KRAS-targeting covalent-induced drug conjugates comprising a topoisomerase payload

Abstract

The present disclosure provides covalent-induced drug conjugates comprising a KRASG12C binding moiety and a topoisomerase 1 payload moiety, as well as compositions and methods of use thereof.

Description

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

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 846,664, filed July 18, 2025; U.S. Provisional Application No. 63 / 757,925, filed February 13, 2025; and U.S. Provisional Application No. 63 / 680,497, filed August 7, 2024; the contents of each of which are herein incorporated by referenceBACKGROUND

[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 topoisomerase 1 payload moiety. As described further herein, provided compounds act as covalent-induced drug conjugates, whereby a cytotoxic payload (e.g., a topoisomerase 1 payload moiety) is specifically delivered to a cell expressing an oncogenic protein (e.g., KRASG12C). Upon binding to KRASG12C, the topoisomerase 1 payload moiety is released and thereby is activated to engage with targets within the cell.

[0004] In some embodiments, the present disclosure provides compounds of Formula I:Page 1 of 373BUSINESS.33352696. 1or 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 the 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, 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,Page 2 of 373BUSINESS.33352696. 1compounds 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., Ci-e). 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-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH2-).

[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,Page 3 of 373BUSINESS.33352696. 1C2-6, 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 10Page 4 of 373BUSINESS.33352696. 1ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[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,Page 5 of 373BUSINESS.33352696. 1decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodi oxolyl, 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 structurePage 6 of 373BUSINESS.33352696. 1may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0023] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4R0; -(CH2)O IOR.°; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O 4CH(OR°)2; -(Cfhjo4SRC; -(CH2)o 4PI1, 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)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(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)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; - C(S)R°; -(CH2)0 4C(O)OR°; -(CH2)O4C(O)SRO; -(CH2)O4C(O)OSiR°3; -(CH2)o4OC(O)R°; - OC(O)(CH2)0 4SRO; -(CH2)O-4SC(0)R°; -(CH2)O4C(0)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)RO; - C(NOR°)R°; -(CH2)O4SSR°; -(CH2)O4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O4OS(O)2RO; - S(O)2NR°2; -(CH2)O4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; - (CH2)O4P(O)2R°; -(CH2)O4P(O)RO2; -(CH2)O4P(O)(ORO)2; -(CH2)O4OP(O)RO2; -(CH2)O-4OP(O)(OR°)2; SiR°3; - (Ci-4straight or branched alkylene)O-N(R°)2; or - (Ci^i straight or branched alkyl ene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -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.Page 7 of 373BUSINESS.33352696. 1

[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)O2OH, -(CH2)o2OR* -(CH2)O2CH(OR*)2; -O(haloR*), -CN, -N3, -(CH2)o2C(O)R’, -(CH2)O2C(O)OH, -(CH2)O2C(O)OR*, -(CH2)O2SR’, -(CH2)O -2SH, -(CH2)O 2NH2, - (CH2)o2NHR*, -(CH2)O-2NR’2, -NO2, -SiR*3, -OSiR\ -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(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R’2))2-3O-, or -S(C(R*2))2-3S- wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2- 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 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 includef,C(O)CH2; wherein each R:is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below,Page 8 of 373BUSINESS.33352696. 1unsubstituted -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 R1', 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 Ci-r 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, the term appears adjacent to a point of atropisomerism. In such cases, it is understood to denote either an “Ra” or “Sa” atropisomer, but the particular isomer was not determined.

[0031] 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

[0032] In some embodiments, the present disclosure provides covalent-induced drug conjugates (CIDCs), as described further herein. Provided CIDCs are bifunctional compounds Page 9 of 373BUSINESS.33352696. 1409894-004WG (220164) 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. 1 A and FIG. IB. First, the protein binding moiety (“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”).

[0033] 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.

[0034] The present disclosure, in particular, relates to CIDCs comprising a KRASG12Cprotein binding moiety and a topoisomerase 1 inhibitor payload moiety.Provided Compounds

[0035] 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 Ci-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 monocyclicPage 10 of 373BUSINESS.33352696. 1heterocyclyl 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 Ci-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 topoisomerase 1 payload moiety.

[0036] 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.

[0037] In some embodiments, the present disclosure provides a compound of Formula I-b:Lb 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:Page 11 of 373BUSINESS.33352696. 1Lais a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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.

[0038] 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 Ci-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 Ci-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroarylPage 12 of 373BUSINESS.33352696. 1having 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-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 Ci-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-e:Page 13 of 373BUSINESS.33352696. 1I-e 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 Ci-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-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:Page 14 of 373BUSINESS.33352696. 1Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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.

[0042] 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.

[0043] 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.

[0044] In some embodiments, the present disclosure provides a compound of Formula I-h-1 :Page 15 of 373BUSINESS.33352696. 1I-h-1 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-1 , Rzis not hydrogen.

[0045] In some embodiments, the present disclosure provides a compound of Formula I-h-2: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.

[0046] In some embodiments of any Formulae described herein, Rxis hydrogen, halogen, cyano, or optionally substituted Ci-6 aliphatic. In some embodiments, Rxis hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, Rxis hydrogen or optionally substituted Ci-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 aliphatic. In somePage 16 of 373BUSINESS.33352696. 1embodiments, Rxis optionally substituted Ci-6 alkyl. In some embodiments, Rxis Ci-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 optionally substituted C3-7 cycloaliphatic. In some embodiments, Rxis C3-7 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 of any Formulae described herein, Rxis not F.

[0047] 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 Ci-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 aliphatic. In some embodiments, Ryis optionally substituted C1-6 alkyl. In some embodiments, Ryis -CH3. 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, RyisPage 17 of 373BUSINESS.33352696. 1optionally 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. In 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.

[0048] 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 Ci-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 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, aPage 18 of 373BUSINESS.33352696. 1

[0049] 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(R")-. In some embodiments, X is -N(H)-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, -L’-TPM is a sufficient leaving group to result in release of the topoisomerase I payload upon binding of the compound to KRASG12C.

[0050] In some embodiments of any Formulae described herein, Rwis hydrogen. In some embodiments, R" is optionally substituted Ci-6 aliphatic. In some embodiments, Rwis Ci-6 aliphatic. In some embodiments, Rwis optionally substituted Ci-6 alkyl. In some embodiments, Rwis Ci-6 alkyl.

[0051] In some embodiments of any Formulae described herein, L1is a covalent bond. In some embodiments, L1is a linking moiety.

[0052] 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)SO2-, or -Cy-, wherein each R is independently hydrogen or an optionally substituted group selected from Ci-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 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.Page 19 of 373BUSINESS.33352696. 1

[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)-, -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-.

[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 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)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units arePage 20 of 373BUSINESS.33352696. 1optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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-.

[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)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated CMO 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-.

[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-, -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-Page 21 of 373BUSINESS.33352696. 1, 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 Cuio 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 Ci-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-.

[0057] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-2o 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-.

[0058] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-2o 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 C1-10 hydrocarbon chain,Page 22 of 373BUSINESS.33352696. 1wherein 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 Ci-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-.O

[0059] 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.

[0060] In some embodiments of any Formulae described herein, L1is, wherein Lais as defined above for Formula I-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. Cy.La6

[0061] In some embodiments of any Formulae described herein, L1isA, 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. La / A N g

[0062] In some embodiments of any Formulae described herein, L1is R , whereinLaand 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.Page 23 of 373BUSINESS.33352696. 1

[0063] 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.O

[0064] In some embodiments of any Formulae described herein, L1isR, wherein 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.,LLby° Ov

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

[0066] 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.

[0067] In some embodiments of any Formulae described herein, L1isR, 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 to TPM.

[0068] In some embodiments of any Formulae described herein, L1is OPage 24 of 373BUSINESS.33352696. 1

[0069] 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 Ci-6 hydrocarbon chain; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0070] In some embodiments of any Formulae described herein, L1is selected from: a covalentPage 25 of 373BUSINESS.33352696. 1wherein the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0071] In some embodiments of any Formulae described herein, wherein L1is selected from:wherein: Lcis an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci- 6 hydrocarbon chain.

[0072] In some embodiments of any Formulae described herein, Lais a covalent bond.

[0073] In some embodiments of any Formulae described herein, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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 Page 26 of 373BUSINESS.33352696. 1optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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 Ci-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-

[0074] 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-

[0075] In some embodiments of any Formulae described herein, Lbis a covalent bond.Page 27 of 373BUSINESS.33352696. 1

[0076] In some embodiments of any Formulae described herein, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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, 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 Ci-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-

[0077] 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)-, -Page 28 of 373BUSINESS.33352696. 1C(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(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 C1.4 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-

[0078] In some embodiments of any Formulae described herein, Lcis an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-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 Ci-6 alkylene. In some embodiments, Leis optionally substituted C1-3 alkylene. In some embodiments, Lcis Ci-6 alkylene. In some embodiments, Lcis C1-3 alkylene. In some embodiments, Lcis -CH2- . In some embodiments, Lcis -CH2CH2-. In some embodiments, Lcis -CH2CH2CH2-.

[0079] In some embodiments of any Formulae described herein, each R is independently hydrogen or an optionally substituted group selected from Ci-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 Ci-6 aliphatic and C3-7 monocyclic carbocyclyl. In some embodiments, each R is independently hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, each R is independently hydrogen or Ci-6 aliphatic optionally substituted with one or more halogen, -OH, -O(Ci-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 Ci-6 alkyl. In some embodiments, each R is independently hydrogen or Ci- 6 alkyl optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, each R is independently hydrogen or Ci-6 alkyl.Page 29 of 373BUSINESS.33352696. 1In some embodiments, each R is hydrogen. In some embodiments, a R is hydrogen. In some embodiments, a R is optionally substituted Ci-6 aliphatic. In some embodiments, a R is Ci-6 aliphatic optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, a R is optionally substituted C1-6 alkyl. In some embodiments, a R is C1-6 alkyl optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2 (e.g., -CH2CH2N(CH3)2). In some embodiments, a R is Ci-6 alkyl (e.g., methyl or isopropyl). 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.

[0080] 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 heterocyclyl ene 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,Page 30 of 373BUSINESS.33352696. 1bridged, 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.

[0081] 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 (e.g., a 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 (e.g., a 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.

[0082] 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 topoisomerase I 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 topoisomerase I payload upon binding of the compound to KRASG12C. KRA PI2CBinding Moiety

[0083] 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 specificallyPage 31 of 373BUSINESS.33352696. 1associates with that protein within a cell (e.g., in vitro or in vivo). Tn 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 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less).

[0084] 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 Ci-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;Page 32 of 373BUSINESS.33352696. 1R6is an optionally substituted Ci-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 Ci-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.

[0085] In some embodiments, the present disclosure provides a compound of Formula Il-a:Il-a or a pharmaceutically acceptable salt thereof, wherein L1, L2, L3, R3, R5, 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.

[0086] In some embodiments, the present disclosure provides a compound of Formula Il-b :Page 33 of 373BUSINESS.33352696. 1Il-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.

[0087] In some embodiments, the present disclosure provides a compound of Formula II-c:II-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 Ci-6 aliphatic.

[0088] In some embodiments, the present disclosure provides a compound of Formula Il-d:Page 34 of 373BUSINESS.33352696. 1Il-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.

[0089] In some embodiments, the present disclosure provides a compound of Formula IF: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 Ci-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;Page 35 of 373BUSINESS.33352696. 1, ,V0^5^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 Ci-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 Ci-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.

[0090] In some embodiments, the present disclosure provides a compound of Formula II’-a or II’-b:Page 36 of 373BUSINESS.33352696. 1ir-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.

[0091] In some embodiments, the present disclosure provides a compound of Formula II’-c orFormula II’-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 Ci-6 aliphatic; and nl’ is 0, 1, 2, 3, 4, 5, or 6.

[0092] In some embodiments, the present disclosure provides a compound of Formula III:Page 37 of 373BUSINESS.33352696. 1III 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 Ci-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.Page 38 of 373BUSINESS.33352696. 1

[0093] In some embodiments, the present disclosure provides a compound of Formula Ill-a: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.

[0094] In some embodiments, the present disclosure provides a compound of Formula Ill-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 Ci-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.

[0095] In some embodiments, the present disclosure provides a compound of Formula IV:Page 39 of 373BUSINESS.33352696. 1IV 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 Ci-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 Ci-6 aliphatic; each R18is independently hydrogen or optionally substituted Ci-6 aliphatic, or two R18groups are taken together to form an oxo; each R19is independently hydrogen or optionally substituted Ci-6 aliphatic; each R20is independently hydrogen or optionally substituted Ci-6 aliphatic; each R’ is independently hydrogen or optionally substituted Ci-6 aliphatic; q is 1 or 2; and p is 1 or 2.

[0096] In some embodiments, the present disclosure provides a compound of Formula IV-a:Page 40 of 373BUSINESS.33352696. 1IV-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.

[0097] 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 Ci-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.Page 41 of 373BUSINESS.33352696. 1

[0098] 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.

[0099] 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;Page 42 of 373BUSINESS.33352696. 1each R’ is independently hydrogen or optionally substituted Ci-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.

[0100] In some embodiments, the present disclosure provides a compound of Formula Vl-a:VI-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.

[0101] In some embodiments, the present disclosure provides a compound of Formula Vl-b:Page 43 of 373BUSINESS.33352696. 1Vl-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 Ci-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.

[0102] 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 Ci-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,Page 44 of 373BUSINESS.33352696. 1oxygen, 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 Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; °x / Cy8R30is 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.

[0103] In some embodiments, the present disclosure provides a compound of Formula Vll-a:Page 45 of 373BUSINESS.33352696. 1VH-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.

[0104] 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 Ci-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;Page 46 of 373BUSINESS.33352696. 1R29is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; °'^ / Cy3R30is 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 Ci-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 Ci-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 R32moi eties 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.

[0105] 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 Ci-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 Ci-6 aliphatic (e.g., optionally substituted Ci-6 alkyl). In some embodiments, each R1is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl).Page 47 of 373BUSINESS.33352696. 1

[0106] In some embodiments of any Formulae described herein, each R2is independently hydrogen, optionally substituted Ci-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).

[0107] 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(Ci-6 alkyl), -NH2, Ci-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, Ci-6 aliphatic, or C1-6 haloaliphatic.

[0108] In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci- 6 aliphatic, or Ci-6 haloaliphatic. In some embodiments, R3is a substituted phenyl. In some embodiments, R3is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.Page 48 of 373BUSINESS.33352696. 1

[0109] In some embodiments, R3is phenyl substituted with one or more of the following groups: halogen, Ci-6 aliphatic, Ci-6 haloaliphatic, or -NH2. In some embodiments, R3is

[0110] In some embodiments, R3is an optionally substituted naphthyl. In some embodiments, R3is a naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-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(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or C1-6 haloaliphatic. In some embodiments, R3is a naphthyl optionally substituted with -CH3.[0U1] 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R3a is 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(Ci-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0112] 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, R3a is 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(Ci-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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.Page 49 of 373BUSINESS.33352696. 1

[0113] 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,

[0114] In some embodiments of any Formulae described herein, R3is an optionally substituted ring selected from:

[0115] In some embodiments, R3is not

[0116] 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 Ci-6 aliphatic (e.g., optionally substituted Ci-6 alkyl). In some embodiments, R33is methyl. In some embodiments, R33is not Cl.

[0117] 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.

[0118] In some embodiments of any Formulae described herein, each R4is independently hydrogen, optionally substituted Ci-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 C1-6 Page 50 of 373BUSINESS.33352696. 1aliphatic (e.g., optionally substituted Ci-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 Ci-6 aliphatic (e.g., optionally substituted Ci-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).

[0119] 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, °^ / Cy1and 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, R5is hydrogen.In some embodiments, R5is -OR6. In some embodiments, R5is. In some embodiments, R5is -O(Ci-4 alkylene)Cy2. In some embodiments, R5is -OCFFCy2. In some embodiments, R3is 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).Page 51 of 373BUSINESS.33352696. 1

[0120] In some embodiments, R5is selected from:

[0121] In some embodiments,some embodiments,someembodiments, R5isIn some embodiments, R5is I In some embodiments,embodiments,

[0122] In some embodiments of any Formulae described herein, R6is an optionally substitutedCi-6 aliphatic or an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0123] In some embodiments, R6is an optionally substituted Ci-6 aliphatic. In some embodiments, R6is an optionally substituted Ci-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 fromPage 52 of 373BUSINESS.33352696. 1nitrogen, oxygen, and sulfur. In some embodiments, R6is monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-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 Ci-6 alkyl.

[0124] 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.

[0125] 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 Ci-6 alkyl.

[0126] 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.

[0127] 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 Ci-6 alkyl. In some embodiments, Cy2is an optionally substituted pyrrolidinyl.Page 53 of 373BUSINESS.33352696. 1

[0128] 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 Ci-6 alkyl.

[0129] In some embodiments,some embodiments, Cy2is. In some embodiments, Cy2isembodiments,

[0130] 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-

[0131] 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’)-.

[0132] 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.Page 54 of 373BUSINESS.33352696. 1

[0133] 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.

[0134] 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.

[0135] 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 Ci-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.

[0136] In some embodiments, Ring A is an optionally substituted bivalent bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independentlyPage 55 of 373BUSINESS.33352696. 1selected 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.

[0137] In some embodiments of any Formulae described herein, Ring A is optionally substituted

[0138] 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.

[0139] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:

[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 selected from:Page 56 of 373BUSINESS.33352696. 1

[0144] In some embodiments of any Formulae described herein, Ring A is:some embodiments, Ring A is:

[0145] 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.

[0146] In some embodiments of any Formulae described herein, each R7is independently optionally substituted Ci-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 Ci-6 aliphatic. In some embodiments, each R7is independently optionally substituted Ci-6 alkyl. In some embodiments, a R7is optionally substituted Ci-6 aliphatic. In some embodiments, a R7is optionally substituted Ci-6 alkyl. In some embodiments, a R7is Ci-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 / or spirofused with the ring to which the R7moieties are attached. In some embodiments, two R7are Page 57 of 373BUSINESS.33352696. 1taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R7moieties are attached.

[0147] 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.

[0148] In some embodiments of any Formulae described herein, each R7is independently optionally substituted Ci-6 aliphatic. In some embodiments, a R7is Ci-6 aliphatic. In some embodiments, a R7is optionally substituted Ci-6 alkyl. In some embodiments, a R7is Ci-6 alkyl optionally substituted with -CN. In some embodiments, a R7is Ci-6 alkyl. In some embodiments, a R7is -CH3. In some embodiments, a R7is -CH2CN. In some embodiments, a R7is -CH3 or - CH2CN.

[0149] 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.

[0150] In some embodiments of any Formulae described herein, R8is hydrogen, halogen, - OR’, optionally substituted Ci-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 Ci-6 aliphatic (e g., optionally substituted Ci-6 alkyl). In some embodiments, R8is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl).

[0151] In some embodiments, R8is not H.

[0152] In some embodiments of any Formulae described herein, R9is hydrogen, halogen, - OR’, optionally substituted Ci-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 Ci-6 aliphatic or an optionally substituted C3-7 cycloaliphatic. In some embodiments, R9is an optionally substituted Ci-6 aliphatic (e.g., optionally substituted Ci-6 alkyl). In some embodiments, R9is an optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted C3-7 cycloalkyl).Page 58 of 373BUSINESS.33352696. 1

[0153] In some embodiments, R9is not a halogen. In some embodiments, R9is not F.

[0154] 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(Ci-6 alkyl), -NH2, Ci-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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.

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

[0156] In some embodiments, R10is an optionally substituted naphthyl. In some embodiments, R10is a naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-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-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, R10is a naphthyl optionally substituted with -CH3.

[0157] 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 more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic. In somePage 59 of 373BUSINESS.33352696. 1embodiments, 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0158] 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(Ci-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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.OHC C

[0159] In some embodiments, R10is F . In some embodiments, R10isF. In some embodiments,

[0160] In some embodiments, R10is not a phenyl. In some embodiments, R10is not aOH( substituted phenyl. In some embodiments, R10is not F .

[0161] 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.Page 60 of 373BUSINESS.33352696. 1

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

[0163] In some embodiments, R11is an optionally substituted naphthyl. In some embodiments, R11is a naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.

[0164] 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or Ci-6 haloaliphatic.

[0165] 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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.

[0166]

[0167] In some embodiments,

[0168] 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,R11is not

[0169] 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 -Page 61 of 373BUSINESS.33352696. 1N(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-

[0170] In some embodiments, L4is not a covalent bond.

[0171] In some embodiments of any Formulae described herein, I is a covalent bond or - (CH2) m N(R’)-. In some embodiments, L5is a covalent bond. In some embodiments, L5is - (CH2)mN(R’)-. In some embodiments, L5is -(CH2)mN(H)-. In some embodiments, I? is - (CH2)mN(CH3)-. In some embodiments, L5is -N(R’)-. In some embodiments, L5is -CH2N(R’)-.

[0172] In some embodiments, L5is not a covalent bond.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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 independentlyPage 62 of 373BUSINESS.33352696. 1selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B 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 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 Ci-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.

[0177] 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.

[0178] In some embodiments of any Formulae described herein, Ring B is optionallyV0 substituted '

[0179] 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.Page 63 of 373BUSINESS.33352696. 1

[0180] In some embodiments, Ring, depicts a bond to L5. In some embodiments, Ring, wherein I depicts a bond to L5.

[0181] 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 ~~l~~ , wherein I depicts a bond toL5.

[0182] 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 Ci-6 alkyl. In some embodiments, each R12is methyl. In some embodiments, a R12is optionally substituted Ci-6 aliphatic. In some embodiments, a R12is optionally substituted Ci-6 alkyl. In some embodiments, aR12is Ci-6 alkyl optionally substituted with -CN. In some embodiments, aR12is -CH3 or-CFfcCN. 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.

[0183] 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.Page 64 of 373BUSINESS.33352696. 1

[0184] In some embodiments of any Formulae described herein, R13is hydrogen, halogen, - OR’, optionally substituted Ci-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 Ci-6 alkyl). In some embodiments, R13is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted an optionally substituted C3-7 cycloalkyl).

[0185] 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 Ci-6 alkyl). 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).

[0186] 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.

[0187] In some embodiments is R15is an optionally substituted phenyl. In some embodiments, R15is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci- 6 aliphatic, or Ci-6 haloaliphatic. In some embodiments, R15is substituted phenyl. In some embodiments, R15is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0188] In some embodiments is R15is an optionally substituted naphthyl. In some embodiments, R15is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci- 6 alkyl), -NH2, Ci-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(Ci-6alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, R15is naphthyl optionally substituted with -CH3.Page 65 of 373BUSINESS.33352696. 1

[0189] In some embodiments is 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, R15is 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0190] In some embodiments is 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(Ci-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-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0191] In some embodiments,some embodiments,some embodiments,

[0192] 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 R16Page 66 of 373BUSINESS.33352696. 1is an optionally substituted Ci-6 aliphatic (e.g., an optionally substituted Ci-6 alkyl). In some embodiments R16is an optionally substituted C3-7 cycloaliphatic (e g., an optionally substituted C3- 7 cycloalkyl).

[0193] 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).

[0194] 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 Ci-6 alkyl). In some embodiments, two R18groups are taken together to form an oxo.

[0195] 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 Ci-6 alkyl).

[0196] 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 Ci-6 alkyl).

[0197] 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.

[0198] 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.

[0199] In some embodiments of any Formulae described herein, R21is hydrogen, halogen, - OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R21is hydrogen. In some embodiments, R21is a halogen. In some embodiments, R21Page 67 of 373BUSINESS.33352696. 1is F. In some embodiments, R21is -OR’. In some embodiments, R21is an optionally substituted Ci. 6 aliphatic (e.g., an optionally substituted Ci-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).

[0200] 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(Ci-6 alkyl), -NH2, Ci-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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.

[0201] In some embodiments, Cy4is an optionally substituted phenyl. In some embodiments, Cy4is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic. In some embodiments, Cy4is substituted phenyl. In some embodiments, Cy4is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), - NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.

[0202] In some embodiments, Cy4is an optionally substituted naphthyl. In some embodiments, Cy4is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, Cy4is substituted naphthyl. In some embodiments, Cy4is naphthyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, Cy4is naphthyl optionally substituted with -CH3.

[0203] In some embodiments, Cy4is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. InPage 68 of 373BUSINESS.33352696. 1some 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(Ci-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(Ci-6 alkyl), - NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0204] 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(Ci-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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0205] In some embodiments,

[0206] 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, 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, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic. In some embodiments, Cy3is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclicPage 69 of 373BUSINESS.33352696. 1heteroaryl 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-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0207] In some embodiments, Cy5is an optionally substituted phenyl. In some embodiments, Cy5is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic, or Ci-6 haloaliphatic. In some embodiments, Cy5is substituted phenyl. In some embodiments, Cy5is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), - NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.

[0208] In some embodiments, Cy5is an optionally substituted naphthyl. In some embodiments, Cy5is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e g., -CH3), or Ci-6 haloaliphatic. In some embodiments, Cy5is substituted naphthyl. In some embodiments, Cy5is naphthyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, Cy5is naphthyl optionally substituted with -CH3.

[0209] 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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-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(Ci-6 alkyl), - NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.

[0210] 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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic. In some embodiments, Cy5is a substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatomsPage 70 of 373BUSINESS.33352696. 1independently 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0211] In some embodiments,

[0212] 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’)-.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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 heteroatomPage 71 of 373BUSINESS.33352696. 1independently 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 Ci-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.

[0217] 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.

[0218] In some embodiments, Ring

[0219] 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.Page 72 of 373BUSINESS.33352696. 1

[0220] 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.

[0221] 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.

[0222] 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 Ci-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.

[0223] 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 optionallyPage 73 of 373BUSINESS.33352696. 1substituted 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.

[0224] In some embodiments of any Formulae described herein, Ring E is optionally substituted

[0225] In some embodiments of any Formulae described herein, Ringwherein R2?and n3 are as defined herein for Formula Vl-b and described in classes and subclasses herein, both singly and in combination.6 N

[0226] In some embodiments, Ring E is —L~ .

[0227] In some embodiments of any Formulae described herein, L7is a covalent bond or -(CH2)mN(R’)-. In some embodiments, L7is a covalent bond. In some embodiments, L7is - (CH2)mN(R’)-.

[0228] 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.

[0229] In some embodiments of any Formulae described herein, R23is hydrogen, halogen, - OR’, optionally substituted Ci-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).

[0230] In some embodiments of any Formulae described herein, R24is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In somePage 74 of 373BUSINESS.33352696. 1embodiments, 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 Ci-6 alkyl). In some embodiments, R24is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0231] 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.

[0232] 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.

[0233] 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.Page 75 of 373BUSINESS.33352696. 1

[0234] In some embodiments, Cy6is selected from:

[0235] 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, wherein depicts a bond to Cy7.

[0236] 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.

[0237] 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 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, -CN, -OH, -O(Ci-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, Cy7Page 76 of 373BUSINESS.33352696. 1is 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0238] 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(Ci-6 alkyl), - NH2, Ci-6 aliphatic, or Ci-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-6 alkyl), -NH2, C1-6 aliphatic, or Ci-6 haloaliphatic.

[0239] 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(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-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(Ci-6 alkyl), - NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.

[0240] 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 having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-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, Cy7Page 77 of 373BUSINESS.33352696. 1is 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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0241]

[0243] In some embodiments of any Formulae described herein, 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. In some embodiments, each R25is independently optionally substituted Ci- 6 aliphatic. In some embodiments, each R25is independently optionally substituted Ci-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, R25is 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 R25are taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R23moieties are attached.

[0244] 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.

[0245] In some embodiments of any Formulae described herein, Y is CR27or N. In some embodiments, Y is CR27. In some embodiments, Y is N.

[0246] In some embodiments of any Formulae described herein, R26is hydrogen, halogen, - OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, 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 optionallyPage 78 of 373BUSINESS.33352696. 1substituted Ci-6 alkyl). In some embodiments, R26is an optionally substituted C3-7 cycloaliphatic (e.g., an optionally substituted C3-7 cycloalkyl).

[0247] 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 Ci-6 alkyl). In some embodiments, R27is an optionally substituted C3-7 cycloaliphatic (an optionally substituted C3-7 cycloalkyl).

[0248] 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(Ci-6 alkyl), -NH2, Ci-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(Ci-6alkyl), -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.

[0249] In some embodiments, R28is an optionally substituted phenyl. In some embodiments, R28is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci- 6 aliphatic, or Ci-6 haloaliphatic. In some embodiments, R28is substituted phenyl. In some embodiments, R28is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic, or Ci-6 haloaliphatic.

[0250] In some embodiments, R28is an optionally substituted naphthyl. In some embodiments, R28is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, R28is a substituted naphthyl. In some embodiments, R28is a naphthyl substituted with one or more halogen, -CN, -Page 79 of 373BUSINESS.33352696. 1OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3), or Ci-6 haloaliphatic. In some embodiments, R3is a naphthyl optionally substituted with -CH3.

[0251] 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(Ci-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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0252] 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(Ci-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(Ci-6 alkyl), -NH2, C1-6 aliphatic, or C1-6 haloaliphatic.

[0253] In some embodiments,. In some embodiments,

[0254] 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-Page 80 of 373BUSINESS.33352696. 16 aliphatic (an optionally substituted Ci-6 alkyl). In some embodiments, R29is an optionally substituted C3-7 cycloaliphatic (an optionally substituted C3-7 cycloalkyl).

[0255] 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.

[0256] 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.

[0257] In some embodiments, R30is -OR31,. In some embodiments, R30is -O(Ci-4 alkylene)Cy9. In some embodiments, R30is -OCFhCy9In 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)?).

[0258] 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.

[0259] 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. InPage 81 of 373BUSINESS.33352696. 1some embodiments, R31is monocyclic 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl.

[0260] 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.

[0261] 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 Ci-6 alkyl.

[0262] 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.

[0263] 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 Ci-6 alkyl. In some embodiments, Cy9is an optionally substituted pyrrolidinyl.

[0264] 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- toPage 82 of 373BUSINESS.33352696. 18-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 Ci-6 alkyl.

[0265] In some embodiments of any Formulae described herein, L8is a covalent bond or - (CH2)mN(R’)-. In some embodiments, L8is a covalent bond. In some embodiments, L8is - (CH2)mN(R’)-.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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 independentlyPage 83 of 373BUSINESS.33352696. 1selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring G 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 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 Ci-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.

[0270] 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.

[0271] In some embodiments of any Formulae described herein, Ring G is optionallywhereindenotes a bond to L8anddenotes a bond to Ring H. In some embodiments, Ring G is, whereindenotes a bond todenotes a bond to Ring H.Page 84 of 373BUSINESS.33352696. 1

[0273] 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 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 a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0274] In some embodiments, Ring H, taken with the ring to which it is fused, is

[0275] 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.

[0276] In some embodiments of any Formulae described herein, each R32is independently optionally substituted Ci-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 Ci-6 aliphatic. In some embodiments, an R32is an optionally substituted Ci-6 alkyl. In some embodiments, an R32is an optionally substituted Ci-6 alkyl. In some embodiments, R32is methyl. In some embodiments, aR32is Ci-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.

[0277] 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 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.Page 85 of 373BUSINESS.33352696. 1

[0278] In some embodiments, Ring J, taken with the rings to which it is fused, is some embodiments, Ring J, taken with the rings to which it is fused, is some embodiments, Ring J, taken with the rings to which it is fused, is

[0279] 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.

[0280] In some embodiments of any Formulae described herein, each R’ is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each R’ is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl. In some embodiments, a R’ is hydrogen. In some embodiments, a R’ is optionally substituted Ci-6 aliphatic. In some embodiments, a R’ is optionally substituted Ci-6 alkyl. In some embodiments, a R’ is Ci-6 alkyl. In some embodiments, a R’ is Ci-6 haloalkyl.Page 86 of 373BUSINESS.33352696. 1embodiments, when L2is -N(R’)(CH2)m-, then L3is a covalent bond. In some embodiments, when L3is -(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’)-.

[0282] In some embodiments of any Formulae described herein, a moietyPage 87 of 373BUSINESS.33352696. 1embodiments, when L4is -N(R’)(CH2)m-, then L5is a covalent bond. In some embodiments, when L5is -(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 bicyclic5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then L5is -(CH2)mN(R’)-.

[0284] In some embodiments of any Formulae described herein, a moiety

[0285] In some embodiments of any Formulae described herein, a moietyis(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, Page 88 of 373BUSINESS.33352696. 1bridged, 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’)-.

[0286] In some embodiments of any Formulae described herein, a moiety

[0287] In some embodiments of any Formulae described herein, a moiety(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’)-.

[0288] In some embodiments of any Formulae described herein, a moietyPage 89 of 373BUSINESS.33352696. 1

[0289] 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’)-.

[0290] In some embodiments of any Formulae described herein, a moietyis selected from:

[0291] In some embodiments, KBM is a KRASG12Cbinding moiety (e.g., a moiety that binds and / or inhibits KRASG12C). The present invention 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 topoisomerase I payload moiety, as defined herein (e.g.,Page 90 of 373BUSINESS.33352696. 1such 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 described in WO2108 / 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 / 1436S9; WO2014 / 152588; W02014 / 160200;WO2015 / 054572; WO2016 / 044772; WO2016 / 049524; WO2016 / 164675; WO2016 / 168540;W02017 / 058805; WO2017 / 015562; WO2017 / 058728; WO2017 / 058768; WO2017 / 058792;W02017 / 058805; W02017 / 058807; WO2017 / 058902; WO2017 / 058915; WO2017 / 087528;W02017 / 100546; W02017 / 201161; WO2018 / 064510; WO2018 / 068017; WO2018 / 119183;W02018 / 140S12; WO2018 / 140513; WO2018 / 140514; WO2018 / 140598; WO2018 / 140599;W02018 / 140600; WO2018 / 143315; WO2018 / 206539; WO2018 / 218070; WO2018 / 218071;WO20 19 / 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;Page 91 of 373BUSINESS.33352696. 1WO2023 / 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; WO 2025 / 137519; WO2025 / 151765; WO2025 / 151738; WO2025 / 151594; and WO2025 / 153038.

[0292] In some embodiments, KBM is AZD4625.

[0293] In some embodiments of any Formulae described herein, KBM is:Page 92 of 373BUSINESS.33352696. 1

[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:Page 93 of 373BUSINESS.33352696. 1

[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:

[0301] In some embodiments of any Formulae described herein, KBM is:Page 94 of 373BUSINESS.33352696. 1

[0302] In some embodiments of any Formulae described herein, KBM is:

[0303] In some embodiments of any Formulae described herein, KBM is:

[0304] In some embodiments of any Formulae described herein, KBM is:

[0305] In some embodiments of any Formulae described herein, KBM is:Page 95 of 373BUSINESS.33352696. 1

[0306] In some embodiments of any Formulae described herein, KBM is:

[0307] In some embodiments of any Formulae described herein, KBM is:

[0308] In some embodiments of any Formulae described herein, KBM is:

[0309] In some embodiments of any Formulae described herein, KBM is:Page 96 of 373BUSINESS.33352696. 1

[0310] In some embodiments of any Formulae described herein, KBM is:

[0311] 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.

[0312] 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.

[0313] In some embodiments of any Formulae described herein, KBM is:Page 97 of 373BUSINESS.33352696. 1wherein R3, R5, and Ring A are as defined herein for Formula II -b and described in classes and subclasses herein, both singly and in combination.

[0314] 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 IF and described in classes and subclasses herein, both singly and in combination.

[0315] 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.

[0316] 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.

[0317] In some embodiments of any Formulae described herein, KBM is:Page 98 of 373BUSINESS.33352696. 1wherein L2, L3, R3, R3, 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.Page 99 of 373BUSINESS.33352696. 1

[0322] 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.

[0323] 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.

[0324] In some embodiments of any Formulae described herein, KBM is:wherein R3, R\ R7, and nl’ are as defined herein for Formula II’-c and Il’-d and described in classes and subclasses herein, both singly and in combination.

[0325] 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 IF-d and described in classes and subclasses herein, both singly and in combination.Page 100 of 373BUSINESS.33352696. 1

[0326] 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.

[0327] In some embodiments of any Formulae described herein, KBM is:wherein R9, R10, R11, and Ring B are as defined herein for Formula Ill-a and described in classes and subclasses herein, both singly and in combination.

[0328] 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.

[0329] 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.Page 101 of 373BUSINESS.33352696. 1

[0330] In some embodiments of any Formulae described herein, KBM is:wherein R13, R14, R13, and R16are as defined herein for Formula IV-a and described in classes and subclasses herein, both singly and in combination.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] In some embodiments of any Formulae described herein, KBM is:Page 102 of 373BUSINESS.33352696. 1wherein 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.

[0335] In some embodiments of any Formulae described herein, KBM is:wherein Cy6, Cy7, R25, n3 and Ring F are as defined herein for Formula Vl-b and described in classes and subclasses herein, both singly and in combination.

[0336] 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.

[0337] 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.Page 103 of 373BUSINESS.33352696. 1

[0338] 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.Topoisomerase I Pay load Moiety

[0339] As described and defined herein, TPM is a topoisomerase 1 inhibitor payload moiety, i.e., a moiety capable of binding and / or inhibiting topoisomerase 1 protein and / or a topoisomerase1-DNA complex. Typically, a TPM is considered to be capable of binding a topoisomerase 1 protein and / or a topoisomerase 1-DNA complex if it specifically (or preferentially) associates with the topoisomerase 1 protein and / or a topoisomerase 1-DNA complex when contacted with topoisomerase 1 protein and / or a topoisomerase 1-DNA complex in the presence of at least one other protein or DNA. In some embodiments, a TPM is considered to be capable of binding topoisomerase 1 protein and / or a topoisomerase 1-DNA complex if it specifically associates with that protein and / or complex within a cell (e.g., in vitro or in vivo). In some embodiments, a TPM is considered capable of binding a topoisomerase 1 protein and / or a topoisomerase 1-DNA complex if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 pM, less than about 1 pM, 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 topoisomerase 1 protein if it inhibits it with measurable affinity (e.g., an IC50 of less than about 10 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less).

[0340] In some embodiments, the present disclosure provides a compound of Formula IX:IXPage 104 of 373BUSINESS.33352696. 1or 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;W is O or S;Z1is a covalent bond or -O-;Z2is a covalent bond or -C(RC)2-;Rais hydrogen or optionally substituted Ci-6 aliphatic;Rbis -ORaa; each Reis independently hydrogen or optionally substituted Ci-6 aliphatic;Rdis hydrogen, halogen, or optionally substituted Ci-6 aliphatic; each Reis independently hydrogen or optionally substituted Ci-6 aliphatic;Rfis hydrogen, halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SRaa, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;Rgis hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rfand Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rhis hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R’ is hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or R11and R1, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 105 of 373BUSINESS.33352696. 1Rj is hydrogen, halogen, -CN, -C02bb, -C(0)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each Raais independently Rbb, -C(O)Rbb, or -C(0)N(Rbb)2; and each Rbbis independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a C3-7 monocyclic carbocyclyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rbbwhen attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0341] In some embodiments, the present disclosure provides a compound of Formula IX-a:IX-a or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, Rf Rx, Ry, Rz, W, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0342] In some embodiments, the present disclosure provides a compound of Formula IX-b:IX-b or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R>, Rx, Ry, Rz, W, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.Page 106 of 373BUSINESS.33352696. 1

[0343] In some embodiments, the present disclosure provides a compound of Formula IX-c:IX-c or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rd, R1, Rg, Rh, R1, Rx, Ry, Rz, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0344] In some embodiments, the present disclosure provides a compound of Formula IX-d:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Re, Rd, Re, Rf, R8, Rh, R1, R>, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0345] In some embodiments, the present disclosure provides a compound of Formula IX-dl :Page 107 of 373BUSINESS.33352696. 1or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rc, Rd, Re, R4, Rg, Rh, R1, R>, Rx, Ry, Rz, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0346] In some embodiments, the present disclosure provides a compound of Formula IX-e:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, R4, Rg, R1, R>, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0347] In some embodiments, the present disclosure provides a compound of Formula IX-el :or a pharmaceutically acceptable salt thereof, wherein L4, Ra, Rb, Rc, Rd, Re, R4, R8, R1, R'. Rx, Ry, Rz, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0348] In some embodiments, the present disclosure provides a compound of Formula IX-f:Page 108 of 373BUSINESS.33352696. 1IX-f or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rb, R1, Rl Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0349] In some embodiments, the present disclosure provides a compound of Formula IX-fl :IX-fl or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rh, R1, R>, Rx, Ry, Rz, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0350] In some embodiments, the present disclosure provides a compound of Formula IX-g:Page 109 of 373BUSINESS.33352696. 1IX-g or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, R8, Rh, R1, R', Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0351] In some embodiments, the present disclosure provides a compound of Formula IX-gl :IX-gl or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Re, Rd, Re, Rg, Rh, R1, R', Rx, Ry, Rz, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0352] In some embodiments, the present disclosure provides a compound of Formula IX-h:Page 110 of 373BUSINESS.33352696. 1IX-h or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, R1, R8, Rh, R1, R', Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0353] In some embodiments, the present disclosure provides a compound of Formula IX-hl :IX-hl or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Re, Rd, Re, Rf, Rg, Rh, R1, Ri, Rx, Ry, Rz, X, and KBM are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0354] In some embodiments, the present disclosure provides a compound of Formula X:XPage 111 of 373BUSINESS.33352696. 1or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;W is O or S;Z2is a covalent bond or -C(RC)2-;Rais hydrogen or optionally substituted Ci-6 aliphatic;Rbis -ORaa; each Rcis independently hydrogen or optionally substituted Ci-6 aliphatic;Rdis hydrogen, halogen, or optionally substituted Ci-6 aliphatic; each Reis independently hydrogen or optionally substituted Ci-6 aliphatic;Rfis hydrogen, halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SRaa, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;Rsis hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or R1and Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rhis hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R1is hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R' is hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each Raais independently Rbb, -C(O)Rbb, or -C(O)N(Rbb)2; andPage 112 of 373BUSINESS.33352696. 1each Rbbis independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a C3-7 monocyclic carbocyclyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rbbwhen attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0355] In some embodiments, the present disclosure provides a compound of Formula X-a:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, R', Rx, Ry, Rz, W, X, Z2, and KBM are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0356] In some embodiments, the present disclosure provides a compound of Formula X-b:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, R', Rx, Ry, Rz, W, X, Z2, and KBM 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:Page 113 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, Rl, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0358] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rb, R1, Rl, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0359] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R>, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0360] In some embodiments of any Formulae described herein, TPM is:Page 114 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rc, Rd, Re, R1. Rg, Rh, R1, R>, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0361] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, Rg, Rh, and R1are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0362] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and R1are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0363] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and R1are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0364] In some embodiments of any Formulae described herein, TPM is:Page 115 of 373BUSINESS.33352696. 1wherein Ra, Rc, Rd, Re, R1, Rg, Rh, R1, R), W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0365] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rc, Rd, Re, Rf, Rg, Rh, R1, Rl, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0366] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Re, Rd, Re, Rf, Rg, R1, R W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0367] In some embodiments of any Formulae described herein, TPM is:Page 116 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, R1, Ri, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0368] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rs, R1, R', and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0369] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, R1, Rl, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0370] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, R1, R>, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0371] In some embodiments of any Formulae described herein, TPM is:Page 117 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rc, Rd, Re, R1, R, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0372] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rb, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0373] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rh, R1, Rl, and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0374] In some embodiments of any Formulae described herein, TPM is:Page 118 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rc, Rd, Re, Rg, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0375] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rs, Rh, R1, R', and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0376] In some embodiments of any Formulae described herein, TPM is:Page 119 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula TX and described in classes and subclasses herein, both singly and in combination.

[0377] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rb, R1, R and W are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0378] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rr, and R1are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0379] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and R1are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0380] In some embodiments of any Formulae described herein, TPM is:Page 120 of 373BUSINESS.33352696. 1wherein Ra, Rb, Rbb, Re, Rd, Re, R1, Rg, Rh, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0381] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Re, Rd, Re, Rf, Rg, Rb, R', Rj, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0382] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, Rj, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0383] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, R1, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.Page 121 of 373BUSINESS.33352696. 1

[0384] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Re, Rd, Re, Rf, Rg, Rh, R1, R W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0385] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Re, Rd, Re, Rf, Rg, Rb, R1, Rl, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0386] In some embodiments of any Formulae described herein, W is O. In some embodiments, W is S.

[0387] In some embodiments of any Formulae described herein, Z1is a covalent bond. In some embodiments, Z1is -O-.

[0388] In some embodiments of any Formulae described herein, Z2is a covalent bond. In some embodiments, Z2is -C(RC)2-. In some embodiments, Z2is -CH2-.

[0389] In some embodiments of any Formulae described herein, Z1is -O- and Z2is a covalent bond. In some embodiments, Z1is -O- and Z2is -C(RC)2-. In some embodiments, Z1is -O- and Z2is -CH2-. In some embodiments, Z1and Z2are both a covalent bond.

[0390] In some embodiments of any Formulae described herein, Rais hydrogen or optionally substituted C1-6 alkyl. In some embodiments, Rais hydrogen. In some embodiments, Rais optionally substituted C1-6 aliphatic. In some embodiments, Rais C1-6 aliphatic. In some embodiments, Rais optionally substituted Ci-6 alkyl. In some embodiments, Rais C1-6 alkyl. In some embodiments, Rais ethyl.Page 122 of 373BUSINESS.33352696. 1

[0391] In some embodiments of any Formulae described herein, Rbis -ORaaIn some embodiments, Rbis -OH. In some embodiments, Rbis -OC(O)Rbb. In some embodiments, Rbis the point of attachment to the rest of the molecule.

[0392] In some embodiments of any Formulae described herein, each Rcis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rcis hydrogen. In some embodiments, each Rcis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rcis independently Ci-6 aliphatic. In some embodiments, each Rcis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rcis independently Ci-6 alkyl. In some embodiments, a Rcis hydrogen. In some embodiments, a Rcis optionally substituted Ci-6 aliphatic. In some embodiments, a Rcis Ci-6 aliphatic. In some embodiments, a Rcis optionally substituted Ci-6 alkyl. In some embodiments, a Rcis Ci-6 alkyl.

[0393] In some embodiments of any Formulae described herein, Rdis hydrogen, halogen, or optionally substituted Ci-6 alkyl. In some embodiments, Rdis hydrogen. In some embodiments, Rdis halogen. In some embodiments, Rdis optionally substituted Ci-6 aliphatic. In some embodiments, Rdis Ci-6 aliphatic. In some embodiments, Rdis optionally substituted Ci-6 alkyl. In some embodiments, Rdis Ci-6 alkyl.

[0394] In some embodiments of any Formulae described herein, each Reis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Reis hydrogen. In some embodiments, each Reis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Reis independently Ci-6 aliphatic. In some embodiments, each Reis independently optionally substituted Ci-6 alkyl. In some embodiments, each Reis independently Ci-6 alkyl. In some embodiments, a Reis hydrogen. In some embodiments, a Reis optionally substituted Ci-6 aliphatic. In some embodiments, a Reis Ci-6 aliphatic. In some embodiments, a Reis optionally substituted Ci-6 alkyl. In some embodiments, a Reis Ci-6 alkyl. In some embodiments, a Reis the point of attachment to the rest of the molecule.

[0395] In some embodiments of any Formulae described herein, Rfis halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SRaa, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, Rris hydrogen, halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, - ORaa, -SRaa, -Si(Rbb)3, optionally substituted Ci-6 alkyl, or optionally substituted C3.7 cycloalkyl. In some embodiments, R1is hydrogen, -CORbb, -C(NORbb)Rbb, -OR”, -Si(Rbb)3, optionallyPage 123 of 373BUSINESS.33352696. 1substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, Rfis hydrogen. In some embodiments, Rfis halogen. In some embodiments, Rfis -CN. In some embodiments, R1is -CORbb(e.g., -CO(Ci-6 alkyl) or -CO(optionally substituted phenyl)). In some embodiments, R1is -CC>2Rbb. In some embodiments, Rfis -C(0)N(Rbb)2. In some embodiments, Rfis -C(NORbb)Rbb(e.g., -C(NO(optionally substituted C1-6 alkyl))H). In some embodiments, Rfis -NO2. In some embodiments, R1is -N(Raa)2. In some embodiments, Rfis -ORaa(e.g., -OH). In some embodiments, R1is -SRaa. In some embodiments, Rfis -Si(Rbb)3 (e.g., -Si(Ci-6 alkyl^). In some embodiments, Rfis optionally substituted Ci-6 aliphatic. In some embodiments, Rfis optionally substituted Ci-6 alkyl. In some embodiments, Rfis Ci-6 aliphatic optionally substituted with one or more halogen, -OR°, -N(R°)2, -N(R°)C(O)R°, or -N(R°)C(0)NR°2. In some embodiments, Rfis Ci-6 aliphatic optionally substituted with one or more halogen, -OR°, -N(R°)2, -N(R°)C(O)R°, - N(R°)C(O)OR°, or -N(R°)C(0)NR°2. In some embodiments, Rfis Ci-6 alkyl optionally substituted with one or more halogen, -OR°, -N(R°)2, -N(R°)C(O)R°, or -N(R°)C(0)NR°2. In some embodiments, R1is Ci-6 alkyl optionally substituted with one or more halogen, -OR°, -N R°)2, - N(R°)C(O)R°, -N(R°)C(O)OR°, or -N(R°)C(0)NR°2. In some such embodiments, each R° is independently hydrogen, Ci-6 aliphatic optionally substituted with -OH or -NH2, or a 3-7- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 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 herein. In some embodiments, Rfis Ci-6 aliphatic optionally substituted with an optionally substituted 3- to 7-membered monocyclic 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, Rris C i—6 aliphatic. In some embodiments, R is Ci— alkyl. In some embodiments, R is optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted monocyclic C3-7 cycloaliphatic or optionally substuted C4-7 bicyclic cycloaliphatic). In some embodiments, Rfis optionally substituted C3-7 cycloalkyl (e.g., optionally substituted with -N(R°)2, wherein each R° is independently hydrogen or Ci-6 aliphatic). In some embodiments, Rris C3-7 cycloaliphatic. In some embodiments, Rfis C3-7 cycloalkyl. In some embodiments, Rfis selected from: hydrogen, -Page 124 of 373BUSINESS.33352696. 1some embodiments, RfisIn some embodiments, Rfis the point of attachment to the rest of the molecule.

[0396] In some embodiments of any Formulae described herein, Rgis halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SRaa, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, Rgis hydrogen, halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, - ORaa, -SRaa, -Si(Rbb)3, optionally substituted C1-6 alkyl, or optionally substituted C3.7 cycloalkyl. In some embodiments, Rgis hydrogen, halogen, -CN, -CORbb, -C(NORbb)Rbb, -NO2, or optionally substituted C1-6 aliphatic. In some embodiments, Rgis hydrogen. In some embodiments, Rgis halogen. In some embodiments, Rgis -CN. In some embodiments, Rgis -CORbb(e.g., -COH). In some embodiments, Rgis -CO2Rbb. In some embodiments, Rgis -C(O)N(Rbb)2. In some embodiments, Rsis -C(NORbb)Rbb(e.g., -C(NO(optionally substituted C1-6 alkyl))H). In some embodiments, Rgis -NO2. In some embodiments, Rgis -N(Raa)2. In some embodiments, Rgis - ORaa. In some embodiments, Rgis -SRaa. In some embodiments, Rgis -Si(Rbb)3. In some embodiments, R8is optionally substituted Ci-6 aliphatic. In some embodiments, R8is optionally substituted C1-6 alkenyl. In some embodiments, Rgis optionally substituted C1-6 alkyl (e.g., C1-6 alkyl substituted with -OH, such as -CH2OH). In some embodiments, Rgis C1-6 aliphatic. In some embodiments, Rgis C1-6 alkenyl (e.g., -CH2CH=CH2). In some embodiments, Rgis C1-6 alkyl. In some embodiments, Rgis optionally substituted C3-7 cycloaliphatic. In some embodiments, Rgis optionally substituted C3-7 cycloalkyl. In some embodiments, Rgis C3-7 cycloaliphatic. In some embodiments, Rgis C3.7 cycloalkyl. In some embodiments, Rgis selected from hydrogen, -CH2OH, and -CH2CH=CH2.Page 125 of 373BUSINESS.33352696. 1

[0397] In some embodiments of any Formulae described herein, R4and Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rfand Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5- 7 carbocyclic ring. In some embodiments, Rfand R8, together with the atoms to which they are attached, combine to form an optionally substituted C5 carbocyclic ring. In some embodiments, R4and Rs, together with the atoms to which they are attached, combine to form an optionally substituted G, carbocyclic ring. In some embodiments, R4and Rg, together with the atoms to which they are attached, combine to form a G carbocyclic ring substituted with N(R°)2. In some embodiments, Rfand Rg, together with the atoms to which they are attached, combine to form a G, carbocyclic ring substituted with NH2. In some embodiments, R4and Rg, together with the atoms to which they are attached, combine to form an optionally substituted C7 carbocyclic ring. In some embodiments, Rfand Rg, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rfand R8, together with the atoms to which they are attached, combine to form an optionally substituted 5- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4and R8, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rfand R8, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered heterocyclic ring having 1 heteroatom that is oxygen. In some embodiments, Rfand R8, together with the atoms to which they are attached, combine to form a 6- membered heterocyclic ring having 1 heteroatom that is oxygen. In some embodiments, R4and R8, together with the atoms to which they are attached, combine to form an optionally substituted 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the ring formed by taking R4and Rgtogether is optionally substituted with one or more halogen, -OR°, -N(R°)2, or -N(R°)C(O)R°. In some such embodiments, each R° is independently hydrogen, Ci 6 aliphatic optionally substituted with -OH or -NH2, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatomsPage 126 of 373BUSINESS.33352696. 1independently selected from nitrogen, oxygen, or sulfur. In some such embodiments, each R° is independently hydrogen, Ci-6 aliphatic optionally substituted with -OH, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the ring formed by taking Rfand Rgtogether is optionally substituted with -NH2, -N(H)C(O)CH3, -N(H)C(O)(CH2)3NH2, or -N(H)C(O)CH2OH. In some embodiments, the ring formed by taking Rfand Rgtogether is optionally substituted with -NH2, -N(H)C(O)CH3, or -N(H)C(O)CH2OH. In some embodiments, the ring formed by taking and Rgtogether is the point of attachment to the rest of the molecule.

[0398] In some embodiments of any Formulae described herein, Rhis halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -OR33, -SRaa, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R11is hydrogen, halogen, -CN, -CO2Rbb, - C(O)N(Rbb)2, -NO2, -N^R33)^ -ORaa, -SRaa, optionally substituted C1-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, Rbis hydrogen, halogen, -N(Raa)2, -ORaa, or optionally substituted C1-6 aliphatic. In some embodiments, Rhis hydrogen. In some embodiments, Rhis halogen. In some embodiments, Rhis -CN. In some embodiments, Rbis -CO2Rbb. In some embodiments, Rhis -C(O)N(Rbb)2. In some embodiments, Rhis -NO2. In some embodiments, Rhis -N(Raa)2(e g., -NH2). In some embodiments, Rhis -OR33(e g., -OH). In some embodiments, Rhis -SR33. In some embodiments, Rbis optionally substituted C1-6 aliphatic. In some embodiments, Rhis optionally substituted C1-6 alkyl. In some embodiments, Rhis C1-6 aliphatic. In some embodiments, Rhis C1-6 alkyl (e.g., methyl). In some embodiments, Rbis optionally substituted C3-7 cycloaliphatic. In some embodiments, Rhis optionally substituted C3-7 cycloalkyl. In some embodiments, Rhis C3-7 cycloaliphatic. In some embodiments, Rhis C3-7 cycloalkyl. In some embodiments, Rhis selected from -OH, -NH2, and -CH3. In some embodiments, Rhis the point of attachment to the rest of the molecule.

[0399] In some embodiments of any Formulae described herein, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5- 7 carbocyclic ring. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5 carbocyclic ring. In some embodiments, RgPage 127 of 373BUSINESS.33352696. 1and Rh, together with the atoms to which they are attached, combine to form an optionally substituted Ce carbocyclic ring. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C7 carbocyclic ring. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rgand Rb, together with the atoms to which they are attached, combine to form an optionally substituted 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted 6- membered heterocyclic ring having 2 heteroatoms that are nitrogen and oxygen. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered heterocyclic ring having 1 heteroatom that is nitrogen. In some embodiments, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0400] In some embodiments of any Formulae described herein, R1is halogen, -CN, -CC>2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, R1is hydrogen, halogen, -CN, -CO2Rbb, - C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, R1is hydrogen or halogen. In some embodiments, R1is hydrogen. In some embodiments, R1is halogen (e.g., fluoro). In some embodiments, R1is -CN. In some embodiments, R1is -CO2Rbb. In some embodiments, R1is - C(O)N(Rbb)2. In some embodiments, R1is -NO2. In some embodiments, R1is -N(Raa)2. In some embodiments, R1is -ORaa. In some embodiments, R1is -SRaa. In some embodiments, R1is optionally substituted C1-6 aliphatic. In some embodiments, R1is optionally substituted C1-6 alkyl. In some embodiments, R1is C1-6 aliphatic. In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is optionally substituted C3-7 cycloaliphatic. In some embodiments, R1is optionally substituted C3-7 cycloalkyl. In some embodiments, R1is C3-7 cycloaliphatic. In somePage 128 of 373BUSINESS.33352696. 1embodiments, R1is C3-7 cycloalkyl. In some embodiments, R1is selected from hydrogen and fluoro. In some embodiments, R1is fluoro.

[0401] In some embodiments of any Formulae described herein, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5- 7 carbocyclic ring. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5 carbocyclic ring. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted G, carbocyclic ring. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C7 carbocyclic ring. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., Rhand R1combine to form a -OCH2O-). In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted 5-membered heterocyclic ring having 2 heteroatoms that are oxygen. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form a 5-membered heterocyclic ring having 2 heteroatoms that are oxygen. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0402] In some embodiments of any Formulae described herein, Rjis halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -OR35, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, Rjis hydrogen, halogen, -CN, -CC>2Rbb, - C(O)N(Rbb)2, -NO2, -N^R^ -ORaa, -SRaa, optionally substituted C1-6 alkyl, or optionallyPage 129 of 373BUSINESS.33352696. 1substituted C3-7 cycloalkyl. In some embodiments, R1is hydrogen or halogen. In some embodiments, R1is hydrogen. In some embodiments, R' is halogen. In some embodiments, R1is - CN. In some embodiments, R' is -CO2Rbb. In some embodiments, R' is -C(0)N(Rbb)2. In some embodiments, R1is -NO2. In some embodiments, R> is -N(Raa)2. In some embodiments, R1is -ORaa. In some embodiments, R' is -SR33. In some embodiments, R1is optionally substituted C1-6 aliphatic. In some embodiments, Rjis optionally substituted C1-6 alkyl. In some embodiments, Rjis Ci- 6 aliphatic. In some embodiments, R> is C1-6 alkyl. In some embodiments, R> is optionally substituted C3-7 cycloaliphatic. In some embodiments, R* is optionally substituted C3-7 cycloalkyl. In some embodiments, Rjis C3-7 cycloaliphatic. In some embodiments, R' is C3-7 cycloalkyl.

[0403] In some embodiments of any Formulae described herein, each Raais independently Rbbor -C(O)Rbb. In some embodiments, each Raais -C(O)Rbbor -C(O)N(Rbb)2. In some embodiments, each Raais Rbb. In some embodiments, a Raais Rbb. In some embodiments, a Raais -C(O)Rbb. In some embodiments, a Raais -C(O)N(Rbb)2.

[0404] In some embodiments of any Formulae described herein, each Rbbis independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a C3-7 monocyclic carbocyclyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Rbbis hydrogen. In some embodiments, each Rbbis hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each Rbbis hydrogen or optionally substituted Ci. 6 alkyl. In some embodiments, two Rbbwhen attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rbbis hydrogen. In some embodiments, a Rbbis optionally substituted C1-6 aliphatic. In some embodiments, a Rbbis optionally substituted C1-6 alkyl. In some embodiments, a Rbbis Ci-6 aliphatic. In some embodiments, a Rbbis C1-6 alkyl. In some embodiments, a Rbbis optionally substituted phenyl. In some embodiments, a Rbbis optionally substituted C3-7 monocyclic carbocyclyl. In some embodiments, a Rbbis optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rbbis optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Page 130 of 373BUSINESS.33352696. 1

[0405] In some embodiments, the present disclosure provides a compound of Formula XI: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; each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic;Rmis hydrogen or optionally substituted Ci-6 aliphatic; each Rnand Rpis independently hydrogen or optionally substituted Ci-6 aliphatic; each Rqis independently halogen, -ORce, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rccis independently hydrogen or optionally substituted Ci-6 aliphatic; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4.

[0406] In some embodiments, the present disclosure provides a compound of Formula Xl-a:XLa or a pharmaceutically acceptable salt thereof, wherein L1, Rk, Rm, R11, Rp, Rq, Rx, Ry, Rz, s, X, and KBM are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination; and wherein t is 0, 1, 2, or 3.

[0407] In some embodiments of any Formulae described herein, TPM is:Page 131 of 373BUSINESS.33352696. 1wherein Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0408] In some embodiments of any Formulae described herein, TPM is:wherein Rk, Rm, R11, Rp, Rq, s, and t are as defined in Formula Xl-a and described in classes and subclasses herein, both singly and in combination.

[0409] In some embodiments of any Formulae described herein, each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rkis independently halogen or -N(RCC)2. In some embodiments, a Rkis halogen (e.g., fluoro). In some embodiments, a Rkis -ORCC. In some embodiments, a Rkis -N(RCC)2 (e.g., -NH2). In some embodiments, a Rkis optionally substituted C1-6 aliphatic. In some embodiments, a Rkis optionally substituted C1-6 alkyl. In some embodiments, a Rkis C1-6 aliphatic. In some embodiments, a Rkis Ci-6 alkyl.

[0410] In some embodiments of any Formulae described herein, Rmis hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Rmis hydrogen. In some embodiments, Rmis optionally substituted Ci-6 aliphatic. In some embodiments, Rmis optionally substituted Ci-6 alkyl. In some embodiments, Rmis C1-6 aliphatic. In some embodiments, Rmis C1-6 alkyl (e.g., methyl).

[0411] In some embodiments of any Formulae described herein, each Rnis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Ruis hydrogen. In some embodiments, each Rnis independently optionally substituted C1-6 aliphatic. In some embodiments, each R11is independently optionally substituted Ci-6 alkyl. In some embodiments, each Rnis independently Ci-6 aliphatic. In some embodiments, each Rnis independently Ci-6 alkyl. In some embodiments, a Rnis hydrogen. In some embodiments, a Rnis optionally substituted Ci-6Page 132 of 373BUSINESS.33352696. 1aliphatic. In some embodiments, aR“ is optionally substituted Ci-6 alkyl. In some embodiments, a Rnis Ci-6 aliphatic. In some embodiments, a Rnis Ci-6 alkyl.

[0412] In some embodiments of any Formulae described herein, each Rpis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rpis hydrogen. In some embodiments, each Rpis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rpis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rpis independently Ci-6 aliphatic. In some embodiments, each Rpis independently Ci-6 alkyl. In some embodiments, a Rpis hydrogen. In some embodiments, a Rpis optionally substituted Ci-6 aliphatic. In some embodiments, a Rpis optionally substituted Ci-6 alkyl. In some embodiments, a Rpis Ci-6 aliphatic. In some embodiments, a Rpis Ci-6 alkyl.

[0413] In some embodiments of any Formulae described herein, each Rqis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 alkyl. In some embodiments, a Rqis halogen. In some embodiments, a Rqis -ORec. In some embodiments, a Rqis -N(Rce)2. In some embodiments, aRqis optionally substituted Ci-6 aliphatic. In some embodiments, aRqis optionally substituted Ci-6 alkyl. In some embodiments, a Rqis Ci-6 aliphatic. In some embodiments, a Rqis Ci-6 alkyl. In some embodiments, a Rqis the point of attachment to the rest of the molecule.

[0414] In some embodiments of any Formulae described herein, each Rccis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Recis hydrogen. In some embodiments, each Rccis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rccis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rccis independently Ci-6 aliphatic. In some embodiments, each Recis independently Ci-6 alkyl. In some embodiments, a Rccis hydrogen. In some embodiments, a Rccis optionally substituted Ci- 6 aliphatic. In some embodiments, a R“ is optionally substituted Ci-6 alkyl. In some embodiments, a Recis Ci-6 aliphatic. In some embodiments, a Recis Ci-6 alkyl.

[0415] In some embodiments of any Formulae described herein, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 2 or 3. In some embodiments, s is 3 or 4. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0416] In some embodiments of any Formulae described herein, t is 0, 1, or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 1 or 2. In some embodiments, t is 2 or 3. InPage 133 of 373BUSINESS.33352696. 1some embodiments, t is 3 or 4. In some embodiments, t is 0. In some embodiments, t is 1 . In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0417] In some embodiments, the present disclosure provides a compound of Formula XII:XII 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 Rris independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic;Rsis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rlis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic, or two Rlcombine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ruis hydrogen or optionally substituted Ci-6 aliphatic; each Rddis independently hydrogen or optionally substituted Ci-6 aliphatic; u is 0, 1, 2, 3, or 4; and v is 0, 1, 2, 3, or 4.

[0418] In some embodiments of any Formulae disclosed herein, TPM is:wherein Rr, Rs, R‘, Ru, u, and v are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.Page 134 of 373BUSINESS.33352696. 1

[0419] In some embodiments of any Formulae disclosed herein, each R1is independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rris independently -ORdd(e.g., -OCH3). In some embodiments, a Rris halogen. In some embodiments, a Rris -ORdd(e.g., -OCH3). In some embodiments, a Rris -N(Rdd)2. In some embodiments, a Rris optionally substituted C1-6 aliphatic. In some embodiments, aRris optionally substituted C1-6 alkyl. In some embodiments, a Rris Ci-6 aliphatic. In some embodiments, a Rris C1-6 alkyl.

[0420] In some embodiments of any Formulae disclosed herein, Rsis hydrogen, halogen, - ORdd, -N(Rdd)2, or optionally substituted Ci-6 alkyl. In some embodiments, Rsis halogen, -ORdd, - N(Rdd)2, or optionally substituted C1-6 aliphatic. In some embodiments, Rsis hydrogen. In some embodiments, Rsis halogen. In some embodiments, Rsis -ORdd. In some embodiments, Rsis - N(Rdd)2. In some embodiments, Rsis optionally substituted C1-6 aliphatic. In some embodiments, Rsis optionally substituted Ci-6 alkyl. In some embodiments, Rsis C1-6 aliphatic. In some embodiments, Rsis Ci-6 alkyl.

[0421] In some embodiments of any Formulae disclosed herein, each Rlis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rlis independently -ORdd. In some embodiments, a Rlis halogen. In some embodiments, a Rlis -ORdd. In some embodiments, a Rlis -N(Rdd)2. In some embodiments, a R1is optionally substituted Ci-6 aliphatic. In some embodiments, a Rlis optionally substituted Ci-6 alkyl. In some embodiments, a Rlis Ci-6 aliphatic. In some embodiments, a Rlis Ci-6 alkyl. In some embodiments, two R‘ combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., two Rlcombine to form a -OCH2O-).

[0422] In some embodiments of any Formulae described herein, Ruis hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Ruis hydrogen. In some embodiments, Ruis optionally substituted Ci-6 aliphatic. In some embodiments, Ruis optionally substituted Ci-6 alkyl (e.g., Ci-6 alkyl optionally substituted with -NH2, -NH(CI-6 alkyl), or -N(CI-6 alkyl^). In some embodiments, Ruis Ci-6 aliphatic. In some embodiments, Ruis Ci-6 alkyl.

[0423] In some embodiments of any Formulae described herein, each Rddis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rddis hydrogen. In some embodiments, each Rddis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rddis independently optionally substituted Ci-6 alkyl. In some embodiments,Page 135 of 373BUSINESS.33352696. 1each Rddis independently Ci-6 aliphatic. In some embodiments, each Rddis independently Ci-6 alkyl. In some embodiments, a Rddis hydrogen. In some embodiments, a Rddis optionally substituted Ci-6 aliphatic. In some embodiments, a Rddis optionally substituted Ci-6 alkyl. In some embodiments, a Rddis Ci-6 aliphatic. In some embodiments, a Rddis Ci-6 alkyl.

[0424] In some embodiments of any Formulae described herein, u is 0, 1, or 2. In some embodiments, u is 0 or 1. In some embodiments, u is 1 or 2. In some embodiments, u is 2 or 3. In some embodiments, u is 3 or 4. 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.

[0425] In some embodiments of any Formulae described herein, 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 3 or 4. 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.

[0426] In some embodiments, TPM is a topoisomerase 1 inhibitor payload moiety (e.g., a moiety that binds and / or inhibits topoisomerase 1 or a topoisomerase 1-DNA complex). The present invention encompasses the recognition that a topoisomerase 1 inhibitor payload moiety in the CIDCs described herein can be made by installing a linking moiety bound to a KRASG1Cbinding moiety, as defined hereinany suitable position on a topoisomerase 1 inhibitor compound. In some embodiments, TPM is a topoisomerase 1 inhibitor (e.g., a radical of such inhibitor compound) described in Li, F., et al. Am. J. Cancer Res. 2017;7(12):2350-94; Talukdar A., et al. Eur. J. Med. Chem. 2022;236: 114304; Yoshinari et al. Cancer Res. 1999 Sep l;59(17):4271-5; Thomas et al. Clin Cancer Res. 2019 Nov 15;25(22):6581- 6589; and Nakano et al. J Antibiot 62, 17-26 (2009).

[0427] In some embodiments, TPM is a means for binding topoisomerase 1 or a topoisomerase 1-DNA complex. In some embodiments, TPM is a means for inhibiting topoisomerase 1.Exemplary Compounds of the Disclosure

[0428] In some embodiments, the present disclosure provides a compound of Formula XIII:Page 136 of 373BUSINESS.33352696. 1XIII 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, Re, Rf, Rs, Rh, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0429] In some embodiments, the present disclosure provides a compound of Formula Xlll-a:Xlll-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, Rc, Rd, Re, Rf, Rs, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0430] In some embodiments, the present disclosure provides a compound of Formula XIILb:Page 137 of 373BUSINESS.33352696. 1XIILb 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 Ra, Rb, Rc, Rd, Re, R1, Rg, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0431] In some embodiments, the present disclosure provides a compound of Formula XIII-c:XIII-c 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, Re, Rh, R1, R1, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0432] In some embodiments, the present disclosure provides a compound of Formula XIILd:Page 138 of 373BUSINESS.33352696. 1xni-d 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, Re, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0433] In some embodiments, the present disclosure provides a compound of Formula Xlll-e: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, R3, R4, R5, Y, 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, Re, Rf, Rs, Rh, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.Page 139 of 373BUSINESS.33352696. 1

[0434] In some embodiments, the present disclosure provides a compound of Formula XIII’ :xnr 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, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, R1, Rg, Rh, R1, RJ, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0435] In some embodiments, the present disclosure provides a compound of Formula XIIF-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, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rc, Rd, Re, Rf, Rg, Rh, R1, R1, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.Page 140 of 373BUSINESS.33352696. 1

[0436] In some embodiments, the present disclosure provides a compound of Formula XIII’- b:xiir-b 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; L2, L3, R1, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rf, Rs, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0437] In some embodiments, the present disclosure provides a compound of Formula XIIF- c:XIIF-c 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; L2, L3, R1, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.Page 141 of 373BUSINESS.33352696. 1

[0438] In some embodiments, the present disclosure provides a compound of Formula XIII’- d:xiir-d

[0439] 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, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0440] In some embodiments, the present disclosure provides a compound of Formula XIII’- e:XIII’ -e 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, R3, R3, R4, R5, Y, and Ring A are as defined herein for Formula II’ and described in classes Page 142 of 373BUSINESS.33352696. 1and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0441] In some embodiments, the present disclosure provides a compound of Formula XIV:XIV 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, Rbb, Rc, Rd, Re, R1, Rg, Rh, R1, R>, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0442] 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; 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, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, R W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0443] In some embodiments, the present disclosure provides a compound of Formula XIV’ : Page 143 of 373BUSINESS.33352696. 1XIV’ 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, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, Rj, W, and Z2are 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 XIV’- a:XIV’ -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, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rbb, Rc, Rd, Re, Rf, R8, Rb, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0445] In some embodiments, the present disclosure provides a compound of Formula XVPage 144 of 373BUSINESS.33352696. 1XV 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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0446] 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, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rk, Rm, Rn, Rp, Rq, s, and t 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 XV’:XV’Page 145 of 373BUSINESS.33352696. 1or 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, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Rk, Rin, Rn, Rp, Rq, s, and t 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 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, 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; and Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0449] 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, R3, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rr, Rs, R’, Ru, u, and v are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.Page 146 of 373BUSINESS.33352696. 1

[0450] In some embodiments, the present disclosure provides a compound of Formula XVI’ :XVI’ 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; L2, L3, R1, R3, R3, R4, R5, and Ring A are as defined herein for Formula IF and described in classes and subclasses herein, both singly and in combination; and Rr, Rs, Rl, Ru, u, and v 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 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; 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, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, Ri, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0452] In some embodiments, the present disclosure provides a compound of Formula XVII-Page 147 of 373BUSINESS.33352696. 1XVII-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 Ra, Rc, Rd, Re, Rf, Rg, Rh, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0453] In some embodiments, the present disclosure provides a compound of Formula XVII- b:XVII-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 Ra, Rb, Rc, Rd, Re, Rf, Rg, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0454] In some embodiments, the present disclosure provides a compound of Formula XVII- c:Page 148 of 373BUSINESS.33352696. 1XVII-c 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 Ra, Rb, Re, Rd, Rc, Rh, R1, R1, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0455] In some embodiments, the present disclosure provides a compound of Formula XVII- d:XVII-d 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 Ra, Rb, Rc, Rd, Re, Rg, Rh, R1, R', W, Z1, andPage 149 of 373BUSINESS.33352696. 1Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0456] In some embodiments, the present disclosure provides a compound of Formula XVII- e:XVII-e 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 Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh, R1, R>, W, Z1, and Z2are 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 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; 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, Rb, Rbb, Rc, Rd, Rc, Rf, Rs, Rh, R1, RPage 150 of 373BUSINESS.33352696. 1W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0458] 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; 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, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, R>, W, and Z2are 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 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; 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 Rk, Rm, R11, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0460] In some embodiments, the present disclosure provides a compound of Formula XlX-a:Page 151 of 373BUSINESS.33352696. 1XlX-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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0461] 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; 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 Rr, Rs, R\ Ru, u, and v are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0462] In some embodiments, the present disclosure provides a compound of Formula XXI:XXIPage 152 of 373BUSINESS.33352696. 1or 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, Re, Rf, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0463] In some embodiments, the present disclosure provides a compound of Formula 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; 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, Rc, Rd, Re, R1, Rg, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0464] In some embodiments, the present disclosure provides a compound of Formula XXI-b:XXI-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 Ra, Rb, Rc, Rd, Re, Rf, Rg, R1,Page 153 of 373BUSINESS.33352696. 1Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0465] In some embodiments, the present disclosure provides a compound of Formula XXI-c: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 Ra, Rb, Re, Rd, Re, Rh, R1, R*, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0466] In some embodiments, the present disclosure provides a compound of Formula XXI-d: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,Page 154 of 373BUSINESS.33352696. 1R14, 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 Ra, Rb, Rc, Rd, Re, Rg, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0467] In some embodiments, the present disclosure provides a compound of Formula XXI-e:XXI-e 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 Ra, Rb, Rc, Rd, Re, Rf, Rg, Rb, R1, RJ, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0468] 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; 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 Ra, Rb, Rbb, Rc, Rd, Rc, Rf, Rs,Page 155 of 373BUSINESS.33352696. 1Rh, R1, Ri, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0469] 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; 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 Ra, Rb, Rbb, Rc, Rd, Re, R1, Rg, Rh, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0470] 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; 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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.Page 156 of 373BUSINESS.33352696. 1

[0471] In some embodiments, the present disclosure provides a compound of Formula XXIII- a:XXIILa 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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0472] 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 combinationR13, 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 Rr, Rs, Rl, Ru, u, and v are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0473] In some embodiments, the present disclosure provides a compound of Formula XXV:Page 157 of 373BUSINESS.33352696. 1XXV 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; L6, R21, Cy4, Cy5, 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, Re, Rf, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0474] 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; L6, R21, Cy4, Cy5, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ra, Rc, Rd, Re, Rf, Rg, Rh, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0475] In some embodiments, the present disclosure provides a compound of Formula XXV- b:Page 158 of 373BUSINESS.33352696. 1XXV-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; L6, R21, Cy4, Cy3, 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, Re, Rf, R8, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0476] In some embodiments, the present disclosure provides a compound of Formula XXV- c:XXV-c 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; L6, R21, Cy4, Cy5, 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, Re, Rh, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0477] In some embodiments, the present disclosure provides a compound of Formula XXV- d:Page 159 of 373BUSINESS.33352696. 1XXV-d 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; L6, R21, Cy4, Cy5, 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, Re, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0478] In some embodiments, the present disclosure provides a compound of Formula XXV- e:XXV-e 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; L6, R21, Cy4, Cy5, 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, Re, Rf, Rs, Rh, R1, R>, W, Z1,Page 160 of 373BUSINESS.33352696. 1and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0479] In some embodiments, the present disclosure provides a compound of Formula XXVI:XXVI 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; L6, R21, Cy4, Cy5, 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, Rbb, Re, Rd, Re, Rf, Rg, Rb, R1, R W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0480] In some embodiments, the present disclosure provides a compound of Formula XXVI- a:XXVl-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; L6, R21, Cy4, Cy5, 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, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0481] In some embodiments, the present disclosure provides a compound of Formula XXVII:Page 161 of 373BUSINESS.33352696. 1XXVII 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; L6, R21, Cy4, Cy5, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0482] 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; L6, R21, Cy4, Cy5, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0483] In some embodiments, the present disclosure provides a compound of FormulaXXVIII:XXVIIIPage 162 of 373BUSINESS.33352696. 1or 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 L6, R21, Cy4, Cy5, and Ring D are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Rr, Rs, R1, Ru, u, and v are as defined in Formula XII and described in classes and subclasses herein, both singly and in combination.

[0484] 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; L7, R23, R24, Cy6, Cy7, 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, Re, Rf, Rg, Rh, R1, R>, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0485] 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; L7, R23, R24, Cy6, Cy7, Ring E, and Ring F are as defined herein for Formula VI and described inPage 163 of 373BUSINESS.33352696. 1classes and subclasses herein, both singly and in combination; and Ra, Rc, Rd, Re, R1, Rg, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0486] In some embodiments, the present disclosure provides a compound of Formula XXIX- b:XXIX-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; L7, R23, R24, Cy6, Cy7, 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, Re, Rf, Rg, R1, Rj, W, Z1, and Z2are 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 XXIX- c:XXIX-c 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; L7, R23, R24, Cy6, Cy7, Ring E, and Ring F are as defined herein for Formula VI and described inPage 164 of 373BUSINESS.33352696. 1classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0488] In some embodiments, the present disclosure provides a compound of Formula XXIX- d:XXIX-d 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; L7, R23, R24, Cy6, Cy7, 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, Re, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0489] In some embodiments, the present disclosure provides a compound of Formula XXIX- e:XXIX-ePage 165 of 373BUSINESS.33352696. 1or 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; L7, R23, R24, Cy6, Cy7, 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, Re, Rf, Rg, Rh, R1, R', W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0490] 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; L7, R23, R24, Cy6, Cy7, 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, Rbb, Rc, Rd, Re, Rf, R8, Rh, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0491] In some embodiments, the present disclosure provides a compound of Formula XXX- a: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; L7, R23, R24, Cy6, Cy7, Ring E, and Ring F are as defined herein for Formula VI and described in Page 166 of 373BUSINESS.33352696. 1classes and subclasses herein, both singly and in combination; and Ra, Rb, Rbb, Rc, Rd, Re, R1, Rg, Rh, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0492] 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; L7, R23, R24, Cy6, Cy7, 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 Rk, Rm, Rn, Rp, Rq, s, and t 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 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; L7, R23, R24, Cy6, Cy7, 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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0494] In some embodiments, the present disclosure provides a compound of Formula XXXII:Page 167 of 373BUSINESS.33352696. 1XXXII 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 L7, R23, R24, Cy6, Cy7, 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 Rr, Rs, Rl, Ru, u, and v 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 FormulaXXXIII: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; 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; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, Rl W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0496] In some embodiments, the present disclosure provides a compound of Formula XXXIII-a:Page 168 of 373BUSINESS.33352696. 1409894-004WG (220164)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; 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; and Ra, Rc, Rd, Re, Rf, Rg, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0497] In some embodiments, the present disclosure provides a compound of Formula XXXIII-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; 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; and Ra, Rb, Rc, Rd, Re, Rf, Rg, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0498] In some embodiments, the present disclosure provides a compound of Formula XXXIII-c:Page 169 of 373BUSINESS.33352696. 1XXXIII-c 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; 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; and Ra, Rb, Rc, Rd, Rc, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0499] In some embodiments, the present disclosure provides a compound of Formula XXXIII-d:XXXIII-d 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; 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; and Ra, Rb, Re, Rd, Re, Rg, Rh, R1,Page 170 of 373BUSINESS.33352696. 1R , W, Z1, and Z2are as defined in Formula TX and described in classes and subclasses herein, both singly and in combination.

[0500] In some embodiments, the present disclosure provides a compound of Formula XXXIII-e:XXXIII-e 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; 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; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, Rj, W, Z1, and Z2are as defined in Formula IX and described in classes and subclasses herein, both singly and in combination.

[0501] In some embodiments, the present disclosure provides a compound of FormulaXXXIV:XXXIV 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; Y, L8, R26, R28, R29, R30, Ring H, and Ring G are as defined herein for Formula VII and described inPage 171 of 373BUSINESS.33352696. 1classes and subclasses herein, both singly and in combination; and Ra, Rb, Rbb, Rc, Rd, Re, R1, Rg, Rh, R1, R', W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0502] In some embodiments, the present disclosure provides a compound of Formula XXXIV-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; 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; and Ra, Rb, Rbb, Rc, Rd, Rc, Rf, Rs, Rh, R1, R>, W, and Z2are as defined in Formula X and described in classes and subclasses herein, both singly and in combination.

[0503] 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; 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; and Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.Page 172 of 373BUSINESS.33352696. 1409894-004WG (220164)

[0504] 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; 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; and Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula XI and described in classes and subclasses herein, both singly and in combination.

[0505] 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 a...

Claims

CLAIMSA 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 Ci-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 topoisomerase 1 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-,Page 342 of 373BUSINESS.33352696. 1-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:Page 343 of 373BUSINESS.33352696. 1wherein:Leis an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled A 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 Ci-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 Ci-6 aliphatic.

9. The compound of claim 8, wherein Rxis hydrogen.Page 344 of 373BUSINESS.33352696.

110. The compound of any one of claims 1 -8, wherein Ryis hydrogen or optionally substituted Ci-6 aliphatic.

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

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

13. The compound of any one of claims 1-11, wherein one Rzis hydrogen, and one Rzis optionally substituted Ci-6 aliphatic.

14. The compound of any one of claims 1-13, wherein the compound is a compound ofFormula II:or a pharmaceutically acceptable salt thereof, wherein: each R1is independently hydrogen, halogen, -OR’, optionally substituted Ci-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,Page 345 of 373BUSINESS.33352696. 1or two R4are taken together to form an oxo or an optionally substituted C3-7 cycloaliphatic ring;Y°\zX^Cy1R is 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.Page 346 of 373BUSINESS.33352696. 1.

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.

23. 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.Page 347 of 373BUSINESS.33352696.

125. 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 II:III or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen, halogen, -OR’, optionally substituted Ci-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’)-;Page 348 of 373BUSINESS.33352696. 1each R’ is independently hydrogen or optionally substituted Ci-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- to6-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.Page 349 of 373BUSINESS.33352696.

137. 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 Ci-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 Ci-6 aliphatic; each R18is independently hydrogen or optionally substituted Ci-6 aliphatic, or two R18groups are taken together to form an oxo; each R19is independently hydrogen or optionally substituted Ci-6 aliphatic; each R20is independently hydrogen or optionally substituted Ci-6 aliphatic; each R’ is independently hydrogen or optionally substituted Ci-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 Ci-6 aliphatic.Page 350 of 373BUSINESS.33352696.

140. The compound of any one of claims 37-39, wherein R15is an optionally substituted ring selected from phenyland 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 Ci-6 aliphatic, or optionally substituted C3.7 cycloaliphatic; each R’ is independently hydrogen or optionally substituted C1-6 aliphatic;Page 351 of 373BUSINESS.33352696. 1Cy4is 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 Ci-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.Page 352 of 373BUSINESS.33352696.

153. The compound of any one of claims 48-52, 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;Page 353 of 373BUSINESS.33352696. 1Ring 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.

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

56. The compound of claim 54 or 55, wherein R25is 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, 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, L7is a covalent bond.Page 354 of 373BUSINESS.33352696.

161. The compound of any one of claims 1-13, wherein the compound is a compound of Formula VII:VII or a pharmaceutically acceptable salt thereof, wherein:Y is CR27or N;R26is hydrogen, halogen, -OR’, optionally substituted Ci-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, orPage 355 of 373BUSINESS.33352696. 1409894-004WG (220164) 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 Ci-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 substitutedPage 356 of 373BUSINESS.33352696.

168. 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:or a pharmaceutically acceptable salt thereof, wherein:Y is CR27or N;R26is hydrogen, halogen, -OR’, optionally substituted Ci-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;Page 357 of 373BUSINESS.33352696. 1R30is 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 Ci-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 Ci-6 aliphatic; each R32is independently optionally substituted Ci-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.Page 358 of 373BUSINESS.33352696.

176. 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 1-13, wherein the compound is a compound of Formula II’:IT or a pharmaceutically acceptable salt thereof, wherein: each R1is independently hydrogen, halogen, -OR’, optionally substituted Ci-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;Page 359 of 373BUSINESS.33352696. 1, ,V0^5^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 Ci-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 Ci-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.

79. The compound of claim 78, wherein each R1is hydrogen.

80. The compound of claim 78 or 79, wherein R3is hydrogen.

81. The compound of any one of claims 78-80, wherein R3an optionally substituted phenyl.

82. The compound of any one of claims 78-81, wherein each R4is hydrogen.Page 360 of 373BUSINESS.33352696.

183. The compound of any one of claims 78-82, wherein R5-O(Ci-4 alkylene)Cy2.The compound of any one of claims 78-83, wherein R5is85. The compound of any one of claims 78-84, 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.

86. The compound of any one of claims 78-85, wherein Ring A is optionally substituted87. The compound of any one of claims 78-86, wherein L2is a covalent bond.

88. The compound of any one of claims 78-87, wherein L3is a covalent bond.

89. The compound of any one of claims 1-88, wherein the compound is a compound of Formula IX:Page 361 of 373BUSINESS.33352696. 1or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;W is O or S;Z1is a covalent bond or -O-;Z2is a covalent bond or -C(RC)2-;Rais hydrogen or optionally substituted Ci-6 aliphatic;Rbis -ORaa; each Reis independently hydrogen or optionally substituted Ci-6 aliphatic;Rdis hydrogen, halogen, or optionally substituted Ci-6 aliphatic; each Reis independently hydrogen or optionally substituted Ci-6 aliphatic;Rfis hydrogen, halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SR”, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;Rgis hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rfand Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rhis hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R’ is hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R' is hydrogen, halogen, -CN, -CO2Rbb, -C(O)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each Raais independently Rbb, -C(O)Rbb, or -C(O)N(Rbb)2; andPage 362 of 373BUSINESS.33352696. 1each Rbbis independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a C3-7 monocyclic carbocyclyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rbbwhen attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

90. The compound of claim 89, wherein Z1is O.

91. The compound of any one of claims 1-88, wherein the compound is a compound ofFormula X:or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;W is O or S;Z2is a covalent bond or -C(RC)2-;Rais hydrogen or optionally substituted C1-6 aliphatic;Rbis -ORaa; each Reis independently hydrogen or optionally substituted C1-6 aliphatic;Rdis hydrogen, halogen, or optionally substituted C1-6 aliphatic; each Reis independently hydrogen or optionally substituted C1-6 aliphatic;Rfis hydrogen, halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SRaa, -Si(Rbb)3, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;Page 363 of 373BUSINESS.33352696. 1Rgis hydrogen, halogen, -CN, -CChR1*, -C(0)N(Rbb)2, -NO2, -N(Raa)2, -0Raa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rfand Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rhis hydrogen, halogen, -CN, -C02Rbb, -C(0)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rsand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R’ is hydrogen, halogen, -CN, -C02Rbb, -C(0)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic, or Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R' is hydrogen, halogen, -CN, -CC>2Rbb, -C(0)N(Rbb)2, -NO2, -N(Raa)2, -ORaa, -SRaa, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; each Raais independently Rbb, -C(O)Rbb, or -C(0)N(Rbb)2; and each Rbbis independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a C3-7 monocyclic carbocyclyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rbbwhen attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

92. The compound of any one of claims 89-91, wherein Z2is a covalent bond.

93. The compound of any one of claims 89-91, wherein Z2is -C(RC)2-.Page 364 of 373BUSINESS.33352696.

194. The compound of any one of claims 89-93, wherein Rais Ci-6 alkyl.

95. The compound of any one of claims 89-94, wherein Rbis -OH.

96. The compound of any one of claims 89-95, wherein each Reis hydrogen.

97. The compound of any one of claims 89-96, wherein Rdis hydrogen.

98. The compound of any one of claims 89-97, wherein each Reis hydrogen.

99. The compound of any one of claims 89-98, wherein Rfis halogen, -CN, -CORbb, -CO2Rbb, -C(O)N(Rbb)2, -C(NORbb)Rbb, -NO2, -N(Raa)2, -ORaa, -SRaa, -Si(Rbb)3, optionally substituted Cu6aliphatic, or optionally substituted C3-7 cycloaliphatic.

100. The compound of any one of claims 89-98, wherein R1is hydrogen, -CORbb, - C(NORbb)Rbb, -ORaa, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic.

101. The compound of any one of claims 89-100, wherein Rgis hydrogen, halogen, -CN, - CORbb, -C(NORbb)Rbb, -NO2, or optionally substituted Ci-6 aliphatic.

102. The compound of any one of claims 89-98, wherein R1and Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

103. The compound of any one of claims 89-102, wherein Rhis hydrogen, halogen, -N(Raa)2, - ORaa, or optionally substituted Ci-6 aliphatic.

104. The compound of any one of claims 89-100, wherein Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or anPage 365 of 373BUSINESS.33352696. 1optionally substituted 5- to 7-membered heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

105. The compound of any one of claims 89-104, wherein R1is hydrogen or halogen.

106. The compound of any one of claims 89-102, wherein Rhand R1, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

107. The compound of any one of claims 89-106, wherein R' is hydrogen or halogen.

108. The compound of any one of claims 89-107, wherein each R33is Rbb.

109. The compound of any one of claims 89-108, wherein each Rbbis hydrogen or optionally substituted C1-6 aliphatic.

110. The compound of any one of claims 89-109, wherein W is O.

111. The compound of any one of claims 89 or 94-110, wherein the compound is a compound of Formula IX-b:IX-b or a pharmaceutically acceptable salt thereof.

112. The compound of any one of claims 89 or 94-110, wherein the compound is a compound of Formulae IX-d, IX-e, TX-f, or IX-g:Page 366 of 373BUSINESS.33352696. 1or a pharmaceutically acceptable salt thereof.

113. The compound of any one of claims 91-110, wherein the compound is a compound ofFormula X-a:or a pharmaceutically acceptable salt thereof.

114. The compound of any one of claims 91-110, wherein the compound is a compound ofFormula X-b:Page 367 of 373BUSINESS.33352696. 1or a pharmaceutically acceptable salt thereof.

115. The compound of any one of claims 1-89, wherein the compound is a compound of Formula XI:XI or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic;Rmis hydrogen or optionally substituted Ci-6 aliphatic; each Rnand Rpis independently hydrogen or optionally substituted Ci-6 aliphatic; each Rqis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rccis independently hydrogen or optionally substituted Ci-6 aliphatic; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4.

116. The compound of claim 115, wherein each Rkis independently halogen or -N(RCC)2.

117. The compound of claim 115 or 116, wherein Rmis optionally substituted Ci-6 aliphatic.

118. The compound of any one of claims 115-117, wherein each Rnis hydrogen.Page 368 of 373BUSINESS.33352696. 1119. The compound of any one of claims 115-118, wherein each Rpis hydrogen.

120. The compound of any one of claims 115-119, wherein s is 0, 1, or 2.

121. The compound of any one of claims 115-120, wherein t is 0, 1, or 2.

122. The compound of any one of claims 115-121, wherein the compound is a compound ofFormula Xl-a:XLa or a pharmaceutically acceptable salt thereof, wherein t is 0, 1, 2, or 3.

123. The compound of any one of claims 1-89, wherein the compound is a compound of Formula XII:XII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Rris independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic;Rsis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rlis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic,Page 369 of 373BUSINESS.33352696. 1or two R1combine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ruis hydrogen or optionally substituted C1-6 aliphatic; each Rddis independently hydrogen or optionally substituted Ci-6 aliphatic; u is 0, 1, 2, 3, or 4; and v is 0, 1, 2, 3, or 4.

124. The compound of claim 123, wherein each Rris independently -ORdd.

125. The compound of claim 123 or 124, wherein Rsis hydrogen.

126. The compound of any one of claims 123-125, wherein each Rlis independently -ORdd.

127. The compound of any one of claims 123-125, wherein two Rlcombine to form an optionally substituted C5-7 carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

128. The compound of any one of claims 123-127, wherein Ruis optionally substituted C1-6 aliphatic.

129. The compound of any one of claims 123-128, wherein u is 0, 1, or 2.

130. The compound of any one of claims 123-129, wherein v is 0, 1, or 2.

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

132. A pharmaceutical composition, comprising the compound of any one of claims 1-131, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.Page 370 of 373BUSINESS.33352696. 1133. A method of inhibiting topoisomerase I, comprising contacting the compound of any one of claims 1-131 or the composition of claim 132 with a KRAS protein (e.g., KRASG12C).

134. A method of releasing a topoisomerase I payload (e.g., a topoisomerase I inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-131 or the composition of claim 132 with a KRAS protein (e.g., KRASG12C).

135. A method of delivering a topoisomerase I payload (e.g., a topoisomerase I inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-131 or the composition of claim 132with a KRAS protein (e.g., KRASG12C).

136. The method of any one of claims 133-135, wherein the contacting occurs in a cell harboring a KRASG12Cmutant protein.

137. The method of any one of claims 133-136, wherein the contacting occurs in a subject (e.g., a human subject).

138. A method, comprising administering the compound of any one of claims 1-131 or the composition of claim 132 to a subject in need thereof.

139. 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 1-131 or the composition of claim 132 to a subject in need thereof.

140. The method of claim 139, wherein the disease, disorder, or condition associated with KRAS is a cancer.Page 371 of 373BUSINESS.33352696. 1141 . A method of treating cancer, comprising administering the compound of any one of claims 1-131 or the composition of claim 132 to a subject in need thereof.

142. The method of claim 140 or 141, wherein the cancer is non-small cell lung cancer or colorectal cancer.Page 372 of 373BUSINESS.33352696. 1

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