments, the present disclosure provides a compound of Formula XXVI:XXVI or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, R7, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rsg, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0469] In some embodiments, the present disclosure provides a compound of Formula XXVI- a:XXVI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XlV-b and described in classes and subclasses herein, both singly and in combination.

[0470] In some embodiments, the present disclosure provides a compound of Formula XXVI- b:XXVI-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L4, L5, R8, R9, R10, R11, and Ring B are as defined herein for Formula III and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0471] In some embodiments, the present disclosure provides a compound of Formula XXVII:XXVIIor a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R13, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0472] In some embodiments, the present disclosure provides a compound of Formula XXVII- a:XXVILa or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14,R15R16RnRI SRWR2O,p,and q are as defined herein forFormuiaiv and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0473] In some embodiments, the present disclosure provides a compound of Formula XXVIII:XXVIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and gare as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0474] In some embodiments, the present disclosure provides a compound of Formula XXVIII-a:XXVIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R13, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0475] In some embodiments, the present disclosure provides a compound of Formula XXVIII-b:XXVIII-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0476] In some embodiments, the present disclosure provides a compound of Formula XXIX:XXIX or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0477] In some embodiments, the present disclosure provides a compound of Formula XXIX- a:XXIX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R13, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Rh, R>, Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0478] In some embodiments, the present disclosure provides a compound of Formula XXX:XXX or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R13, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Q, Rm, Rn, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0479] In some embodiments, the present disclosure provides a compound of Formula XXX-XXX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R13, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0480] In some embodiments, the present disclosure provides a compound of Formula XXX- b:XXX-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R13, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0481] In some embodiments, the present disclosure provides a compound of Formula XXXI:XXXI or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0482] In some embodiments, the present disclosure provides a compound of Formula XXXI- a:XXXI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Xlll-b and described in classes and subclasses herein, both singly and in combination.

[0483] In some embodiments, the present disclosure provides a compound of Formula XXXII:XXXII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0484] In some embodiments, the present disclosure provides a compound of Formula XXXII- a:XXXII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XlV-b and described in classes and subclasses herein, both singly and in combination.

[0485] In some embodiments, the present disclosure provides a compound of Formula XXXII- b:XXXII-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; R13, R14, R15, R16, R17, R18, R19, R20, p, and q are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0486] In some embodiments, the present disclosure provides a compound of Formula XXXIII:XXXIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0487] In some embodiments, the present disclosure provides a compound of Formula XXXIII-a:XXXIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ra, Rh, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0488] In some embodiments, the present disclosure provides a compound of Formula XXXIV:XXXIVor a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Re, R1, Rg, Ring Z, e, f, and g are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0489] In some embodiments, the present disclosure provides a compound of FormulaXXXIV-a:XXXIV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Re, Rf, R8, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0490] In some embodiments, the present disclosure provides a compound of Formula XXXI V-b:XXXIV-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Re, R1, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0491] In some embodiments, the present disclosure provides a compound of Formula XXXV:XXXV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rh, Rj, Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0492] In some embodiments, the present disclosure provides a compound of Formula XXXV- a:XXXV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rh, Rj, Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0493] In some embodiments, the present disclosure provides a compound of Formula XXXVI:XXXVI or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Q, Rm, Rn, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0494] In some embodiments, the present disclosure provides a compound of FormulaXXXVI-a:XXXVI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0495] In some embodiments, the present disclosure provides a compound of Formula XXXVI-b:XXXVI-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0496] In some embodiments, the present disclosure provides a compound of Formula XXXVII:XXXVII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, Rl, Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0497] In some embodiments, the present disclosure provides a compound of Formula XXXVII-a:XXXVII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Xlll-b and described in classes and subclasses herein, both singly and in combination.

[0498] In some embodiments, the present disclosure provides a compound of FormulaXXXVIII:XXXVIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, R88, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0499] In some embodiments, the present disclosure provides a compound of Formula XXXVIII-a:XXXVIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XlV-b and described in classes and subclasses herein, both singly and in combination.

[0500] In some embodiments, the present disclosure provides a compound of Formula XXXVIII-b:XXXVIII-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy4, Cy5, L6, R21, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0501] In some embodiments, the present disclosure provides a compound of Formula XXXIX:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Re, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0502] In some embodiments, the present disclosure provides a compound of Formula XXXIX-a:XXXIX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0503] In some embodiments, the present disclosure provides a compound of Formula XL:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0504] In some embodiments, the present disclosure provides a compound of Formula XL-a:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0505] In some embodiments, the present disclosure provides a compound of Formula XL-b:XL-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classesand subclasses herein, both singly and in combination; and Re, R1, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0506] In some embodiments, the present disclosure provides a compound of Formula XLI:XLI or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0507] In some embodiments, the present disclosure provides a compound of Formula XLI-a:XLI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0508] In some embodiments, the present disclosure provides a compound of Formula XLII:XLII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Q, Rm, Rn, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0509] In some embodiments, the present disclosure provides a compound of Formula XLII-or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0510] In some embodiments, the present disclosure provides a compound of Formula XLII- b:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0511] In some embodiments, the present disclosure provides a compound of Formula XLIII:XLIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0512] In some embodiments, the present disclosure provides a compound of Formula XLIII- a:XLIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, Rl, Ring X, q, r, and s are as defined in Formula Xlll-b and described in classes and subclasses herein, both singly and in combination.

[0513] In some embodiments, the present disclosure provides a compound of Formula XLIV:XLIV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0514] In some embodiments, the present disclosure provides a compound of Formula XLIV- a:XLIV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rft, Rgg, u, and v are as defined in Formula XlV-b and described in classes and subclasses herein, both singly and in combination.

[0515] In some embodiments, the present disclosure provides a compound of Formula XLIV- b:XLIV-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Cy6, Cy7, L7, R23, R24, Ring E, and Ring F are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0516] In some embodiments, the present disclosure provides a compound of Formula XLV:XLV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, y Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0517] In some embodiments, the present disclosure provides a compound of Formula XLV- a:XLV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula IX-b and described in classes and subclasses herein, both singly and in combination.

[0518] In some embodiments, the present disclosure provides a compound of Formula XLVI:XLVI or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VIT and described in classes and subclasses herein, both singly and in combination; and Re, R1, Rg, Ring Z, e, f, and g are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0519] In some embodiments, the present disclosure provides a compound of Formula XLVI- a:XLVI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Re, Rf, R8, Ring Z, e, f, and g are as defined in Formula X-f and described in classes and subclasses herein, both singly and in combination.

[0520] In some embodiments, the present disclosure provides a compound of Formula XLVI- b:XLVI-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Ring Z, e, and f are as defined in Formula X-g and described in classes and subclasses herein, both singly and in combination.

[0521] In some embodiments, the present disclosure provides a compound of Formula XLVII:XLVII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, Z1, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0522] In some embodiments, the present disclosure provides a compound of Formula XLVII- a:XLVII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, h, and k are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0523] In some embodiments, the present disclosure provides a compound of Formula XLVIII:XLVIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Q, Rm, Rn, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0524] In some embodiments, the present disclosure provides a compound of Formula XLVIII- a:XLVIII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0525] In some embodiments, the present disclosure provides a compound of Formula XLVIII- b:XLVIII-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0526] In some embodiments, the present disclosure provides a compound of Formula XLIX:XLIX or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R\ Ring X, q, r, and s are as defined in Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0527] In some embodiments, the present disclosure provides a compound of Formula XLIX- a:XLIX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Xlll-b and described in classes and subclasses herein, both singly and in combination.

[0528] In some embodiments, the present disclosure provides a compound of Formula L:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rsg, u, and v are as defined in Formula XIV and described in classes and subclasses herein, both singly and in combination.

[0529] In some embodiments, the present disclosure provides a compound of Formula L-a:L-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula XlV-b and described in classes and subclasses herein, both singly and in combination.

[0530] In some embodiments, the present disclosure provides a compound of Formula L-b:L-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L8, R26, R28, R29, R30, Y, Ring G, and Ring H are as defined herein for Formula VIT and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula XIV and described in...

Claims

1. CLAIMS1. A compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:KBM is a KRASG12Cbinding moiety;Rxis hydrogen, halogen, cyano, or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ryis hydrogen, halogen, cyano, or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rzis independently hydrogen, halogen, or optionally substituted C1-6 aliphatic;X is a covalent bond, -O-, -N(RW)-, or -S-;Rwis hydrogen or optionally substituted C1-6 aliphatic;L1is a covalent bond or a linking moiety; andTPM is a tubulin inhibitor payload moiety.

2. The compound of claim 1, wherein:L1is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

3. The compound of claim 2, wherein L1is a covalent bond.

4. The compound of claim 2, wherein L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -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 1-2 methylene units are optionally and independently replaced by -Cy-.

5. The compound of claim 2, wherein L1is selected from:wherein:Lcis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain; the bond labeled X is attached to X; and the bond labeled B is attached to TPM.

6. The compound of claim 2, wherein L1is selected from:wherein:Lcis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain.

7. The compound of any one of claims 1-6, wherein X is -O-.

8. The compound of any one of claims 1-7, wherein Rxis hydrogen or optionally substituted C1-6 aliphatic.

9. The compound of claim 8, wherein Rxis hydrogen.

10. The compound of any one of claims 1-9, wherein Ryis hydrogen or optionally substituted C1-6 aliphatic.

11. The compound of claim 10, wherein Ryis hydrogen.

12. The compound of any one of claims 1-11, one Rzis hydrogen, and one Rzis optionally substituted C1-6 aliphatic.

13. The compound of any one of claims 1-11, wherein each Rzis hydrogen.

14. The compound of any one of claims 1-13, wherein the compound is a compound of Formula II:II or a pharmaceutically acceptable salt thereof, wherein: each R1is independently hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R2is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R2are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring;R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R4is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or two R4are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring;, ,R5is hydrogen, -OR6,, -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R6is an optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy1and Cy2are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L2is a covalent bond or -N(R’)(CH2)m-;L3is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

15. The compound of claim 14, wherein each R1is hydrogen.

16. The compound of claim 14 or 15, wherein each R2is hydrogen.

17. The compound of any one of claims 14-16, wherein R3is an optionally substituted naphthyl.

18. The compound of any one of claims 14-17, wherein19. The compound of any one of claims 14-18, wherein R33is not Cl.

20. The compound of any one of claims 14-18, wherein R3is not21. The compound of any one of claims 14-20, wherein each R4is hydrogen.

22. The compound of any one of claims 14-21, wherein R5-O(Ci-4 alkylene)Cy2.The compound of any one of claims 14-22, wherein R5is selected from:

24. The compound of any one of claims 14-23, wherein Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

25. The compound of any one of claims 14-24, wherein Ring A is optionally substituted26. The compound of any one of claims 14-25, wherein L2is a covalent bond.

27. The compound of any one of claims 14-26, wherein L3is a covalent bond.

28. The compound of any one of claims 1-13, wherein the compound is a compound of Formula III:III or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R9is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R10is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R11is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L4is a covalent bond or -N(R’)(CH2)m-;V is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring B is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

29. The compound of claim 28, wherein R8is hydrogen.

30. The compound of claim 28 or 29, wherein R9is a halogen.

31. The compound of any one of claims 28-30, wherein R10is an optionally substituted phenyl.

32. The compound of any one of claims 28-31, wherein R11is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

33. The compound of any one of claims 28-32, wherein Ring B is optionally substituted34. The compound of any one of claims 28-33, wherein L4is a covalent bond.

35. The compound of any one of claims 28-34, wherein L5is a covalent bond.

36. The compound of any one of claims 28-35, wherein Rxis not F.

37. The compound of any one of claims 1-13, wherein the compound is a compound of Formula IV:IV or a pharmaceutically acceptable salt thereof, wherein:R13is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R14is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R1?is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R16is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R17is independently hydrogen or optionally substituted C1-6 aliphatic; each R18is independently hydrogen or optionally substituted C1-6 aliphatic, or two R18groups are taken together to form an oxo; each R19is independently hydrogen or optionally substituted C1-6 aliphatic; each R20is independently hydrogen or optionally substituted C1-6 aliphatic; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic; q is 1 or 2; and p is 1 or 2.

38. The compound of claim 37, wherein R13is hydrogen.

39. The compound of claim 37 or 38, wherein R14is an optionally substituted C1-6 aliphatic.

40. The compound of any one of claims 37-39, wherein R15is an optionally substituted ring selected from phenyl and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

41. The compound of any one of claims 37-40, wherein R16is a halogen.

42. The compound of any one of claims 37-41, wherein each R17is hydrogen.

43. The compound of any one of claims 37-42, wherein p is 1.

44. The compound of any one of claims 37-43, wherein each R18is hydrogen.

45. The compound of any one of claims 37-44, wherein each R19is hydrogen.

46. The compound of any one of claims 37-45, wherein each R20is hydrogen.

47. The compound of any one of claims 37-46, wherein q is 2.

48. The compound of any one of claims 1-13, wherein the compound is a compound of Formula V:V or a pharmaceutically acceptable salt thereof, wherein:R21is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Cy4is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy5is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L6is a covalent bond or -(CH2)mN(R’)-; m is 0, 1, or 2; andRing D is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

49. The compound of claim 48, wherein R21is an optionally substituted C1-6 aliphatic.

50. The compound of claim 48 or 49, wherein Cy4is an optionally substituted 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

51. The compound of any one of claims 48-50, wherein Cy5is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

52. The compound of any one of claims 48-51, wherein Ring D is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur.

53. The compound of any one of claims 48-51, wherein L6is a covalent bond.

54. The compound of any one of claims 1-13, wherein the compound is a compound of Formula VI:VI or a pharmaceutically acceptable salt thereof, wherein:Ring E is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L7is a covalent bond or -(CH2)mN(R’)-; m is 0, 1, or 2;R23is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R24is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Cy6is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring F is an optionally substituted 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andCy7is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, abicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

55. The compound of claim 54, wherein R23is hydrogen.

56. The compound of claim 54 or 55, wherein R2?is hydrogen.

57. The compound of any one of claims 54-56, wherein Cy6is an optionally substituted ring selected from a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

58. The compound of any one of claims 54-57, wherein Cy7is an optionally substituted ring selected from a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

59. The compound of any one of claims 54-58, wherein Ring E is an optionally substituted bivalent ring selected a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

60. The compound of any one of claims 54-59, wherein L7is a covalent bond.

61. The compound of any one of claims 1-13, wherein the compound is a compound of Formula VIEVII or a pharmaceutically acceptable salt thereof, wherein:Y is CR27or N;R26is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R27is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R28is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R29is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R30is hydrogen, -OR31,, -O(C 1-4 alkylene)Cy9, or an optionally substituted3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R31is optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy8and Cy9are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L8is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Ring G is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring H is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 0, 1, or 2.

62. The compound of claim 61, wherein Y is CR27.

63. The compound of claim 61 or 62, wherein R27is a halogen.

64. The compound of any one of claims 61-63, wherein R26is hydrogen.

65. The compound of any one of claims 61-64, wherein R29is a halogen.

66. The compound of any one of claims 61-65, wherein R30is hydrogen.

67. The compound of any one of claims 61-66, wherein Ring G is optionally substituted68. The compound of any one of claims 61-67, wherein Ring H, taken with the ring to which it is fused,69. The compound of any one of claims 61-68, wherein L8is a covalent bond.

70. The compound of any one of claims 1-13, wherein the compound is a compound of Formula VIII:VIII or a pharmaceutically acceptable salt thereof, wherein:Y is CR27or N;R26is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R27is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R28is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R29is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R30is hydrogen, -OR31,, -O(Ci-4 alkylene)Cy9, or an optionally substituted3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R31is optionally substituted C1-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Cy8and Cy9are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic; each R32is independently optionally substituted C1-6 aliphatic, or two R32are taken together to form an optionally substituted 4- to 7-membered ring that is fused, bridged, and / or spirofused with the ring to which the R32moieties are attached;Ring J is an optionally substituted monocyclic 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0, 1, 2, 3, 4, 5, or 6.

71. The compound of claim 70, wherein Y is CR27.

72. The compound of claim 70 or 71, wherein R27is a halogen.

73. The compound of any one of claims 70-72, wherein R26is hydrogen.

74. The compound of any one of claims 70-73, wherein R29is a halogen.

75. The compound of any one of claims 70-74, wherein R30is hydrogen.

76. The compound of any one of claims 70-75, wherein Ring J, taken with the rings to which it is fused,77. The compound of any one of claims 70-76, wherein an R32is an optionally substituted Ci- 6 alkyl.

78. The compound of any one of claims 1-77, wherein the compound is a compound of Formula III:III or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Rais independently halogen, -OR33, -N(Raa)2, or optionally substituted C1-6 aliphatic; each Rbis independently halogen, -ORaa, -N(Raa)2, or optionally substituted C1-6 aliphatic;Rcand Rdare each independently hydrogen, halogen or optionally substituted C1-6 aliphatic; each Raais independently hydrogen or optionally substituted C1-6 aliphatic; a is 0, 1, 2, 3, 4, or 5; and b is 0, 1, 2, 3, 4, or 5.

79. The compound of claim 78, wherein at least one Rais -ORaa.

80. The compound of claim 78 or 79, wherein at least one Rbis -ORaa.

81. The compound of any one of claims 78-80, wherein each Rbis -ORaa.

82. The compound of any one of claims 78-81, wherein Rcis hydrogen.

83. The compound of any one of claims 78-82, wherein Rdis hydrogen.

84. The compound of any one of claims 78-83, wherein each R33is independently optionally substituted C1-6 aliphatic.

85. The compound of any one of claims 78-84, wherein a is 1 or 2.

86. The compound of any one of claims 78-85, wherein b is 3.

87. The compound of any one of claims 78-86, wherein the compound is a compound ofFormula Ill-b :or a pharmaceutically acceptable salt thereof.

88. The compound of any one of claims 1-77, wherein the compound is a compound ofFormula IV:IV or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 aliphatic, or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rfis independently halogen or optionally substituted C1-6 aliphatic, each Rgis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted C1-6 aliphatic; each Rbbis independently hydrogen or optionally substituted C1-6 aliphatic;e is 0, 1, 2, 3, 4, or 5; f is 0, 1, 2, or 3; and g is 0, 1, 2, 3, 4, or 5.

89. The compound of claim 88, wherein Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

90. The compound of claim 89, wherein Ring Z is selected from:wherein each ring is substituted with / instances of Rf.

91. The compound of any one of claims 88-90, wherein at least one Reis -ORbb.

92. The compound of any one of claims 88-91, wherein two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

93. The compound of any one of claims 88-92, wherein at least one Rgis -ORbb.

94. The compound of any one of claims 88-93, wherein each Rgis -ORbb.

95. The compound of any one of claims 88-94, wherein each Rbbis independently optionally substituted C1-6 aliphatic.

96. The compound of any one of claims 88-95, wherein e is 1, 2, or 3.

97. The compound of any one of claims 88-96, wherein f is 0.

98. The compound of any one of claims 88-97, wherein g is 3.

99. The compound of any one of claims 88-98, wherein the compound is a compound ofor a pharmaceutically acceptable salt thereof.

100. The compound of any one of claims 1-77, wherein the compound is a compound ofFormula V:V or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z’ is NH, O, or S; each Rhis independently halogen, -ORCC, -N(RCC)2, or optionally substituted C1-6 aliphatic;R' is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted phenyl; each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted C1-6 aliphatic; each RCCis independently hydrogen or optionally substituted C1-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

101. The compound of claim 100, wherein Z1is NH.

102. The compound of claim 100 or 101, wherein at least one Rhis -ORCC.

103. The compound of any one of claims 100-102, wherein R' is optionally substituted C1-6 aliphatic or optionally substituted phenyl.

104. The compound of any one of claims 100-103, wherein at least one Rkis -ORCC.

105. The compound of any one of claims 100-104, wherein each Rkis -ORce.

106. The compound of any one of claims 100-105, wherein each Rccis independently optionally substituted C1-6 aliphatic.

107. The compound of any one of claims 100-106, wherein h is 1.

108. The compound of any one of claims 100-107, wherein k is 3.

109. The compound of any one of claims 100-108, wherein the compound is a compound of Formula V-b:V-b or a pharmaceutically acceptable salt thereof.

110. The compound of any one of claims 1-77, wherein the compound is a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z2is CH or N;Ring Y is phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Q is -CH2- or -C(O)-;W is -CH2-, -CHOH-, -C(O)-, -NH-, or -O-;Rmis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6 aliphatic; each Rnis independently halogen or optionally substituted C1-6 aliphatic; each Rpis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6 aliphatic; each Rddis independently hydrogen or optionally substituted C1-6 aliphatic; n4 is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

111. The compound of claim 110, wherein Z2is CH.

112. The compound of claim 110, wherein Z2is N.

113. The compound of any one of claims 110-112, wherein Ring Y is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

114. The compound of any one of claims 110-112, wherein Ring Y is a 3- to 7-membered carbocyclic ring.

115. The compound of any one of claims 110-114, wherein Q is -C(O)-.

116. The compound of any one of claims 110-115, wherein W is -NH-.

117. The compound of any one of claims 110-116, wherein Rmis -N(H)(Rdd).

118. The compound of any one of claims 110-117, wherein at least one Rpis -ORdd.

119. The compound of any one of claims 110-118, wherein each Rddis optionally substituted C1-6 aliphatic.

120. The compound of any one of claims 110-119, wherein n4 is 0.

121. The compound of any one of claims 110-120, wherein p is 1.

122. The compound of any one of claims 110-121, wherein the compound is a compound ofFormula Vl-b or Formula VI-c:

123. The compound of any one of claims 1-77, wherein the compound is a compound ofFormula VII:VII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rqis independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 aliphatic; each Rris independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 aliphatic; each Rsis independently halogen or optionally substituted C1-6 aliphatic;Rlis -N(Ree)(Ci-4alkylene)CN; each Reeis independently hydrogen or optionally substituted C1-6 aliphatic; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, or 4; and s is 0, 1, or 2.

124. The compound of claim 123, wherein the Ring X is125. The compound of claim 123 or 124, wherein Rlis -N(H)(CI-4 alkylene)CN.

126. The compound of any one of claims 123-125, wherein q is 0.

127. The compound of any one of claims 123-126, wherein r is 0.

128. The compound of any one of claims 123-127, wherein s is 0.

129. The compound of any one of claims 123-128, wherein the compound is a compound ofFormula Vll-b:VILb or a pharmaceutically acceptable salt thereof.

130. The compound of any one of claims 1-77, wherein the compound is a compound of Formula VIII:VIII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;M is a covalent bond or Ci-4 alkylene; each Ruis independently halogen, -ORff, -N(Rft)2, or optionally substituted C1-6 aliphatic; each Rvis independently halogen, -ORff, -N(Rff)2, or optionally substituted C1-6 aliphatic; each Rffis independently hydrogen or optionally substituted C1-6 aliphatic;Rggis hydrogen or optionally substituted C1-6 aliphatic; u is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, 3, or 4.

131. The compound of claim 130, wherein M is a covalent bond.

132. The compound of claim 130 or 131 , wherein at least one Ruis -ORff.

133. The compound of any one of claims 130-132, wherein each Rflis independently optionally substituted C1-6 aliphatic.

134. The compound of any one of claims 130-133, wherein Rssis hydrogen.

135. The compound of any one of claims 130-134, wherein u is 1 or 2.

136. The compound of any one of claims 130-135, wherein v is 0.

137. The compound of any one of claims 130-136, wherein the compound is a compound ofFormula Vlll-b or Formula VIII-c:or a pharmaceutically acceptable salt thereof.

138. The compound of claim 1, wherein the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

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

140. A method of inhibiting tubulin, comprising contacting the compound of any one of claims 1-138 or the composition of claim 139 with a KRAS protein (e.g., KRASG12C).

141. A method of releasing a tubulin inhibitor payload (e.g., a tubulin inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-138 or the composition of claim 139 with a KRAS protein (e.g., KRASU12C).

142. A method of delivering a tubulin inhibitor payload (e.g., a tubulin inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-138 or the composition of claim 139 with a KRAS protein (e.g., KRASG12C).

143. The method of any one of claims 140-142, wherein the contacting occurs in a cell harboring a KRASG12Cmutant protein.

144. The method of any one of claims 140-143, wherein the contacting occurs in a subject (e.g., a human subject).

145. A method, comprising administering the compound of any one of claims 1-138 or the composition of claim 139 to a subject in need thereof.

146. A method of treating a disease, disorder, or condition associated with KRAS (e.g., mutant KRAS, e.g., KRASG12C), comprising administering the compound of any one of claims 1-138 or the composition of claim 139 to a subject in need thereof.

147. The method of claim 146, wherein the disease, disorder, or condition associated with KRAS is a cancer.

148. A method of treating cancer, comprising administering the compound of any one of claims 1-138 or the composition of claim 139 to a subject in need thereof.

149. The method of claim 147 or 148, wherein the cancer is non-small cell lung cancer or colorectal cancer.

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