Covalent-induced drug conjugates targeting KRAS and comprising a topoisomerase payload

Abstract

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

Description

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

[0001] The application claims the benefit of priority to U. S. Provisional Application No.63 / 846,632, filed July 18, 2025; U. S. Provisional Application No. 63 / 757,944, filed February 13, 2025; and U. S. Provisional Application No. 63 / 680,509, filed August 7, 2024; the contents of each of which are herein incorporated by reference.BACKGROUND

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

[0003] The present disclosure provides bifunctional compounds comprising a KRASG12Cbinding moiety and a topoisomerase 1 inhibitor payload moiety. As described further herein, provided compounds act as covalent-induced drug conjugates, whereby a cytotoxic payload (e.g., a topoisomerase 1 inhibitor payload moiety) is specifically delivered to a cell expressing an oncogenic protein (e.g., KRASG12C). Upon binding to KRASG12C, the topoisomerase 1 inhibitor payload moiety is released and thereby is allowed to engage with targets within the cell.

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

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

[0006] FIG. 1B 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,compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

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

[0011] The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1.5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 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, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (–CH2–).

[0013] The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8,C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0014] The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0015] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.

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

[0018] The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0019] As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety or a 10- to 16-membered polycyclic (i.e., comprising three or more rings) moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, 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 (eg., 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 structuremay 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)0–4R°; –(CH2)0–4OR°; –O(CH2)0–4R°, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; –N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°;–N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR°2; –N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; –(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, –(CH2)0–4OC(O)NR°2; –C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; –(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; –(CH2)0–4S(O)R°; –N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –(CH2)0–4P(O)2R°; –(CH2)0–4P(O)R°2; –(CH2)0–4P(O)(OR°)2; –(CH2)0–4OP(O)R°2; –(CH2)0–4OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, –CH2-(5-6 membered heteroaryl ring), or a 3–7-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0024] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)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*3, -C(O)SR* -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0025] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =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, –O(CH2)0–1Ph, 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; whereineach R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Suitable substituents on the aliphatic group of R†are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, 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. In some embodiments, the term appears adjacent to a stereocenter. In such cases, it is understood to denote either an “R” or “S” stereoisomer, but the particular isomer was not determined.

[0031] In some embodiments, a bond is denoted by “ In such cases, it is understood to denote either an “R” or “S” stereoisomer, but the particular isomer was not determined.

[0032] In some embodiments, a double bond is denoted by “ A ”, In such cases, it is understood to denote a mixture of “Z” and “E” double bond geometry.Covalent-Induced Drug Conjugates

[0033] In some embodiments, the present disclosure provides covalent-induced drug conjugates (CIDCs), as described further herein. Provided CIDCs are bifunctional compounds that deliver a cytotoxic payload specifically to cancer cells expressing an oncogenic protein. Such CIDCs comprise (i) a protein binding moiety, typically targeting an oncogenic protein capable of covalently interacting with the protein binding moiety, such as through a reactive cysteine residue; (ii) a payload moiety; and (iii) a linking moiety connecting the protein binding moiety to the payload moiety. Exemplary schemes are shown in FIG. 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”).

[0034] 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.

[0035] The present disclosure, in particular, relates to CIDCs comprising aKRASG12Cprotein binding moiety and a topoisomerase 1 inhibitor payload moiety.Provided Compounds

[0036] In some embodiments, the present disclosure provides a compound of Formula I:Ior 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 inhibitor payload moiety.

[0037] In some embodiments, the present disclosure provides a compound of Formula I-a:I-aor 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.

[0038] In some embodiments, the present disclosure provides a compound of Formula I-b:Lbor 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 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; andeach 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-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 C1-6aliphatic, phenyl, C3-7monocyclic 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; andeach 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-d:I-dor 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; andeach 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-e:I-eor a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated 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; andeach 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-f:I-for 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; andeach 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.

[0043] In some embodiments, the present disclosure provides a compound of Formula I-g:I-gor 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.

[0044] In some embodiments, the present disclosure provides a compound of Formula I-h:I-hor 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.

[0045] In some embodiments, the present disclosure provides a compound of Formula I-h-1:I-h-1or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-1, Rzis not hydrogen.

[0046] In some embodiments, the present disclosure provides a compound of Formula I-h-2:I-h-2or 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.

[0047] 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 C3-7cycloaliphatic, 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 Ci-6 aliphatic. In some embodiments, Rxis Ci-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 some embodiments, Rxis optionally substituted C1-6 alkyl. In some embodiments, Rxis C1-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Rxis C1-6 alkyl. In some embodiments, Rxis -CH3. In some embodiments, Rxis 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, Rxis -CH2C(CH3)2N(H)CH3.

[0048] In some embodiments of any Formulae described herein, Ryis hydrogen, halogen, cyano, or optionally substituted C1-6 aliphatic. In some embodiments, Ryis hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, Ryis hydrogen or optionally substituted C1-6 alkyl. In some embodiments, Ryis an optionally substituted group selected from C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis an optionally substituted group selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis hydrogen. In some embodiments, Ryis halogen (e.g., fluoro). In some embodiments, Ryis cyano. In some embodiments, Ryis optionally substituted Ci-6 aliphatic. In some embodiments, Ryis Ci-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 C1-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ryis C1-6 alkyl. In some embodiments, Ryis -CH3. In some embodiments, Ryis optionally substituted C3-7 cycloaliphatic. In some embodiments, Ryis C3-7 cycloaliphatic. In some embodiments, Ryis optionally substituted C3-7 cycloalkyl. In some embodiments, Ryis C3-7 cycloalkyl. In some embodiments, Ryis optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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.

[0049] 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 Ci-6 alkyl optionally substituted with one or more halogen atoms. In some embodiments, a Rzis Ci-6 alkyl optionally substituted with one or more fluorine atoms. In some embodiments, a Rzis CF3. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), -NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rzis Ci-6 alkyl. In some embodiments, a Rzis hydrogen, -

[0050] In some embodiments of any Formulae described herein, X is -O- or -N(RW)-. In some embodiments, X is -O-. In some embodiments, X is -N(RW)-. In some embodiments, X is -N(H)- In some embodiments, X is -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 1 inhibitor payload upon binding of the compound to KRASG12C.

[0051] In some embodiments of any Formulae described herein, Rwis hydrogen. In some embodiments, Rwis optionally substituted C1-6 aliphatic. In some embodiments, Rwis C1-6 aliphatic. In some embodiments, Rwis optionally substituted C1-6 alkyl. In some embodiments, Rwis Ci-6 alkyl.

[0052] In some embodiments of any Formulae described herein, L1is a covalent bond. In some embodiments, L1is a linking moiety.

[0053] 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.

[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)-, -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-.

[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 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 C1-10hydrocarbon 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 C1-6hydrocarbon 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-.

[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)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally andindependently 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-.

[0057] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6hydrocarbon 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-.

[0058] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or -Cy-.

[0059] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -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 C1-6hydrocarbon 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-.OI ® S'Nz /

[0060] 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.

[0061] In some embodiments of any Formulae described herein, L1iswherein 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'L>XB[0062| In some embodiments of any Formulae described herein, L1isA, wherein Lais as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.R-NJI LaN Ve

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

[0064] 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.

[0065] In some embodiments of any Formulae described herein, L1iswherein 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.

[0066] In some embodiments of any Formulae described herein, L1is °, 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.

[0067] In some embodiments of any Formulae described herein, L1is, 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.I b ^ 8 T

[0068] 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.

[0069] In some embodiments of any Formulae described herein, L1is O

[0070] 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^ is attached to X; and the bond labeled B is attached to TPM.

[0071] In some embodiments of any Formulae described herein, L1is selected from:wherein R is as defined herein; each Lcis independently an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled^ is attached to X; and the bond labeled B is attached to TPM.

[0072] In some embodiments of any Formulae described herein, L1is selected from:optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain.

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

[0074] In some embodiments of any Formulae described herein, L1is selected from: a covalentand the bond labeled B is attached to TPM.

[0075] In some embodiments of any Formulae described herein, Lais a covalent bond.

[0076] 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 optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or moremethylene 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 C1-6hydrocarbon 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, 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-

[0078] In some embodiments of any Formulae described herein, Lbis a covalent bond.

[0079] In some embodiments of any Formulae described herein, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one ormore 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-, -0C(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(0)0-, -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(0)0-, -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(0)0-, 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(0)0-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0080] In some embodiments of any Formulae described herein, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - methylene unit isoptionally 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(0)0-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(0)0-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0081] 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 C1-6 alkylene. In some embodiments, Lcis 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-.

[0082] 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. In 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-6aliphatic 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 Ci-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.

[0083] In some embodiments of any Formulae described herein, each Cy is independently an optionally substituted, mono- or multi cyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, phenylene, a bicyclic C9-10 arylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, phenylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, a bicyclic C9-10 arylene, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0084] In some embodiments of any Formulae described herein, 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.

[0085] 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 1 inhibitor payload is released from the compound. It will be appreciated therefore that, in some embodiments, when both X and L1are a covalent bond, TPM is a sufficient leaving group to result in release of the topoisomerase 1 inhibitor payload upon binding of the compound to KRASG12C.KRASG12CBinding Moiety

[0086] 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 specificallyassociates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a KBM is considered capable of binding a KRASG12Cprotein if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less).

[0087] 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:Yis CR2orN;R1is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R2is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R4is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;-°\ / 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 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; andeach m is independently 0, 1, or 2.

[0088] In some embodiments, the present disclosure provides a compound of Formula Il-a:Il-aor a pharmaceutically acceptable salt thereof, wherein L1, R2, R3, R4, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein:Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.

[0089] In some embodiments, the present disclosure provides a compound of Formula Il-b:Il-bor a pharmaceutically acceptable salt thereof, wherein Cy2, L1, R2, R3, R4, 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, 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; andn is 0, 1, 2, 3, 4, 5, or 6.

[0090] In some embodiments, the present disclosure provides a compound of Formula II-c:or a pharmaceutically acceptable salt thereof, wherein L1, R3, R4, R, 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 Il-d:Il-dor a pharmaceutically acceptable salt thereof, wherein Cy2, L1, R3, R4, 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, 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; andn is 0, 1, 2, 3, 4, 5, or 6.

[0092] In some embodiments of any Formulae described herein, KBM is:wherein 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.

[0093] In some embodiments of any Formulae described herein, KBM is:wherein R2, R3, R4, R5, and Ring A are as defined herein for Formula Il-a and described in classes and subclasses herein, both singly and in combination.

[0094] In some embodiments of any Formulae described herein, KBM is:wherein Cy2, n, R2, R3, R4, and R7are as defined herein for Formula Il-b and described in classes and subclasses herein, both singly and in combination.

[0095] In some embodiments of any Formulae described herein, KBM is:wherein R3, R4, R5, and Ring A are as defined herein for Formula II-c and described in classes and subclasses herein, both singly and in combination.

[0096] In some embodiments of any Formulae described herein, KBM is:wherein Cy2, n, R3, R4, and R7are as defined herein for Formula Il-d and described in classes and subclasses herein, both singly and in combination.

[0097] In some embodiments of any Formulae described herein, Y is CR2. In some embodiments, Y is N.

[0098] In some embodiments of any Formulae described herein, R1is hydrogen, halogen, -OR’, optionally substituted Ci-6 alkyl, or optionally substituted C3.7 cycloalkyl. In some embodiments, R1is hydrogen. In some embodiments, R1is halogen (e.g., fluoro or chloro). In some embodiments, R1is -OR’ (e.g., -O(Ci-6 alkyl) or -O(Ci-6 haloalkyl)). In some embodiments, R1is optionally substituted C1-6 aliphatic. In some embodiments, R1is C1-6 aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R1is Ci-6 aliphatic. Insome embodiments, R1is optionally substituted Ci-6 alkyl. In some embodiments, R1is Ci-6 alkyl optionally substituted with one or more halo (e.g., fluoro) (e.g., -CF3). In some embodiments, R1is C1-6 alkyl (e.g., -CH3). In some embodiments, R1is optionally substituted C3-7 cycloaliphatic. In some embodiments, R1is C3-7 cycloaliphatic. In some embodiments, Rfis optionally substituted C3-7 cycloalkyl. In some embodiments, R1is C3-7 cycloalkyl (e.g., cyclopropyl).

[0099] In some embodiments of any Formulae described herein, R2is hydrogen, halogen, -OR’, optionally substituted Ci-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, R2is hydrogen. In some embodiments, R2is halogen (e.g., fluoro or chloro). In some embodiments, R2is chloro. In some embodiments, R2is fluoro. In some embodiments, R2is -OR’ (e.g., -O(Ci-6 alkyl) or-O(Ci-6 haloalkyl)). In some embodiments, R2is optionally substituted C1-6 aliphatic. In some embodiments, R2is C1-6 aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R2is C1-6 aliphatic. In some embodiments, R2is optionally substituted Ci-6 alkyl. In some embodiments, R2is C1-6 alkyl optionally substituted with one or more halo (e.g., fluoro) (e.g., -CF3). In some embodiments, R2is Ci-6 alkyl (e.g., -CH3). In some embodiments, R2is optionally substituted C3-7 cycloaliphatic. In some embodiments, R2is C3-7 cycloaliphatic. In some embodiments, R2is optionally substituted C3-7 cycloalkyl. In some embodiments, R2is C3-7 cycloalkyl (e.g., cyclopropyl).

[0100] 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, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3). 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-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3).

[0101] In some embodiments of any Formulae described herein, R3is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is asubstituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is an optionally substituted ring selected from naphthyl and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a substituted ring selected from naphthyl and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments of any Formulae described herein, R3is optionally substituted phenyl. In some embodiments, R3is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci.6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is substituted phenyl. In some embodiments, R3is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3).

[0103] In some embodiments of any Formulae described herein, R3is optionally substituted naphthyl. In some embodiments, R3is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is substituted naphthyl. In some embodiments, R3is naphthyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3).

[0104] In some embodiments of any Formulae described herein, R3is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 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 (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 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 (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 5-membered monocyclic heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 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 (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted pyridyl. In some embodiments, R3is pyridyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3).

[0105] In some embodiments of any Formulae described herein, R3is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 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 (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). 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 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 (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted 9-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 9-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 (e.g., -CH3 or -C≡CH), or Ci-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 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 (e.g., -CH3 or -C≡CH), or Ci-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted benzothiophenyl, optionally substituted benzothiazolyl, optionallysubstituted benzimidazolyl, or optionally substituted indazolyl. In some embodiments, R3is benzothiophenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is benzothiazolyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C≡CH), or C1-6 haloaliphatic (e.g., -CF3).

[0106] In some embodiments of any Formulae described herein, R3is an optionally substituted ring selected from:wherein the ring is substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3).

[0108] In some embodiments of any Formulae described herein, R3is selected from:

[0109] In some embodiments of any Formulae described herein, R3is selected from:

[0110] In some embodiments of any Formulae described herein, R4is hydrogen, halogen, - OR’, optionally substituted Ci-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is halogen (e.g., fluoro or chloro). In some embodiments, R4is chloro. In some embodiments, R4is fluoro. In some embodiments, R4is -OR’ (e.g., -O(Ci-6 alkyl) or-O(Ci-6 haloalkyl)). In some embodiments, R4is optionally substitutedCi-6 aliphatic. In some embodiments, R4is Ci-6 aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R4is Ci-6 aliphatic. In some embodiments, R4is optionally substituted Ci-6 alkyl. In some embodiments, R4is Ci-6 alkyl optionally substituted with one or more halo (e.g., fluoro) (e.g., -CF3). In some embodiments, R4is C1-6 alkyl (e.g., -CH3). In some embodiments, R4is optionally substituted C3-7 cycloaliphatic. In some embodiments, R4is C3-7 cycloaliphatic. In some embodiments, R4is optionally substituted C3-7 cycloalkyl. In some embodiments, R4is C3-7 cycloalkyl (e.g., cyclopropyl).y0\ ^-Cy1

[0111] In some embodiments of any Formulae described herein, R5is -OR6,, -O(Ci-4alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In someembodiments, R3is -OR6,, or -O(Ci-4 alkylene)Cy2. In some embodiments, R3ishydrogen. In some embodiments, R5is -OR6. In some embodiments, R5is. In some embodiments, R5is -O(Ci-4 alkylene)Cy2. In some embodiments, R5is -OCH2Cy2. In some embodiments, R5is an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is 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)?).

[0112] In some embodiments of any Formulae described herein, R3is selected from hydrogen,me embodiments, R3isIn some embodiments, R5isome embodiments,some embodiments, R5is. In some embodiments, R5. In some embodiments,some embodiments,some embodiments, R5isme embodiments,some embodiments, R5isme embodiments, R5is. In some embodiments, R3is

[0113] In some embodiments of any Formulae described herein, R6is optionally substituted Ci-6 alkyl or 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 Ci-6 aliphatic. In some embodiments, R6is Ci-6 aliphatic optionally substituted with -N(CI-6 alkyl). In some embodiments, R6is optionally substituted Ci-6 alkyl. In some embodiments, R6is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)?. In some embodiments, R6is -CH2CH2N(CH3)2. In some embodiments, R6is optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur. In some embodiments, R6is monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently 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. In some embodiments, R6is optionally substituted piperidinyl. In some embodiments, R6is piperidinyl optionally substituted with Ci-6 alkyl. In some embodiments, R6is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)2 or 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl.

[0114] In some embodiments of any Formulae described herein, Cy1is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments of any Formulae described herein, 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. In some embodiments, Cy1is an optionally substituted monocyclic 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted monocyclic 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted monocyclic 5-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted pyrrolidine). In some embodiments, Cy1is an optionally substituted monocyclic 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1is an optionally substituted monocyclic 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 or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0116] In some embodiments of any Formulae described herein, 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. In some embodiments, Cy1is an optionally substituted bicyclic 5-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-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 7-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 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 9-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 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0117] In some embodiments of any Formulae described herein, Cy1is an optionally substituted ring selected from:

[0118] In some embodiments of any Formulae described herein, Cy1is selected from:

[0119] In some embodiments of any Formulae described herein, Cy2is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0120] In some embodiments of any Formulae described herein, 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 monocyclic 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted monocyclic 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted monocyclic 5-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted pyrrolidinyl). In some embodiments, Cy2is an optionally substituted monocyclic 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted piperidinyl). In some embodiments, Cy2is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments of any Formulae described herein, 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 someembodiments, 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. In some embodiments, Cy2is an optionally substituted bicyclic 6- to 8-membered fused heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted bicyclic 5-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-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 7-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 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted hexahydro-lH-pyrrolizinyl). In some embodiments, Cy2is an optionally substituted bicyclic 9-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 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen.

[0122] In some embodiments of any Formulae described herein, Cy2is an optionally substituted ring selected from:

[0123] In some embodiments of any Formulae described herein, Cy2is selected from:embodiments, Cy2isIn some embodiments,some embodiments,

[0124] In some embodiments of any Formulae described herein, 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 monocyclic C3-7 carbocyclylene. In some embodiments, Ring A is an optionally substituted monocyclic C3-7 cycloalkylene. In some embodiments, Ring A is an optionally substituted bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring A is an optionally substituted bicyclic C4-10 fused, bridged, or spirocyclic cycloalkylene.

[0125] 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.

[0126] In some embodiments of any Formulae described herein, Ring A is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionallysubstituted 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.

[0127] In some embodiments of any Formulae described herein, Ring A is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-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 6-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 7-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a bivalent 2,6-diazaspiro[3.3]heptane ring). In some embodiments, Ring A is an optionallysubstituted 8-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a bivalent 3,8-diazabicyclo[3.2.1]octane ring). In some embodiments, Ring A is an optionally substituted 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 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0128] In some embodiments of any Formulae described herein, Ring A is optionallysubstituted

[0129] In some embodiments of any Formulae described herein, Ringwherein R7and n are as defined herein for Formula II-b and described in classes and subclasses herein, both singly and in combination.

[0130] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:

[0131] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:

[0132] In some embodiments of any Formulae described herein, Ring A is selected from:

[0133] In some embodiments of any Formulae described herein, Ring A is selected from:

[0134] In some embodiments of any Formulae described herein, each R7is independently optionally substituted Ci-6 alkyl, 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 taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R7moieties are attached.

[0135] In some embodiments of any Formulae described herein, n is 0, 1, 2, 3, or 4. 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.

[0136] In some embodiments of any Formulae described herein, 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-.

[0137] In some embodiments of any Formulae described herein, 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’)-.

[0138] 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.

[0139] In some embodiments of any Formulae described herein, each m is independently 0 or 1. In some embodiments, each m is independently 1 or 2. In some embodiments, an m is 0. In some embodiments, an m is 1. In some embodiments, an m is 2.embodiments, 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’)-.

[0141] In some embodiments of any Formulae described herein, a moietyis selected from:

[0143] 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 1 inhibitor payload moiety, as defined herein (e.g.,such suitable position where an a, P-unsaturated carbonyl moiety is located on a KRASG12Cinhibitor compound. In some embodiments, a KBM is a KRASG12Cbinding moiety (e.g., without an a, P-unsaturated carbonyl moiety) of a KRASG12Cinhibitor selected from sotorasib, adagrasib, divarasib, opnurasib, garsorasib, MRTX-1257, BI-0474, ASP2453, BBO-8520, AZD4625, LY3537982, ARS-1620, and AZD4747. In some embodiments, KBM is a KRASG12Cbinding moiety (e.g., without an a, P-unsaturated carbonyl moiety) of a KRASG12Cinhibitor described in WO2018 / 119183; WO2018 / 217651; WO2019 / 051291; WO2020 / 259432; WO2019 / 241157; WO2021 / 104431; W02020 / 156285; CN112225734; WO2021 / 027943; CN112390796; W02021 / 037018; WO2021 / 043322; WO2021 / 063346; CN112574199; CN112778302; CN112920183; WO2021 / 118877; CN113004269; WO2021 / 124222; W02021 / 120890; WO2021 / 121371; WO2021 / 143693; WO2021 / 249563; WO2022 / 135591; CN113754653; CN114380827; WO2022 / 111527; WO2022 / 135546; CN114685460; CN114874234; W02023 / 045960; WO2023 / 066371; WO2023 / 072297; CN116120315; CN116199703; CN116217592; WO2023 / 196959; WO2023 / 199180; WO2023 / 226902; WO2013 / 155223; WO2014 / 143659; WO2014 / 152588; 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; W02017 / 058902; WO2017 / 058915; WO2017 / 087528; W02017 / 100546; W02017 / 201161; WO2018 / 064510; WO2018 / 068017; WO2018 / 119183; W02018 / 140512; W02018 / 140513; W02018 / 140514; WO2018 / 140598; WO2018 / 140599; WO2018 / 140600; WO2018 / 143315; WO2018 / 206539; WO2018 / 218070; WO2018 / 218071; WO2019 / 099524; WO2019 / 110751; W02019 / 141250; W02019 / 150305; WO2019 / 155399; WO2019 / 213516; WO2019 / 213526; WO2019 / 217307; WO2019 / 217691; WO2019 / 232419; W02020 / 050890; W02020 / 035031; W02020 / 047192; W02020 / 081282; W02020 / 086739; W02020 / 106640; W02020 / 113071; WO2021 / 055728; W02021 / 058018; WO2021 / 086833; WO2022 / 083569; WO2022 / 087375; WO2022 / 087371; WO2022 / 093856; WO2022 / 109487; WO2022 / 109485; WO2022 / 119748; WO2022 / 152233; WO2022 / 221528; WO2022 / 232318; WO2022 / 232320; WO2022 / 269508; WO2022 / 269525; WO2023 / 225252; WO2023 / 133181; W02023 / 004102; WO2023 / 283213; WO2023 / 284730; WO2023 / 287896; WO2023 / 284537; WO2023 / 283933; W02023 / 001141; W02023 / 018809; W02023 / 018699; W02023 / 034290; W02023 / 030495; W02023 / 030517; W02024 / 050640; W02023 / 039240; WO2023 / 049697; WO2023 / 046135; WO2023 / 056421; WO2023 / 057985; WO2023 / 064857; W02023 / 081840; WO2023 / 086341; WO2023 / 086383; WO2023 / 097227; WO2023 / 101928; WO2023 / 099623; WO2023 / 099612; WO2023 / 099592; WO2023 / 105491; WO2023 / 114733; WO2023 / 125627; WO2023 / 133183; W02023 / 141300; WO2023 / 150284; WO2023 / 154766; WO2023 / 152255; WO2023 / 159086;WO2023 / 159087; WO2023 / 173014; WO2023 / 172737; WO2023 / 183755; WO2023 / 179703; WO2023 / 183585; WO2023 / 205719; WO2023 / 212548; WO2023 / 212549; WO2023 / 215801; WO2023 / 213269; WO2023 / 219941; WO2023 / 220421; WO2023 / 225302; W02023 / 230190; WO2023 / 240263; WO2023 / 240189; WO2023 / 240188; WO2023 / 244604; WO2023 / 244599; WO2023 / 244615; WO2023 / 244713; WO2023 / 246777; W02024 / 008610; W02024 / 008068; W02024 / 009191; W02024 / 008179; W02024 / 008834; W02024 / 015262; WO2024 / 015731; W02024 / 030647; W02024 / 030633; W02024 / 036270; W02024 / 032703; W02024 / 032704; W02024 / 032702; W02024 / 040109; W02024 / 040131; WO2024 / 041621; WO2024 / 041573; WO2024 / 047135; WO2024 / 054926; WO2024 / 051721; WO2024 / 054647; WO2024 / 064353; WO2024 / 076674; W02024 / 076670; WO2024 / 085661; WO2024 / 083168; WO2024 / 083246; W02024 / 091409; WO2024 / 097559; W02024 / 103010; WO2024 / 107686; WO2024 / 112654; WO2024 / 120419; WO2024 / 153116; WO2024 / 155706; WO2024 / 153119; WO2024 / 158778; WO2024 / 159471; WO2024 / 159470; WO2024 / 173842; WO2024 / 178304; WO2024 / 178313; WO2024 / 179546; WO2024 / 192424; WO2024 / 197503; WO2024 / 206747; WO2024 / 206766; WO2024 / 209339; WO2024 / 213979; WO2024 / 215754; WO2024 / 220532; WO2024 / 220645; WO2024 / 218686; WO2024 / 227091; WO2024 / 229317; WO2024 / 229442; WO2024 / 229444; WO2024 / 229447; WO2024 / 230734; WO2024 / 233776; WO2024 / 236452; WO2024 / 238343; WO2024 / 238633; WO2024 / 235286; WO2024 / 243025; WO2024 / 241248; WO2024 / 246099; WO2024 / 259169; WO2024 / 255795; W02025 / 006704; W02025 / 007000; W02025 / 006962; W02025 / 006720; W02025 / 123007; WO2025 / 122619; WO2025 / 123318; WO2025 / 124415; WO2025 / 137519; WO2025 / 151765; WO2025 / 151738; WO2025 / 151594; and WO2025 / 153038.

[0144] In some embodiments, KBM is a means for binding KRASG12C. In some embodiments, KBM is a means for targeting KRASG12C.Topoisomerase 1 Inhibitor Payload Moiety

[0145] 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 topoisomerase 1-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 oneother 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).

[0146] In some embodiments, the present disclosure provides a compound of Formula III: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;W is O or S;Z1is a covalent bond or -O-;Z2is a covalent bond or -C(RC)2-;Rais hydrogen or optionally substituted C1-6 aliphatic;Rbis -ORaa;each Rcis 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;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 Ri, 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; Rjis 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; andeach 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 to form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0147] In some embodiments, the present disclosure provides a compound of Formula Ill-a:Ill-aor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rx, Ry, Rz, W, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0148] In some embodiments, the present disclosure provides a compound of Formula Ill-b:Ill-bor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rx, Ry, Rz, W, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0149] In some embodiments, the present disclosure provides a compound of Formula III-c:III-cor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rd, Rf, Rg, Rh, Ri, Rx, Ry, Rz, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0150] In some embodiments, the present disclosure provides a compound of Formula Ill-d:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0151] In some embodiments, the present disclosure provides a compound of Formula Ill-dl:Ill-dlor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rx, Ry, Rz, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0152] In some embodiments, the present disclosure provides a compound of Formula Ill-e:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0153] In some embodiments, the present disclosure provides a compound of Formula III-el:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, Rx, Ry, Rz, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0154] In some embodiments, the present disclosure provides a compound of Formula Ill-f:III-for a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rh, Ri, Rj, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0155] In some embodiments, the present disclosure provides a compound of Formula Ill-fl:Ill-flor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rh, Ri, Rj, Rx, Ry, Rz, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0156] In some embodiments, the present disclosure provides a compound of Formula III-g:III-gor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rj, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0157] In some embodiments, the present disclosure provides a compound of Formula III-g 1:Ill-glor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rj, Rx, Ry, Rz, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0158] In some embodiments, the present disclosure provides a compound of Formula Ill-h:Ill-hor a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rx, Ry, Rz, W, X, Z1, Z2, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0159] In some embodiments, the present disclosure provides a compound of Formula Ill-hl:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rx, Ry, Rz, X, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0160] In some embodiments, the present disclosure provides a compound of Formula IV:IVor 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 C1-6aliphatic, or optionally substituted C3-7cycloaliphatic;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 Ri, 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; Rjis 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; andeach 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.

[0161] In some embodiments, the present disclosure provides a compound of Formula IV-a:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R‘, R', Rx, Ry, Rz, W, X, Z2, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0162] In some embodiments, the present disclosure provides a compound of Formula IV-b:or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, R‘, R', Rx, Ry, Rz, W, X, Z2, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0163] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0164] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0165] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0166] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, Rg, Rh, and Riare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0167] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and Riare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0168] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and Riare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0169] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0170] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0171] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0172] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0173] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0174] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0175] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0176] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0177] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Re, Rd, Re, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0178] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0179] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rh, Ri, Rjand W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0180] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0181] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0182] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0183] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, and W are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0184] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and R1are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0185] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rd, Rf, and Riare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0186] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0187] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0188] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0189] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0190] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0191] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0192] In some embodiments of any Formulae described herein, W is O. Tn some embodiments, W is S.

[0193] In some embodiments of any Formulae described herein, Z1is a covalent bond. In some embodiments, Z1is -O-.

[0194] In some embodiments of any Formulae described herein, Z2is a covalent bond. In some embodiments, Z2is -C(RC)2-. In some embodiments, Z2is -CH2-.

[0195] 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.

[0196] 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 Cue aliphatic. In some embodiments, Rais C1-6 aliphatic. In someembodiments, Rais optionally substituted Ci-6 alkyl. In some embodiments, Rais Ci-6 alkyl. In some embodiments, Rais ethyl.

[0197] In some embodiments of any Formulae described herein, Rbis -ORaa. In 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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, 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 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, Rfis hydrogen, -CORbb, -C(NORbb)Rbb, -OR”, -Si(Rbb)3, optionally substituted 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, Rfis -CORbb(e.g., -CO(Ci-6 alkyl) or -CO(optionally substituted phenyl)). In some embodiments, Rfis -CO2Rbb. 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, Rfis -N(Raa)2. In some embodiments, Rfis -ORaa(e.g., -OH). In some embodiments, Rfis -SR3’1. In some embodiments, Rfis -Si(Rbb)3 (e.g., -Si(Ci-6 alkyl^). In some embodiments, Rfis optionally substituted C1-6 aliphatic. In some embodiments, Rfis optionally substituted C1-6 alkyl. In some embodiments, Rfis C1-6 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(0)R°, -N(R°)C(O)OR°, or -N(R°)C(0)NR°2. In some embodiments, Rfis C1-6 alkyl optionally substituted with one or more halogen, -OR°, -N(R°)2, -N(R°)C(0)R°, 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(0)R°, -N(R°)C(0)0R°, or -N(RO)C(O)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, Rfis Ci-6 aliphatic. In some embodiments, Rfis Ci-6 alkyl. In some embodiments, Rfis optionally substituted C3-7 cycloaliphatic (e.g., optionally substituted monocyclic C3-7 cycloaliphatic or optionally substituted C4-7 bicyclic cycloaliphatic). In some embodiments, R1isoptionally 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, Rfis C3-7 cycloaliphatic. In some embodiments, Rfis C3-7 cycloalkyl. In some embodiments, Rfis selected from: hydrogen, -some embodiments, Rfis. In some embodiments, Rfis the point of attachment to the rest of the molecule.

[0202] 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 C1-6 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, Rgis -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, Rgis optionally substituted Ci-6 aliphatic. In some embodiments, Rgis 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, Rgisoptionally 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.

[0203] In some embodiments of any Formulae described herein, 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. 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 Rg, together with the atoms to which they are attached, combine to form an optionally substituted C5 carbocyclic ring. In some embodiments, Rfand Rg, together with the atoms to which they are attached, combine to form an optionally substituted C6carbocyclic ring. In some embodiments, Rfand Rg, together with the atoms to which they are attached, combine to form a C6carbocyclic ring substituted with N(R°)2. In some embodiments, Rfand Rg, together with the atoms to which they are attached, combine to form a C6carbocyclic ring substituted with NH2. In some embodiments, Rfand 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 Rg, 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, Rfand Rg, 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 Rg, 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 Rg, 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, Rfand Rg, 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 Rfand Rgtogether isoptionally substituted with one or more halogen, -OR°, -N(R°)2, or -N(R°)C(0)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 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some such embodiments, each R° is independently hydrogen, C1-6 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 Rfand Rgtogether is the point of attachment to the rest of the molecule.

[0204] In some embodiments of any Formulae described herein, Rhis 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. In some embodiments, Rhis 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, Rhis 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, Rhis -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 -ORaa(e.g., -OH). In some embodiments, Rhis -SRaa. In some embodiments, Rhis 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, Rhis 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.

[0205] 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 heteroatomsindependently 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, Rgand Rh, together with the atoms to which they are attached, combine to form an optionally substituted C6carbocyclic 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 Rh, 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.

[0206] In some embodiments of any Formulae described herein, Riis 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. In some embodiments, Riis 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, Riis hydrogen or halogen. In some embodiments, Riis hydrogen. In some embodiments, Riis halogen (e.g., fluoro). In some embodiments, Riis -CN. In some embodiments, Riis -CO2Rbb. In some embodiments, Riis -C(O)N(Rbb)2. In some embodiments, Riis -NO2. In some embodiments, Riis -N(Raa)2. In some embodiments, Riis -ORaa. In some embodiments, Riis -SRaa. In some embodiments, Riisoptionally substituted Ci-6 aliphatic. In some embodiments, R1is optionally substituted Ci-6 alkyl. In some embodiments, R1is Ci-6 aliphatic. In some embodiments, R1is Ci-6 alkyl. In some embodiments, R1is optionally substituted C3-7 cycloaliphatic. In some embodiments, Rfis optionally substituted C3-7 cycloalkyl. In some embodiments, R1is C3-7 cycloaliphatic. In some embodiments, R1is C3-7 cycloalkyl. In some embodiments, R1is selected from hydrogen and fluoro. In some embodiments, R1is fluoro.

[0207] In some embodiments of any Formulae described herein, Rhand Ri, 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 Ri, together with the atoms to which they are attached, combine to form an optionally substituted C5-7 carbocyclic ring. In some embodiments, Rhand Ri, together with the atoms to which they are attached, combine to form an optionally substituted C5 carbocyclic ring. In some embodiments, Rhand Ri, together with the atoms to which they are attached, combine to form an optionally substituted C6carbocyclic ring. In some embodiments, Rhand Ri, together with the atoms to which they are attached, combine to form an optionally substituted C7 carbocyclic ring. In some embodiments, Rhand Ri, 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 Ri, 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 Ricombine to form a -OCH2O-). In some embodiments, Rhand Ri, 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 Ri, 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 Ri, 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 Ri, 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.

[0208] In some embodiments of any Formulae described herein, Rjis 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. In some embodiments, Rjis 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, Rjis hydrogen or halogen. In some embodiments, Rjis hydrogen. In some embodiments, Rjis halogen. In some embodiments, Rjis -CN. In some embodiments, Rjis -CO2Rbb. In some embodiments, Rjis -C(O)N(Rbb)2. In some embodiments, Rjis -NO2. In some embodiments, Rjis -N(Raa)2. In some embodiments, Rjis -ORaa. In some embodiments, Rjis -SRaa. In some embodiments, Rjis optionally substituted C1-6 aliphatic. In some embodiments, Rjis optionally substituted C1-6 alkyl. In some embodiments, Rjis C1-6aliphatic. In some embodiments, Rjis C1-6 alkyl. In some embodiments, Rjis optionally substituted C3-7 cycloaliphatic. In some embodiments, Rjis optionally substituted C3-7 cycloalkyl. In some embodiments, Rjis C3-7 cycloaliphatic. In some embodiments, Rjis C3-7 cycloalkyl.

[0209] 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.

[0210] 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 C1-6 aliphatic. In some embodiments, a Rbbis C1-6 alkyl. In some embodiments, a Rbbis optionally substituted phenyl. In some embodiments, a Rbbis optionally substituted C3-7monocyclic 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.

[0211] In some embodiments, the present disclosure provides a compound of Formula V:Vor 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 C1-6aliphatic; Rmis hydrogen or optionally substituted Ci-6 aliphatic;each Rnand Rpis independently hydrogen or optionally substituted C1-6aliphatic;each Rqis independently halogen, -ORcc, -N(Rcc)2, or optionally substituted C1-6aliphatic; each Rccis independently hydrogen or optionally substituted Ci-6 aliphatic;s is 0, 1, 2, 3, or 4; andt is 0, 1, 2, 3, or 4.

[0212] In some embodiments, the present disclosure provides a compound of Formula V-a:or a pharmaceutically acceptable salt thereof, wherein L1, Rk, Rm, R", Rp, Rq, Rx, Ry, Rz, s, X, and KBM are as defined in Formula V and described in classes and subclasses herein, both singly and in combination; and wherein t is 0, 1, 2, or 3.

[0213] In some embodiments of any Formulae described herein, TPM is:wherein Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0214] In some embodiments of any Formulae described herein, TPM is:wherein Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula V-a and described in classes and subclasses herein, both singly and in combination.

[0215] In some embodiments of any Formulae described herein, each Rkis independently halogen, -ORcc, -N(Rcc)2, or optionally substituted C1-6alkyl. 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 Ci-6 aliphatic. In some embodiments, a Rkis optionally substituted Ci-6 alkyl. In some embodiments, a Rkis Ci-6 aliphatic. In some embodiments, a Rkis Ci-6 alkyl.

[0216] 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 C1-6aliphatic. In some embodiments, Rmis optionally substituted Ci-6 alkyl. In some embodiments, Rmis Ci-6 aliphatic. In some embodiments, Rmis Ci-6 alkyl (e.g., methyl).

[0217] In some embodiments of any Formulae described herein, each Rnis independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, each Rnis hydrogen. In some embodiments, each Rnis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rnis 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-6 aliphatic. In some embodiments, a Rnis optionally substituted Ci-6 alkyl. In some embodiments, a Rnis Ci-6 aliphatic. In some embodiments, a Rnis Ci-6 alkyl.

[0218] 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.

[0219] In some embodiments of any Formulae described herein, each Rqis independently halogen, -ORcc, -N(Rcc)2, or optionally substituted C1-6alkyl. In some embodiments, a Rqis halogen. In some embodiments, a Rqis -ORcc. In some embodiments, a Rqis -N(Rcc)2. In some embodiments, a Rqis optionally substituted Ci-6aliphatic. In some embodiments, a Rqis optionally substituted Ci-6alkyl. 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.

[0220] In some embodiments of any Formulae described herein, each Rccis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rccis hydrogen. In some embodiments, each Rccis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rccis independently optionally substituted C1-6alkyl. In some embodiments, each Rccis independently C1-6aliphatic. In some embodiments, each Rccis independently C1-6alkyl. In some embodiments, a Rccis hydrogen. In some embodiments, a Rccis optionally substituted Ci-6 aliphatic. In some embodiments, aR“is optionally substituted Ci-6 alkyl. In some embodiments, a Rccis C1-6aliphatic. In some embodiments, a Rccis C1-6alkyl.

[0221] 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.

[0222] 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. In some 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.

[0223] In some embodiments, the present disclosure provides a compound of Formula VI:VIor 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-6aliphatic; Rsis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6aliphatic;each Rtis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6aliphatic, or two Rtcombine to form an optionally substituted C5-7carbocyclic 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 C1-6aliphatic;each Rddis independently hydrogen or optionally substituted C1-6aliphatic;u is 0, 1, 2, 3, or 4; andv is 0, 1, 2, 3, or 4.

[0224] In some embodiments of any Formulae disclosed herein, TPM is:wherein Rr, Rs, Rt, Ru, u, and v are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0225] In some embodiments of any Formulae disclosed herein, each Rris independently halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6alkyl. 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 C1-6aliphatic. In some embodiments, a Rris optionally substituted C1-6alkyl. In some embodiments, a Rris C1-6 aliphatic. In some embodiments, a Rris C1-6 alkyl.

[0226] 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 C1-6 alkyl. In some embodiments, Rsis C1-6 aliphatic. In some embodiments, Rsis Ci-6 alkyl.

[0227] In some embodiments of any Formulae disclosed herein, each Rtis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6alkyl. In some embodiments, each Rtis independently -ORdd. In some embodiments, a Rtis halogen. In some embodiments, a Rtis -ORdd. In some embodiments, a Rtis -N(Rdd)2. In some embodiments, a Rtis optionally substituted C1-6aliphatic. In some embodiments, a Rtis optionally substituted C1-6alkyl. In some embodiments, a Rtis Ci-6aliphatic. In some embodiments, a Rtis Ci-6alkyl. In some embodiments, two Rtcombine 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 Rtcombine to form a -OCH2O-).

[0228] In some embodiments of any Formulae described herein, Ruis hydrogen or optionally substituted C1-6alkyl. In some embodiments, Ruis hydrogen. In some embodiments, Ruisoptionally substituted Ci-6 aliphatic. In some embodiments, Ruis optionally substituted Ci-6alkyl (e.g., Ci-6alkyl optionally substituted with -NH2, -NH(C1-6alkyl), or -N(C1-6alkyl)2). In some embodiments, Ruis C1-6 aliphatic. In some embodiments, Ruis C1-6 alkyl.

[0229] In some embodiments of any Formulae described herein, each Rddis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rddis hydrogen. In some embodiments, each Rddis independently optionally substituted C1-6 aliphatic. In some embodiments, each Rddis independently optionally substituted C1-6 alkyl. In some embodiments, each Rddis independently C1-6 aliphatic. In some embodiments, each Rddis independently C1-6 alkyl. In some embodiments, a Rddis hydrogen. In some embodiments, a Rddis optionally substituted C1-6 aliphatic. In some embodiments, a Rddis optionally substituted C1-6 alkyl. In some embodiments, a Rddis C1-6 aliphatic. In some embodiments, a Rddis C1-6 alkyl.

[0230] 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.

[0231] 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.

[0232] 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 KRASG12Cbinding 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).

[0233] 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

[0234] In some embodiments, the present disclosure provides a compound of Formula VII:VIIor 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, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0235] In some embodiments, the present disclosure provides a compound of Formula VII-a:VII-aor 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, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, Z1, andZ2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0236] In some embodiments, the present disclosure provides a compound of Formula VII-a1:VII-a1or 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, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0237] In some embodiments, the present disclosure provides a compound of Formula VII-a2 and VII-a3:VII-a3or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0238] In some embodiments, the present disclosure provides a compound of Formula VII-a4 and VII-a5:VII-a4VII-a5or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0239] In some embodiments, the present disclosure provides a compound of Formula VII-b:VII-bor 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, Rg, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0240] In some embodiments, the present disclosure provides a compound of Formula VII-b1:VII-b1or 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, Rg, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0241] In some embodiments, the present disclosure provides a compound of Formula VII-b2 or Formula VII-b3:VII-b3or 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; R2,R3, R4, R7, n, and Cy2are as defined herein for Formula II-b and Formula II-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0242] In some embodiments, the present disclosure provides a compound of Formula VII-b4 or Formula VII-b5:VII-b5or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0243] In some embodiments, the present disclosure provides a compound of Formula VII-c:VII-cor 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, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0244] In some embodiments, the present disclosure provides a compound of Formula VII-cl:VII-clor 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, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0245] In some embodiments, the present disclosure provides a compound of Formula VII-c2 and VII-c3:VII-c3or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0246] In some embodiments, the present disclosure provides a compound of Formula VII-c4 and VII-c5:VII-c5or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0247] In some embodiments, the present disclosure provides a compound of Formula VII-d:VII-dor 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, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0248] In some embodiments, the present disclosure provides a compound of Formula VII-d1:VII-d1or 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, Rg, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0249] In some embodiments, the present disclosure provides a compound of Formula VII-d2 orVII-d3:VII-d3or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d 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 III and described in classes and subclasses herein, both singly and in combination.

[0250] In some embodiments, the present disclosure provides a compound of Formula VII-d4 orVII-d5:VII-d5or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0251] In some embodiments, the present disclosure provides a compound of Formula Vll-e:VII-eor 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, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0252] In some embodiments, the present disclosure provides a compound of Formula Vll-el:VII-e1or 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, Rg, Rh, Ri, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0253] In some embodiments, the present disclosure provides a compound of Formula VII-e2 andVII-e3:VII-e3or 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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, Z1, and Z2are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0254] In some embodiments, the present disclosure provides a compound of Formula VII-e4 and VII-e5: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; R2, R3, R4, R7, n, and Cy2are as defined herein for Formula Il-b and Formula Il-d and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, and Rjare as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0255] In some embodiments, the present disclosure provides a compound of Formula VIII:VIIIor 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, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0256] In some embodiments, the present disclosure provides a compound of Formula VIII-a:VIII-aor 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, Rbb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, W, and Z2are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0257] In some embodiments, the present disclosure provides a compound of Formula IX:IXor 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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0258] In some embodiments, the present disclosure provides a compound of Formula IX-a:IX-aor 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 Rk, Rm, Rn, Rp, Rq, s, and t are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0259] In some embodiments, the present disclosure provides a compound of Formula X:Xor 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 Rr, Rs, R’, Ru, u, and v are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0260] In some embodiments, the present disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.Table 1. Compound StructuresTable 2.Preparing Provided Compounds

[0261] Provided compounds generally can be prepared using the processes described in the ensuing schemes and examples.

[0262] In some embodiments, provided compounds (e.g., compounds wherein KBM comprises an amine, either a cyclic amine as in A.l or a primary amine as in A.2) are prepared according to the following Schemes:A.2 B.1 C.2 wherein KBM, TPM, L', RX, Ry, Rz, and X are as defined in Formulae herein. Accordingly, in some embodiments, a compound C.l or C.2 is prepared by a process comprising contacting intermediate A.l or A.2 with intermediate B.l in the presence of a suitable couple agent and optionally in the presence of a suitable base. In some embodiments, B.l is first converted to an acyl chloride before coupling with the amine of intermediate A.1 or A.2.

[0263] In some embodiments, provided compounds (e.g., compounds wherein X is not a covalent bond and L1comprises a carbonyl moiety) are prepared according to the following Scheme:A.3 B.2 C.3 wherein KBM, TPM, L1RX, Ry, Rz, and X are as defined in Formulae herein. Accordingly, in some embodiments, a compound C.3 is prepared by a process comprising contacting intermediate A.3 with intermediate B.2 in the presence of a suitable couple agent and optionally in the presence of a suitable base.

[0264] In some embodiments, provided compounds (e.g., compounds wherein X is not a covalent bond) are prepared according to the following Scheme:wherein KBM, TPM, L1, Rx, Ry, Rz, and X are as defined in Formulae herein. Accordingly, in some embodiments, a compound C.4 is prepared by a process comprising contacting intermediate A.4 with intermediate B.3 in the presence of a suitable base.

[0265] In some embodiments, provided compounds (e.g., compounds wherein L1is bound to X via a carbonyl-containing moiety, such as an amide, urea, or carbamate) are prepared according to the following Schemes:A.5 B.5 C.6wherein KBM, TPM, Cy, L1, Rx, Ry, Rz, and X are as defined in Formulae herein; and LG is a suitable leaving group. Accordingly, in some embodiments, a compound C.5 or C.6 is prepared by a process comprising contacting intermediate A.5 with intermediate B.4 or B.5 in the presence of a suitable couple agent and optionally in the presence of a suitable base.Compositions

[0266] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.

[0267] In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-h-1, 1-h-2, II, ILa, Il-b, II-c, ILd, III, Ill-a, Ill-b, III-c, IILd, Ill-dl, Ill-e, IILel, III-f, III-fl, IILg, IILgl, IILh, IILhl, IV, IV-a, IV-b, V, V-a, VI, VII, VII-a, VII-al, VII-a2, VII-a3, VII-a4, VII-a5, VII-b, VII-bl, VII-b2, VII-b3, VII-b4, VII-b5, VII-e, VII-el, VILc2, VII-c3, VII-c4, VII-c5, VII-d, VII-d1, VII-d2, VII-d3, VII-d4, VII-d5, VII-e, VII-el, VII-e2, VII-e3, VII-e4, VII-e5, VIII, Vlll-a, IX, IX-a, and X)

[0268] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, Lh-1, I-h-2, II, ILa, Il-b, II-c, ILd, III, IILa, IILb, III-c, IILd, IILdl, IIL e, IILel, III-f, III-fl, IILg, IILgl, IILh, IILhl, IV, IV-a, IV-b, V-a, VI, VII, VII-a, VII-al, VII-a2, VII-a3, VII-a4, VII-a5, VII-b, VII-bl, VII-b2, VII-b3, VII-b4, VII-b5, VILc, VII-el, VILc2, VILc3, VILc4, VILc5, VII-d, VII-dl, VII-d2, VII-d3, VII-d4, VII-d5, VII-e, VII-el, VII-e2, VIL e3, VII-e4, VII-e5, VIII, VIII-a, IX, IX-a, and X) and further comprises a pharmaceutically acceptable carrier.

[0269] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fdlers, disintegrants, lubricants, glidants, anti -adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.

[0270] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0271] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose.In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0272] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example as described herein.

[0273] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition.Uses

[0274] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0275] In some embodiments, provided compounds are useful as covalent-induced drug conjugates, e.g., CIDCs targeting cells expressing mutant KRAS (e.g., KRASG12C).

[0276] In some embodiments, the present disclosure provides methods of inhibiting topoisomerase 1, comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C) in the presence of a topoisomerase 1 protein and / or topoisomerase 1-DNA complex. In some embodiments, contacting occurs in a cell. In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0277] In some embodiments, the present disclosure provides methods of releasing a topoisomerase 1 inhibitor payload (e.g., a topoisomerase 1 inhibitor) in a cell expressing anoncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C). In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0278] In some embodiments, the present disclosure provides methods of delivering a topoisomerase 1 inhibitor payload (e g., a topoisomerase 1 inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C). In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0279] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with KRAS (e.g., mutant KRAS, e.g., KRASG12C).

[0280] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with KRAS (e.g., mutant KRAS, e.g., KRASG12C), comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, provided methods are for treating cancer. In some embodiments, a cancer is characterized by a solid tumor. In some embodiments, a cancer is characterized by a hematologic tumor. In some embodiments, a cancer is selected from hematopoietic cancers, including leukemias, lymphomas (e.g., Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastrointestinal cancers and nervous system cancers, benign lesions such as papillomas, and the like. In some embodiments, provided methods are for treating a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.) In some embodiments, provided methods are for treating a disease, disorder, or condition selectedfrom acute myeloid leukemia (AML), neuroblastoma, non-small cell lung cancer (NCSLC), small cell lung cancer (SCLC), colorectal cancer, melanoma, and prostate cancer. In some embodiments, a cancer is non-small cell lung cancer or colorectal cancer. In some embodiments, a cancer is non-small cell lung cancer. In some embodiments, a cancer is colorectal cancer.

[0281] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0282] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and / or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).EXAMPLES

[0283] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.Preparation of IntermediatesPreparation of Intermediate A (Int-A)

[0284] Step 1: To a solution of 1 (4.9 g, 19.4 mmol, 1.0 equiv.) and 2 (3.9 g, 19.4 mmol, 1.0 equiv.) in THF (50 mL) was added DIEA (7.5 g, 58.3 mmol, 3.0 equiv.). The resulting mixture was stirred under N2 at rt for 1 hr. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and theresidue was purified by flash column chromatography on silica gel to afford 3 (3.7 g, 8.9 mmol, yield: 45.6%) as a white solid. LCMS(ESI)[M+1]+=416.2, tR =1.900 min.

[0285] Step 2: To a solution of 3 (3.7 g, 8.9 mmol, 1.0 equiv.) and DIEA (1.3 g, 10.6 mmol, 1.2 eq) in dioxane (37.0 mL) was added 4 (3.5 g, 22.2 mmol, 2.5 equiv.). The mixture was stirred under N2 at 80°C overnight. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with DCM, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford 5 (2.5 g, 4.6 mmol, yield: 51.7%) as a white solid. LCMS(ESI)[M+1]+=239.3, tR=0.822 min.

[0286] Step 3: To a stirred mixture of 5 (3.2 g, 5.9 mmol, 1.0 equiv.), 6 (3.2 g, 7.1 mmol, 1.2 equiv.) and K3PO4 (3.7 g, 17.8 mmol, 3.0 equiv.) in THF (32 mL) and water (8 mL) was added CataCXium (430.0 mg, 0.6 mmol, 0.1 equiv). The resulting mixture was stirred at 80°C for 2 h under N2. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The combined organic layer was dried over anhydrous Na2SO4 and purified by flash column chromatography on silica gel to afford 7 (3.5 g, 4.2 mmol, yield: 71.1%) as a white solid. LCMS(ESI)[M+1]+=829.7, tR=1.627 min.

[0287] Step 4: To a stirred mixture of 7 (3.5 g, 4.2 mmol, 1.0 equiv.) in DMF (35.0 mL) was added CsF (1.9 g, 12.6 mmol, 3.0 equiv.). The resulting mixture was stirred at r.t. for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with DCM three times. The organic layer was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to afford 8 (2.8 g, 4.16 mmol, yield: 98.5%) as a white solid. LCMS(ESI)[M+1]+=673.5, tR=1.191 min.

[0288] Step 5: To a stirred mixture of 8 (200 mg, 300 mmol, 1.0 equiv.) in DCM (10.0 mL) were added TMSOTf (0.1 mL, 300 µmmol, 1.0 equiv.) and HMDS (0.2 mL, 300 µmmol, 1.0 equiv.). The resulting mixture was stirred at 0°C for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with DCM three times. The organic layer was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to afford Int-A (50 mg, 90 µmmol yield: 29.3%) as a black solid. LCMS(ESI)[M+1]+=573.4, tR=0.520 min.Preparation of Intermediate B (Int-B)

[0289] Step 1: To a solution of B.7 (2.0 g, 7.8 mmol, 1.0 equiv.) in DMF was added NaH (560 mg, 7.8 mmol, 1.0 equiv.) at 0 °C under N2, and the mixture was stirred at 0 °C for 1 hr. Then, PMBCl (6.5 g, 23.4 mmol, 3.0 equiv.) was added at 0 °C. The mixture was stirred at rt for additional 3 hrs. LCMS showed the reaction was completed. The mixture was poured into water, extracted with ethyl acetate (EA) twice. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography to afford B.8 (2.8 g, 5.7 mmol, yield: 72.1%) as a white solid. LCMS(ESI) [M+l]+= 495.2.

[0290] Step 2: To a solution of B.1 (25.0 g, 75.7 mmol, 1.0 equiv.) and DIEA (24.4 g, 189.2 mmol, 2.5 equiv.) in THF (130.0 mL) was added B.2 (22.7 g, 113.5 mmol, 1.5 equiv.) at 0 °C. The mixture was warmed to room temperature and stirred for 1 hr. LCMS showed the reaction was completed. The mixture was cooled to 0 °C, poured into water (100 mL), and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with petroleum ether (PE): DCM = 10:1 and filtered. The filter cake was further triturated with PE: EA(20:l, 50 mLx 2) and filtered to afford B.3 (36.5 g, 73.8 mmol, yield: 97.5%) as white solid. LCMS (ESI) [M+l]+= 493.0.

[0291] Step 3: To a solution of B.3 (34.0 g, 68.7 mmol, 1.0 equiv.) in DMA (200.0 mL) was added CsF (49.9 g, 859.9 mmol, 12.5 equiv.). The reaction mixture was heated to 110 °C and stirred overnight. LCMS showed the reaction was completed. The mixture was cooled down and poured into water (500 ml), and extracted with EtOAc (200 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was triturated with DCM: PE=1:10 (300 ml) and filtered to give a crude product, which was further triturated with DCM: PE=1:10 (50 ml x 3) to afford B.4 (32.0 g, 67.0 mmol, 97.3%) as a white solid. LCMS (ESI) [M+l]+= 497.2.

[0292] Step 4: To a mixture of B.4 (10.0 g, 20.9 mmol, 1.0 equiv.) and B.5 (3.6 g, 31.3 mmol, 1.5 equiv.) in THF (100.0 mL) was added t-BuONa (3.0 g, 31.3 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed the reaction was completed. Then the reaction mixture was poured into water and extracted with EtOAc twice. The organic layer was washed with brine, dried over Na2SO4and concentrated to give a crude product, which was purified by flash chromatography eluting with DCM: MeOH =100:5 to afford B.6 (6.0 g, 10.4 mmol, yield: 50.0%) as a yellow solid. LCMS(ESI) [M+l]+= 574.2.

[0293] Step 5: To a solution of B.6 (1.1 g, 1.9 mmol, 1.0 equiv.) in THF (10.0 mL) was added dropwise i-PrMgCl. LiCl (1.3 mL, 2 M solution in THF, 2.5 mmol, 1.3 equiv.) at -70 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 30 min. To the mixture was added zinc chloride (1.0 mL, 2 M solution in THF, 2.5 mmol, 1.3 equiv.) at -10 °C, and the resulting reaction mixture was stirred for additional 1 h to give a solution A. To a solution of B.8 (950 mg, 1.9 mmol, 1.0 equiv.) and Pd(PPh₃)₂Cl₂ (280.7 mg, 0.4 mmol, 0.2 equiv.) in dioxane (9 mL) was added solution A under N2 atmosphere, and the mixture was stirred at 50 °C overnight. LCMS showed the reaction was completed. The mixture was poured into water (20 ml) and extracted with EtOAc(20 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography eluted with DCM: MeOH=10:1 to afford B.9 (1.3 g, 1.4 mmol, yield: 74.5%) as a yellow solid. LCMS(ESI) [M+1]+= 909.4.

[0294] To a mixture of B.9 (1.3 g, 1.4 mmol, 1.0 equiv.) in DCM (10.0 mL) was added TFA (3.0 mL). The mixture was stirred at r.t. for 2 h. LCMS showed the reaction was completed. The solvent was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography to afford Int-B (800.0 mg, 1.0 mmol, 69.1%) as a yellow solid. LCMS(ESI) [M+1]+= 808.6.Preparation of Intermediate C (Int-C)

[0295] Step I: To a stirred mixture of C.l (5.0 g, 12.6 mmol, 1.0 equiv.) in DCM (50.0 mL) was added SOCl₂ (3.0 g, 25.3 mmol, 2.0 equiv.), and the resulting mixture was stirred at room temperature for 16 hrs. LCMS showed the reaction was completed. The reaction mixture was concentrated to afford C.2 (crude) as a yellow oil. LCMS(ESI)[M+1]+=413.2.

[0296] Step 2: To a stirred mixture of C.2 (12.6 mmol, 1.0 equiv. from step 1) in DMSO (50.0 mL) was added NaN₃ (1.2 g, 18.9 mmol, 1.5 equiv.), and the resulting mixture was stirred at room temperature for 2 hrs. LCMS showed the reaction was completed. The reaction mixture was pouredinto water (50.0 mL) and filtered, and the cake was dried under reduced pressure to afford C.3 (4.0 g, 9.5 mmol, yield: 75.3%) as a yellow solid. LCMS(ESI)[M+1]+=420.2.

[0297] Step 3: To a stirred mixture of C.3 (4.0 g, 9.5 mmol, 1.0 equiv.) in DMF (40.0 mL) were added TBSC1 (2.1 g, 14.2 mmol, 1.5 equiv.) and DIEA (2.4 g, 19.0 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 2 hrs. LCMS showed the reaction was completed. The reaction mixture was poured into water (50.0 mL) and filtered, and the cake was dried under reduced pressure to afford C.4 (5.0 g, 9.3 mmol, yield: 98.3%) as a yellow solid. LCMS(ESI)[M+1]+=534.2.

[0298] Step 4: To a stirred solution of C.4 (5.0 g, 9.3 mmol, 1.0 equiv.) in MeOH (50.0 mL) was added Pd / C (1.0 g, 10%wt). The reaction was stirred under H2 at room temperature for 3 hrs. LCMS showed the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give Int-C (1.5 g, 2.9 mmol, yield: 31.9%) as a yellow solid. LCMS(ESI)[M+1]+=508.2.Preparation of Intermediate E (Int-E)

[0299] Step 1: To a solution of E.l (3.0 g, 7.7 mmol, 1.0 equiv.) and pyridine (Py) (18.2 mL, 224.8 mmol, 29.4 equiv.) in DCM (100.0 mL) was added BOC2O (2.2 g, 9.9 mmol, 1.3 equiv.), and the reaction was stirred at rt for 18 hrs. LCMS showed the reaction was completed. The reaction mixture was washed with 0.5N HCl and saturated NaHCO₃, dried over anhydrous Na2SO4and concentrated under reduced pressure to give E.2 (3.2 g, 6.5 mmol, yield: 84.9%) as a yellow solid. LCMS(ESI) [M+1]+= 493.2.1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 9.2 Hz, 1H), 8.10 (d,J= 2.2 Hz, 1H), 7.74 (dd, J= 9.1, 2.4 Hz, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 3.20 (d, J= 7.6 Hz, 2H), 1.93 - 1.81 (m, 2H), 1.54 (s, 9H), 1.29 (t, J= 7.6Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0300] Step 2: To a solution of E.2 (500.0 mg, 1.0 mmol, 1.0 equiv.), E.3 (637.1 mg, 3.0 mmol, 3.0 equiv.) and DMAP (124.0 mg, 1.0 mmol, 1.0 equiv.) in DCM (10.0 mL) was added EDCI (583.8 mg, 3.0 mmol, 3.0 equiv.), and the reaction mixture was stirred at rt for 3 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give E.4 (500.0 mg, 731.0 pmol, yield: 72.0%) as a white solid. LCMS(ESI) [M+l]+= 684.2.1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J= 9.2 Hz, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.83 (s, 1H), 7.72 (dd, J= 9.2, 2.4 Hz, 1H), 7.35 - 7.25 (m, 5H), 7.15 (s, 1H), 5.51 (s, 2H), 5.34 (d, J= 3.6Hz, 2H), 5.06 (t, J= 13.8 Hz, 2H), 4.07 (d, J= 6.2 Hz, 1H), 3.96 (d, J= 6.0 Hz, 1H), 3.20 (d, J= 7.6 Hz, 2H), 2.12 (dd, J= 7.4, 2.7 Hz, 2H), 1.54 (s, 9H), 1.28 (s, 3H), 0.88 (dd, J= 7.6, 4.9 Hz, 3H).

[0301] Step 3: To a solution of E.4 (600.0 mg, 878.0 pmol, 1.0 equiv.) in MeOH (50.0 mL) was added Pd / C (93.4 mg, 0.8 mmol, 10%), and the reaction mixture was stirred under H2 at rt for 5 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give Int-E (390.0 mg, 710.0 pmol, yield: 80.9%) as a yellow solid. LCMS(ESI) [M+l]+= 550.3.Preparation of Intermediate D (Int-D)

[0302] Step 1: At room temperature, D.l (24.0 g, 95.07 mmol, 1.0 equiv.) and DIEA (29.5 g, 228.2 mmol, 2.4 equiv.) were dissolved in DCM (280.0 mL) and cooled in a water bath. D.2 (21.2 g, 99.82 mmol, 1.5 equiv.) was added, then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 200 mL DCM, and washed with 100 mL of water and 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (PE / EA=90 / 10 to 75 / 25) to give D.3 (40.0 g, 93.40 mmol, 98.2%) as a yellow solid.

[0303] Step 2: To a solution of D.3 (20.0 g, 46.7 mmol, 1.0 equiv.) in dioxane (200.0 mL) were added D.4 (11.2 g, 70.1 mmol, 1.5 equiv.) and DIEA (12.1g, 93.4 mmol). The reaction solution was stirred at 80 °C for 12 hours and cooled to room temperature. 100 mL of water was added tothe reaction mixture, and the resulting solution was extracted with ethyl acetate, the organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain D.5 (11.3 g, 20.54 mmol, yield: 44.0%). LCMS (ESI) [M+H]+=551.5.

[0304] Step 3: To a mixture of D.5 (3.0 g, 5.4 mmol, 1.0 equiv.), D.6 (3.4 g, 6.5 mmol, 1.2 equiv.) and tripotassium phosphate (3.5 g, 16.3 mmol, 3.0 equiv.) in THF (24.0 mL) and H2O (6.0 mL) was added CataCXium A Pd G3 (0.4 g, 0.5 mmol, 0.1 equiv.) under N2. The mixture was stirred at 80 °C for 2 hours under N2. After completion, the mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column to afford D.7 (3.8 g, 4.2 mmol, yield: 77.5%) as a yellow solid. LCMS(ESI)[M+1]+=901.46.

[0305] Step 4: To a solution of D.7 (3.8 g, 4.2 mmol, 1.0 equiv.) in DMF (20.0 mL) was added CsF (6.4 g, 42.2 mmol, 10.0 equiv.). The reaction mixture was stirred at rt under N2 for 2 hours. LCMS showed reaction was completed. The reaction was purified by prep-HPLC to afford D.8 (3.0 g, 4.0 mmol, yield: 95.5%) as a brown solid. LCMS(ESI)[M+1]+=745.32.

[0306] Step 5: To a stirred mixture of D.8 (3.0 g, 4.03 mmol, 1.0 equiv.) in DCM (20.0 mL) were added TMSOTf (2.0 mL) and HMDS (4.0 mL). The resulting mixture was stirred under N2 at 0 °C for 1 hr. LCMS showed reaction was completed. After completion, the mixture was quenched with NaHCO₃(aq) and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated to afford Int-D (2.5 g, 3.9 mmol, yield: 96.3%) as a brown solid. LCMS(ESI)[M+1]+=645.27.Preparation of Intermediate F (Int-F)

[0307] Step 1: To a solution of BCl3(37.4 g, 319.6 mmol, 1.3 equiv.) in DCE (1.0 L) was added F.l (50.0 g, 399.5 mmol, 1.0 equiv.) under 0 °C, and the reaction was stirred at 0 °C for 30min. Then were added F.2 (29.8 mL, 471.4 mmol 1.2 equiv.) and AlCl₃ (69.3 g, 519.4 mmol, 1.3 equiv.), and the reaction was stirred at 75 °C for 16 hrs. TLC showed the reaction was completed. The reaction mixture was cooled 0 °C, then 200 mL 2N HCl slowly was added, and the mixture was extracted with DCM three times. The combined organic layer was washed with water, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by prep-HPLC to give F.3 (16.7 g, 83.1 mmol, yield: 20.8 %) as a yellow solid. LCMS(ESI) [M+l]+= 202.0. ’HNMR (400 MHz, DMSO-d6) 87.68 (d, J= 8.7 Hz, 1H), 7.30 (s, 2H), 6.53 (d, J= 12.5 Hz, 1H), 4.97 (s, 2H), 2.10 (s, 3H).

[0308] Step 2: To a solution of F.3 (5.0 g, 24.8 mmol, 1.0 equiv.) and F.4 (7.8 g, 29.8 mmol, 1.2 equiv.) in toluene (50.0 mL) was addedPTSA(210 mg, 1.2 mmol, 0.05 equiv.), and the reaction was stirred at 95 °C for 18 hr. LCMS showed the reaction was completed. The solution was filtered and the filter cake was washed with EAto give Int-F (9.7 g, 22.6 mmol, 91.2%) as a yellow solid. LCMS(ESI)[M+1]+=429.2.Preparation of Intermediate G (Int-G)G.2Int-G

[0309] Step 1: To a solution of G.l (5.0 g, 21.3 mmol, 1.0 equiv.) in THF (50.0 mL) was added G.2 (4.6 g, 32.0 mmol, 1.5 equiv.). The mixture was stirred at rt for 2 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography to afford G.3 (6.5 g, 19.7 mmol, yield: 92.2%) as a colorless oil. LCMS(ESI)[M+1]+=331.

[0310] Step 2: To a solution of G.3 (6.5 g, 19.7 mmol, 1.0 equiv.) in THF (70.0 mL) was added NaH (1.6 g, 39.4 mmol, 2.0 equiv.) at 0 °C, the mixture was stirred at 0 °C for 1 h. Then iodomethane (3.194 mL, 39.357 mmol, 2.0 equiv.) was added. The mixture was stirred at rt for 2h. LCMS showed the reaction was completed. The reaction mixture was quenched with water and extracted with EA (50 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography to give G.4 (5.3 g, 15.4 mmol, yield: 78.22%) as a white solid. LCMS(ESI)[M+1]+=345.

[0311] Step 3: To a solution of G.4 (5.3 g, 15.4 mmol, 1.0 equiv.) in MeOH (30.0 mL) was added K2CO3(15.0 mL, 20% in H2O). The mixture was stirred at 40 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by prep-HPLC to afford Int-G (3.8 g, 15.3 mmol, yield: 99.4%) as a white solid. LCMS(ESI)[M+1]+=249.Preparation of Intermediate H (Int-H)

[0312] Step 1: To a solution of H.l (5.0 g, 24.9 mmol, 1.0 equiv.) in THF (30.0 mL) were added K2CO3(6.9 g, 49.9 mmol, 2.0 equiv.) and CbzCl (4.3 g, 24.9 mmol, 1.0 equiv.) at 0°C, and the reaction was stirred at 25 °C for 16 hrs. The mixture poured into water (60.0 mL) and extracted with EA (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EA = 3: 1) to give H.2 (6.5 g, 19.4 mmol, yield: 85.9%) as a white solid. LCMS(ESI)[M+1]+=335.1.

[0313] Step 2: To a solution of H.2 (6.0 g, 17.9 mmol, 1.0 equiv.) in THF (50.0 mL) was added NaH (0.8 g, 35.9 mmol, 2.0 equiv.) at 0 °C, and the reaction was stirred at 0 °C for 30 mins. CH3I (2.9 mL, 35.9 mmol, 2.0 equiv.) in THF (5.0 mL) was added. The reaction was stirred at 25 °C for 16 hrs. LCMS showed the reaction was completed. The mixture poured into water (60.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EA = 3: 1) to give H.3 (5.0 g, 14.3 mmol, yield: 79.9%) as a white solid. LCMS(ESI)[M+1]+=349.4.

[0314] Step 3: To a solution of H.3 (6.0 g, 17.2 mmol, 1.0 equiv.) in MeOH (50.0 mL) was added Pd / C 10% (1.0 g, 9.4 mmol). The mixture was degassed for three times under H2atmosphere and stirred at room temperature for 16 hrs under a H2 balloon. The mixture was filtered through Celite® and the filtrate was concentrated to give Int-H (3.5 g, 16.3 mmol, yield: 94.8%) as a white solid. LCMS(ESI)[M+1]+=215.3.Preparation of Intermediate J (Int- J)

[0315] Step 1: To a mixture of J.l (5.0 g, 20.2 mmol, 1.0 equiv.) and B0CNH2 (2.8 g, 24.2 mmol, 1.2 equiv.) in toluene (50.0 mL) were added X-Phos (1.9 g, 4.0 mmol, 0.2 equiv), Cs₂CO₃ (13.1 g, 40.3 mmol, 2.0 equiv.), and Pdzldba) (0.9 g, 1.0 mmol, 0.05 equiv.). The mixture was degassed for three times under N2 atmosphere and stirred at 90 °C for 12 hours. The reaction mixture was diluted with water (50.0 mL), extracted with EA (50.0 mL), dried over anhydrous Na2SO4and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EA= 20: 1-10:1) to give J.l (5.1 g, 17.9 mmol, yield: 89.5%) as a yellow solid.

[0316] Step 2: A mixture of J.l (5.1 g, 17.9 mmol, 1.0 equiv.), iron powder (4.0 g, 71.8 mmol, 4.0 equiv.), and NH4Cl (1.5 g, 28.7 mmol, 1.6 equiv.) in EtOH (60.0 mL) and water (15.0 mL) was stirred at 80 °C for 12 hrs. TLC (PE: EA= 4:1) indicated the reaction was complete. The reaction was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EA= 4:1) to give J.3 (2.1 g, 8.3 mmol, yield: 45.2%) as a yellow oil. LCMS(ESI)[M+1]+=255.1.

[0317] Step 3: To a solution of J.3 (2.0 g, 7.8 mmol, 1.0 equiv.) in anhydrous toluene (20.0 mL) were added TsOH (0.1 g, 0.7 mmol, 0.1 equiv.) and J.4 (1.7 g, 6.5 mmol, 1.2 equiv.). The mixture was degassed for three times under N2 atmosphere and stirred at 110 °C for 2 hours. Thereaction mixture was cooled to r.t and filtered. The solid was washed with tert-butyl methyl ether and dried under reduced pressure to give J.5 (2.8 g, 5.8 mmol, yield: 90.1%) as a yellow solid. LCMS(ESI)[M+1]+=482.2.

[0318] Step 4: To a stirred mixture of J.5 (1.0 g, 2.1 mmol, 1.0 equiv.) in MeOH (90.0 mL) was added a solution of FeSO₄·7H₂O (0.3 g) and H2SO4(0.07 mL) in water (1.0 mL). The reaction was heated to 65 °C while H2O2(6.0 mL) was added over 30 min. After stirring at 65 °C for another 30 min, the reaction was cooled to 25 °C, the resulting solid was filtered and dried to give Int-J (190 mg, 0.4 mmol, yield: 17.9%) as a yellow solid. LCMS(ESI)[M+1]+= 512.4.

[0319] Step 1: To a stirred mixture of K.1 (15.0 g, 41.2 mmol, 1.0 equiv.) in MeOH / H2O (450.0 mL / 375.0 mL) was added dropwise H2SO4(96%, 195 mL) at 0 °C, Then FeSO47H2O (11.5 g, 41.2 mmol, 1.0 equiv.) was added. The resulting solution was cooled at -10 °C and then H2O2(30%, 36 mL) was added. The mixture was stirred at r.t for 16 hrs. 280 mL of H2O was added, the precipitate was filtered to give K.2 (13.0 g, 32.9 mmol, yield: 80.1%) as a light yellow solid. LCMS(ESI)[M+1]+=395.1.

[0320] Step 2: To a stirred mixture of K.2 (10.0 g, 26.3 mmol, 1.0 equiv.) in DMF (100.0 mL) were added K2CO3(10.9 g, 78.8 mmol, 3.0 equiv.) and K3 (6.4 g, 28.9 mmol, 1 equiv.). The resulting mixture was stirred at r.t for 16 hrs. The reaction mixture was poured into H2O (50 mL) and filtered. The cake was triturated with EA and filtered to give K.4 (4.5 g, 8.6 mmol, yield: 32.9%) as a light yellow solid. LCMS(ESI)[M+1]+=535.3.

[0321] Step 3: To a stirred mixture of K.4 (6.6 g, 12.3 mmol, 1.0 equiv.) in DCM / DMSO (60.0 mL / 600.0 mL) was added DMP (7.8 g, 18.5 mmol, 1.5 equiv.) and the resulting mixturewas stirred at r.t for 2 hrs. LCMS showed the reaction was complete. The mixture was poured into H2O (500 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (PE / EA (10% DCM) = 1: 2) to give Int-K (4.8 g, 9.1 mmol, yield: 73.4 %) as a light yellow solid. LCMS(ESI)[M+1]+=533.3.Preparation of Intermediate L (Int-L)

[0322] Step 1: To a solution of L.l (200.0 mg, 466.0 pmol, 1.0 equiv.) in DMSO (2.0 mL) was added NaNj (45.4 mg, 700.0 pmol, 1.5 equiv.). The mixture was stirred at rt for 2 h. LCMS showed the reaction was completed. The reaction mixture was poured into water and filtered. The filter cake was dried in vacuo to give L.2 (180.0 mg, 413.0 pmol, yield: 88.6%) as a solid. LCMS(ESI)[M+1]+= 436.3.

[0323] Step 2: To a solution of L.2 (180.0 mg, 413.0 pmol, 1.0 equiv.) in toluene (6.0 mL) was added P(OEt)s (171.7 mg, 1.0 mmol, 2.5 equiv.). The mixture was stirred at 100 °C for 4 h. Then 4M HCl / MEOH (3.0 mL) was added. The mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered. The filter cake was dried in vacuo to give L.3 (150.0 mg, 366.0 pmol, yield: 88.6%) as a solid. LCMS(ESI)[M+1]+= 410.4.

[0324] Step 3: To a solution of L.3 (700.0 mg, 1.7 mmol, 1.0 equiv.) in DMF (7.0 mL) were added BOC2O (746.3 mg, 3.4 mmol, 2.0 equiv.), TEA (0.7 mL, 5.1 mmol, 3.0 equiv.) and DMAP (208.8 mg, 1.7 mmol, 1.0 equiv.). The mixture was stirred at rt for 16 h. LCMS showed the reaction was completed. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reducedpressure to give a crude product which was purified by column chromatography on silica gel to give Int-L (750.0 mg, 1.4 mmol, yield: 86.0%) as a yellow solid. LCMS(ESI)[M+1]+= 510.4. Preparation of Intermediate M (Int-M)

[0325] Step 1: To a solution ofM.l (80.0 g, 204.0 mmol, 1.0 equiv.) and K₂CO₃ (56.3 g, 408.0 mmol, 2.0 equiv.) in DMF (800 mL) and DMSO (800 mL) was added L-2 (57.3 g, 244.8 mmol, 1.2 equiv.) at 25°C. The reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with aqueous NH4Cl and extracted with EA, the organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to give 7.7 g of racemic compound. The racemic compound was further purified by SFC separation to give a first eluting isomer M.3-1 (3.0 g, 4.9 mmol, 1.9 %) and a second eluting isomer M.3-2 (3.0 g, 4.9 mmol, 1.9 %) as a colorless soild. LCMS(ESI)[M+l]+= 547.3.1H NMR (400 MHz, DMSO-6) 58.08 (d, J= 9.2 Hz, 1H), 7.51 (dd, J= 9.2, 2.6 Hz, 1H), 7.35 (d, J= 2.6 Hz, 1H), 7.26 (s, 1H), 6.49 (s, 1H), 6.14 (s, 1H), 5.84 (s, 1H), 5.49 (q, J= 6.2 Hz, 1H), 5.42 (s, 2H), 5.27 (s, 2H), 3.10 (dp, J= 28.0, 7.5 Hz, 2H), 1.86 (hept, J = 7.2 Hz, 2H), 1.55 (d, J= 6.3 Hz, 3H), 1.47 (s, 9H), 1.26 (t, J= 7.6 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). SFC separation was performed according to the following method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPakAD, 250*30 mm I. D., 5 pm; Mobile phase: A for CO2 and B for MeOH; Gradient: B 50%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm; Run time: 15.3 min; Cycletime: 15.3 min; Injection volume: 2.5 mL; Number of injection needles: 30; Eluted time: 6h. M.3-1 Retention time: 2.762 min; M.3-2 Retention time: 3.689 min.

[0326] Step 2: To a solution of M.3-1 (3.0 g, 5.5 mmol, 1.0 equiv.) in DCM (30 mL) was added TFA (10 mL) at 25 °C, and the reaction was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The solvent was concentrated in vacuo to give crude Int-M-1 (2.6 g, 5.3 mmol, 96.6%) which was used to the next step without further purification. LCMS(ESI)[M+ 1 ]+= 491.4.

[0327] Step 3: To a solution of M.3-2 (3.0 g, 5.5 mmol, 1.0 equiv.) in DCM (30 mL) was added TFA (10 mL) at 25 °C, and the reaction was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The solvent was concentrated in vacuo to give crude Int-M-2 (2.6 g, 5.3 mmol, 96.6%) which was used to the next step without further purification. LCMS(ESI)[M+l]+= 491.2.Preparation of Intermediate N (Int-N)

[0328] Step 1: To a solution of N.1 (10.0 g, 39.6 mmol, 1.0 equiv.) in THF (100.0 mL) was added N.2 (9.4 g, 41.6 mmol, 1.2 equiv). The mixture was cooled to 0 °C, and DIEA (15.4 g, 118.8 mmol, 3.0 equiv.) was added to the mixture. The resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford N.3 (17.0 g, 38.5 mmol, yield: 97.3%) as a yellow solid. LCMS (ESI) [M+l]+= 442.0.

[0329] Step 2: To a solution of N.3 (8.2 g, 18.6 mmol, 1.0 equiv.) in dioxane (90.0 mL) were added N.4 (3.9 g, 24.2 mmol, 1.3 equiv.) and DIEA (4.8 g, 37.2 mmol, 2.0 equiv.) at 0 °C. The mixture was stirred at 80 °C for 48 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash silica chromatography to give N.5 (8.1 g, 14.4 mmol, yield: 77.3%) as a yellow solid. LCMS (ESI) [M+l]+= 563.9.

[0330] Step 3: To a solution of N.5 (8.1 g, 14.4 mmol, 1.0 equiv.) in THF (80.0 mL) and H2O (16.0 mL) were added N.6 (8.8 g, 17.2 mmol, 1.2 equiv.), CataCXium A Pd G3 (1.1 g, 1.4 mmol, 0.1 equiv.), and K3PO4 (9.1 g, 43.1 mmol, 3.0 equiv.). The mixture was stirred at 80 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was poured into water, and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford N.7 (10.4 g, 11.4 mmol, yield: 79.2%) as a yellow solid. LCMS (ESI) [M+l]+= 914.5.

[0331] Step 4: To a solution of N.7 (5.0 g, 5.5 mmol, 1.0 equiv.) in DMF (10.0 mL) was added CsF (8.3 g, 54.7 mmol, 10.0 equiv.), and the mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was poured into water, and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford N.8 (4.0 g, 5.3 mmol, yield: 96.5%) as a yellow solid. LCMS (ESI) [M+l]+= 758.6.

[0332] Step 5: To a solution of N.8 (1.0 g, 1.3 mmol, 1.0 equiv.) in DCM (2.0 mL) were added TMSOTf (0.6 mL) and HMDS (1.2 mL) and the mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into saturated sodium bicarbonate aqueous and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated to give Int-N (800.0 mg, 1.2 mmol, yield: 92.2%) as a brown solid. LCMS (ESI) [M+l]+= 658.5.Preparation of Intermediate P (Int-P)

[0333] Step 1: To a solution of P.l (10.0 g, 39.6 mmol, 1.0 equiv.) in THF (100.0 mL) was added P.2 (7.9 g, 39.6 mmol, 1.0 equiv.). The mixture was cooled to 0 °C and DIEA (15.4 g, 118.8 mmol, 3.0 equiv.) was added. The resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over NazSCU and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford P.3 (16.0 g, 38.4 mmol, yield: 97.0%) as ayellow solid. LCMS (ESI) [M+l]+= 418.0.

[0334] Step2: To a solution of P.3 (16.0 g, 38.4 mmol, 1.0 equiv.) in dioxane (200.0 mL) were added P.4 (7.3 g, 46.1 mmol, 1.2 equiv.) and DIEA (14.9 g, 115.3 mmol, 3.0 equiv.) at 0 °C. The mixture was stirred at 80 °C for 48 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous NazSCU and concentrated under vacuum. The residue was purified by flash silica chromatography to give P.5 (16.0 g, 29.7 mmol, yield: 77.2%) as a yellow solid. LCMS (ESI) [M+l]+= 539.4.

[0335] Step 3: To a solution of P.5 (15.0 g, 27.8 mmol, 1.0 equiv.) in THF (150.0 mL) and H2O (40.0 mL) were added P.6 (17.1 g, 33.4 mmol, 1.2 equiv.), CataCXium APd G3 (2.0 g, 2.8 mmol, 0.1 equiv.) and K3PO4 (17.7 g, 83.5 mmol, 3.0 equiv.). The mixture was stirred at 80 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered. The filtrate waspoured into water and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford P.7 (22.0 g, 24.7 mmol, yield: 88.9%) as a yellow solid. LCMS (ESI) [M+l]+= 889.5.

[0336] Step 4: To a solution of P.7 (1.0 g, 1.1 mmol, 1.0 equiv.) in DMF (10.0 mL) was added CsF (1.7 g, 11.3 mmol, 10.0 equiv.), and the mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered. The filtrate was poured into water and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford P.8 (800.0 mg, 1.1 mmol, yield: 97.1%) as a yellow solid. LCMS (ESI) [M+l]+= 733.6.

[0337] Step 5: To a solution of P.8 (1.0 g, 1.4 mmol, 1.0 equiv.) in DCM (10.0 mL) were added TMSOTf (2.0 mL) and HMDS (4.0 mL). The mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated to give Int-P (600 mg, 949.4 pmol, yield: 69.5%) as a brown solid. LCMS (ESI) [M+l]+= 633.5.Preparation of Intermediate Q (Int-Q)

[0338] Step 1: To a solution of Q.l (20.0 g, 85.1 mmol, 1.0 equiv.) in DCM (200.0 mL) were added BOC2O (24.1 g, 1.1 mol, 1.3 equiv.) and DMAP (1.0 g, 8.5 mmol, 0.1 equiv.). The mixture was stirred at RT for 16 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give Q.2 (20.0 g, 59.6 mmol, yield: 70.1%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 14.0 Hz, 1H), 1.50 (s, 9H).

[0339] Step 2: To a solution of Q.2 (30.0 g, 68.9 mmol, 1.0 equiv.), Na₂CO₃ (21.9 g, 206.7 mmol, 3.0 equiv.) and Pd(dppf)C12 (2.5 g, 3.4 mmol, 0.05 equiv.) in dioxane (300.0 mL) and H2O (30.0 mL) was added Q.3 (15.9 g, 103.3 mmol, 1.5 equiv.) under N2. The mixture was stirred at 100 °C for 16 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give Q.4 (10.0 g, 26.1 mmol, yield: 37.9%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.22 (d, J= 8.5 Hz, 1H), 7.02 (dd, J = 17.2, 11.0 Hz, 1H), 6.02 (d, J = 17.4 Hz, 1H), 5.85 (d, J = 17.1 Hz, 1H), 1.49 (s, 10H).

[0340] Step 3: To a solution of Q.4 (20.0 g, 52.3 mmol, 1.0 equiv.) in dioxane (200.0 mL) and H2O (20.0 mL) were added NaIO₄ (33.5 g, 156.9 mmol, 3.0 equiv.) and K₂OsO₄ (1.9 g, 5.2 mmol, 0.1 equiv.). The mixture was stirred at RT for 2 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give Q.5 (12.0 g, 42.2 mmol, yield: 80.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.02 (s, 1H), 8.87 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 14.7 Hz, 1H), 1.52 (s, 9H).

[0341] Step 4: To a solution of Q.5 (300.0 mg, 1.0 mmol, 1.0 equiv.) in EtOH (10.0 mL) and H2O (2.0 mL) were added iron powder (176.8 mg, 3.1 mmol, 3.0 equiv.) and NH4Cl (112.9 mg, 2.1 mmol, 2.0 equiv). The mixture was stirred at 70 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered, TEA was added to the filtrate to adjust the pH to 8-9, and the solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give Q.6 (114.0 mg, 450.0 pmol, yield: 42.4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.80 (s, 1H), 7.69 (d, J = 13.6 Hz, 1H), 7.21 (d, J = 9.8 Hz, 1H), 5.27 (s, 2H), 1.47 (s, 9H).

[0342] Step 5: To a solution of Q.6 (300.0 mg, 1.1 mmol, 1.0 equiv.) and DIEA (457.5 mg, 3.5 mmol, 3.0 equiv.) in dioxane (5.0 mL) was added triphosgene (140.0 mg, 470.0 pmol, 0.4 equiv.) at 0 °C. The mixture was stirred at 100 °C for 10 min. Then, Q.7 (609.6 mg, 3.5 mmol, 3.0 equiv.) was added. The resulting reaction mixture was stirred at 100 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give Q.8 (60.0 mg, 130.0 pmol, yield: 11.2%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.88 (s, 1H), 9.60 (s, 1H), 8.14 (d, J = 6.7 Hz, 1H), 7.98 (d, J = 13.3 Hz, 1H), 6.14 (s, 1H), 5.85 (s, 1H), 5.53 (q, J = 6.4 Hz, 1H), 1.49 (s, 9H), 1.45 (s, 9H), 1.38 (d, J = 6.5 Hz, 3H).

[0343] Step 6: To a solution of Q.8 (1.7 g, 3.7 mmol, 1.0 equiv.) and Q.9 (1.3 g, 4.9 mmol, 1.3 equiv.) in toluene (20.0 mL) were added PPTS (1.2 g, 4.8 mmol, 1.3 equiv.) and silica gel (2.0g). The mixture was stirred at 120 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 260 mg of racemate (Int-Q), which was further purified by SFC to give a first eluting isomer Int-Q-1 (120.0 mg, 430.0 pmol, yield: 5.5%) and a second eluting isomer Int-Q-2 (120.0 mg, 430.0 pmol, yield: 5.5%), both as a yellow solid. LCMS (ESI) [M+l]+= 580.3. SFC was performed using the following conditions: Instruments: Shimadzu E-UC03; Injection Volume: 5 uL; Column temperature: 40 °C; ABPR: 10 MPa; Mobile phase: A:CO2; B: MeOH. Int-Q-1, retention time: 2.877 min; Int-Q-2, retention time: 3.711 min.Preparation of Intermediate R (Int-R)

[0344] Step 1: To a solution of R.l (40 g, 399.3 mmol, 1.0 equiv.) in 1-butanol (3200 mL) was added CbzCl (68.8 g, 403.3 mmol, 1.1 equiv.) over 90 min at 0-10 °C. The reaction mixture was stirred at 0-10 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between 25% aqueous NaOH (250 mL) and toluene (300 mL). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to give R.2 (70.0 g, 298.7 mmol, 74.8%) as a colorless oil. ’H NMR (400 MHz, DMSO-d6) 57.35 (d, J= 2.0 Hz, 5H), 5.07 (s, 2H), 3.81 (d, J= 12.6 Hz, 2H), 2.82 (d, J= 11.7 Hz, 2H), 2.59 - 2.46 (m, 3H), 2.40 (d, J= 28.2 Hz, 1H), 0.94 (d, J= 6.2 Hz, 3H).

[0345] Step2: To a solution of R.3 (56.4 g, 170.7 mmol, 1.0 equiv.) and TEA (71.0 mL, 512.1 mmol, 3.0 equiv.) in THF (500 mL) was added R.2 (40.0 g, 170.7 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at RT for 1.5 h. The reaction was monitored by LCMS. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mLx 3). The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was triturated with PE: DCM (10:1) and filtered. The filter cake was further triturated with PE: EA (20:1) and filtered to afford R.4 (70.0 g, 132.5 mmol, 77.6%) as a white solid. LCMS (ESI) [M+l]+= 529.2.

[0346] Step 3: To a solution of R.4 (70.0 g, 132.5 mmol, 1.0 equiv.) in DMA (300 mL) was added potassium fluoride (153.9 g, 2650.4 mmol, 20.0 equiv.) at 25 °C under N2. The mixture was stirred at 120 °C for 16 hours. TLC indicated the reaction was complete. The reaction was quenched with water and extracted with EA three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give R.5 (65.0 g, 97.8 mmol, 74.3%) as a yellow oil. LCMS (ESI) [M+l]+= 511.3.

[0347] Step 4: To a solution of R.5 (65.0 g, 127.0 mmol, 1.0 equiv.) and R.6 (20.2 g, 127.0 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (10 mL) at -10 °C was added t-BuONa (12.2 g, 127.0 mmol, 1.0 equiv.) at -10 °C. The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was poured into a saturated aqueous NH4Cl solution and extracted with EA three times. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 20-30% EtOAc in petroleum ether to afford R.7 (40.0 g, 55.3 mmol, 43.5%) as a colorless oil. LCMS (ESI) [M+l]+= 652.3.

[0348] Step 5: To a mixture of R.7 (15.0 g, 23.0 mmol, 1.0 equiv), R.8 (15.5 g, 34.5 mmol, 1.5 equiv.), K3PO4 (14.6 g, 69.1 mmol, 3.0 equiv.) in dioxane (200 mL) and toluene (200 mL) were added potassium fluoride (4.0 g 69.1 mmol, 3.0 equiv.) and Pd(DPEphos)Ch (3.3 g, 4.6 mmol, 0.2 equiv.). The reaction mixture was heated to 90 °C under nitrogen and stirred for 16 hours. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous MgSCU, filtered, and concentrated. The crude product was purified by flash silica gel chromatography, eluting with a gradient of 0 to 10% MeOH in DCM to afford R.9 (10.0 g, 11.6 mmol, 50.3%) as ayellow solid. LCMS (ESI) [M+l]+= 862.6.

[0349] Step 6: To a solution of R.9 (15.0 g, 23.1 mmol, 1.0 equiv.) in methanol (100 mL) was added Pd / C (5.0 g, 11.60 mmol). The mixture was stirred at 25 °C for 16 h under a H2atmosphere (25 psi). LCMS showed the reaction was complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with a gradient of 0 to 10% MeOH in DCM to give Int-R (10 g) which was further purified by SFC to give a first eluting rotamer Int-R-1 (3.9 g, 6.3 mmol, 30.9%) and a second eluting rotamer Int-R-2 (4.0 g, 6.3 mmol, 31.7%) as a yellow solid. Int-R-1: LCMS (ESI) [M+l]+= 728.5. Int-R-2: LCMS (ESI) [M+l]+= 728.5. SFC separation was performed according to the following method: Column: CHIRALPAK IE (IE00CE-BS027); Column size: 0.46 cm I. D. x 25 cm L; Injection: 3 pL; Mobile phase: MeOH / DEA= 100 / 0.1 (V / V); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 35 °C; HPLC equipment: Shimadzu LC-20AD CP-HPLC-05. Int-R-1 Retention time: 4.526 min; Int-R-2 Retention time: 6.015 min.Preparation of Intermediate S (Int-S)

[0350] Step 1: To a solution of S.l (32.0 g, 96.9 mmol, 1.0 equiv.) in THF (250.0 mL) was added DIEA (31.3 g, 242.2 mmol, 2.5 equiv.), the mixture was cooled to 0 °C, then S.2 (25.0 g, 96.9 mmol, 1.0 equiv.) was added, and the resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to 0 °C, poured into water and extracted with EA three times. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to afford S.3 (55.0 g, 95.4 mmol, 98.5%) as a yellow solid. LCMS(ESI)[M+1]+= 551.3.

[0351] Step 2: To a solution of S.3 (55.0 g, 99.4 mmol, 1.0 equiv.) in DMA (500.0 mL) was added potassium fluoride (69.3 g, 1193.0 mmol, 12.0 equiv.), and the mixture was stirred at 120 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was cooled down, poured into water and extracted with EA. The organic layer was washed with brine, dried overNa2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 28% ethyl acetate in petroleum ether to afford S.4 (52.0 g, 96.9 mmol, 97.4%) as a yellow solid. LCMS(ESI)[M+1]+= 536.2.

[0352] Step 3: To a solution of S.4 (50.0 g, 85.7 mmol, 1.0 equiv.) and S.5 (13.6 g, 85.7 mmol, 1.0 equiv.) in 2-MeTHF (500.0 mL) was added t-BuONa (12.3 g, 128.5 mmol, 1.5 equiv.) at -10 °C, and the mixture was stirred at -10 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into NH4Cl aqueous and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 70% ethyl acetate in petroleum ether to afford S.6 (38.5 g, 57.0 mmol, 66.5%) as yellow oil. LCMS(ESI)[M+1] ’ = 675.3.

[0353] Step 4: To a solution of S.6 (10.0 g, 14.8 mmol, 1.0 equiv.) in toluene (150.0 mL) and 1,4-dioxane (150.0 mL) was added S.7 (9.0 g, 22.2 mmol, 1.5 equiv.), Pd(DPEphos)C12 (2.1 g, 2.9 mmol, 0.2 equiv.), K3PO4 (9.4 g, 44.4 mmol, 3.0 equiv.) and potassium fluoride (2.6 g, 44.4 mmol, 3.0 equiv.). The mixture was stirred at 90 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was filtered, the filtrate was poured into water, and extracted with EA three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 6% methanol in DCM to give a crude product which was further purified by reversed phase CombiFlash® (40% MeOH in H2O (0.1% HCOOH)) to afford S.8 (6.1 g, 6.9 mmol, 46.5%) as a yellow solid. LCMS(ESI)[M+1]+= 887.4.

[0354] Step 5: To a solution of S.8 (16.0 g, 13.4 mmol) in MeOH (120.0 mL) and THF (20.0 mL) was added Pd / C (8.0 g), and the suspension was stirred at room temperature for 6 hours under H2atmosphere. LCMS showed the reaction was complete. The reaction mixture was filtered through celite and filtrate was concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 10% methanol in DCM to give 11 g of Int-S as a mixture of atropisomers which was further purified by SFC separation to afford a first eluting isomer Int-S-1 (3.7 g, 4.9 mmol, 36.2%) as a yellow solid and a second eluting isomer Int-S-2 (3.9 g, 5.2 mmol, 38.9%) as a yellow solid. Int-S-1: LCMS(ESI)[M+1]+= 753.2; Int-S-2: LCMS(ESI)[M+1]+= 753.2. SFC was performed using the following conditions: Column: CHIRALPAK IA (IA00CE-VD015); Column size: 0.46 cm I. D. x 25 cm L; Injection: 0.5 μl; Mobile phase: EtOH / TFADEA= 100 / 0.1 / 0.03 (V / V / V); Flow rate: 1.0 ml / min; Wave length: UV 254 nm;Temperature: 35 °C; HPLC equipment: Shimadzu LC-20AT CP-HPLC-09. Int-S-1, retention time: 8.352 min; Int-S-2, retention time: 18.661 min.Preparation of Intermediate T (Int-T)Int-T-1 and Int-T-2

[0355] Step 1: To a solution of T.1 (10.0 g, 20.4 mmol, 1.0 equiv.) and T.2 (3.2 g, 20.4 mmol, 1.0 equiv.) in THF (100.0 mL) was added t-BuONa (3.9 g, 40.8 mmol, 2.0 equiv.) at -10 °C under an N2 atmosphere. The reaction was stirred at -10 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into a saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM: MeOH = 15:1) to afford T.3 (8.0 g, 12.7 mmol, yield: 62.5%) as a yellow solid. LCMS (ESI) [M+l]+= 628.2 / 630.2.

[0356] Step 2: To a solution of T.3 (8.0 g, 12.7 mmol, 1.0 equiv.) in DCM (50.0 mL) was added TFA (15.0 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EA and concentrated under reduced pressure. The residue was basified with sat. Na2CO3and extracted with EA. The organic layer was washed with brine and water, dried over anhydrous Na2SO4and concentrated to dryness to give T.4 (6.0 g, 11.3 mmol, yield: 89.0%) as a white solid. LCMS (ESI) [M+l]+= 528.2 / 530.2.

[0357] Step 3: To a mixture of T.4 (6.0 g, 11.3 mmol, 1.0 equiv.), T.5 (9.1 g, 22.6 mmol, 2.0 equiv.), K3PO4 (7.2 g, 33.9 mmol, 3.0 equiv), KF (2.0 g, 33.9 mmol, 3.0 equiv), and Pd(DPEphos)Ch (1.6 g, 2.3 mmol, 0.2 equiv.) in a flask was added toluene (160.0 mL). The mixture was evacuated and backfilled with N2 several times. The reaction mixture was stirred at 80 °C for 5 hours. LCMS showed the reaction was complete. The mixture was diluted with EA and washed with water. The organic layer was concentrated and the residue was purified by reverse-phase flash column chromatography (H2O / ACN + 0.1% HCOOH) to give Int-T (1.5 g, 2.0 mmol, yield: 17.7%) as a yellow oil. LCMS (ESI) [M+l]+= 740.2. It was then separated by SFC to give a first eluting isomer Int-T-1 (420 mg, 56.8 pmol, yield: 5.0%) and a second eluting isomer Int-T-2 (450 mg, 60.8 pmol, yield: 5.4%), both as a yellow solid. SFC was performed using the following conditions: Column: CHIRALPAK IE-3 (IE30CE-XB011); Column size: 0.46 cm I. D. x 25 cm L; Injection: 5 μl; Mobile phase: EtOH / ACN / DEA / TFA=70 / 30 / 0.1 / 0.05(V / V / V / V); Flow rate: 1.0 ml / min; Wave length: UV 254 nm; Temperature: 35 °C; HPLC equipment: Shimadzu LC-20AD. Int-T-1: tR= 5.904 min, Int-T-2: tR= 18.781 min.Preparation of Intermediate U (Int-U)Int-U-1 and Int-U-2Int-U

[0358] Step 1: To a solution of U.1 (56.4 g, 170.7 mmol, 1.0 equiv.) and TEA (70.9 mL, 512.1 mmol, 3.0 equiv.) in THF (500 mL) was added U.2 (40.0 g, 170.7 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at RT for 1.5 h. The reaction was quenched with water and extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was triturated with PE: DCM = 10:1 and filtered. The filter cake was further triturated with PE: EA = 20: 1 and filtered to afford U.3 (70.0 g, 132.5 mmol, 77.6%) as a white solid. LCMS (ESI) [M+l]+= 529.2.

[0359] Step 2: To a solution of U.3 (70.0 g, 132.5 mmol, 1.0 equiv.) in DMA (300 mL) was added potassium fluoride (153.9 g, 2650.4 mmol, 20.0 equiv.) at 25 °C under N2. The mixture was stirred at 120 °C for 16 h. TLC indicated the reaction was complete. The reaction was quenched with water. The aqueous phase was extracted with EA three times. The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give U.4 (65.0 g, 97.8 mmol, 74.3%) as a yellow solid. LCMS (ESI) [M+l]+= 511.3.

[0360] Step 3: To a solution of U.4 (10.0 g, 19.5 mmol, 1.0 equiv.) and U.5 (2.3 g, 19.5 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (100 mL) at -10 °C was added t-BuONa (4.2 g, 39.0 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was poured into NH4Cl (aq) and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford U.6 (8.0 g, 13.2 mmol, 67.5%) as a yellow solid. LCMS (ESI) [M+l]+= 606.1.

[0361] Step 4: To a solution of U.6 (5.0 g, 8.3 mmol, 1.0 equiv.), U.7 (5.0 g, 12.5 mmol, 1.5 equiv.) and K3PO4 (1.7 g, 24.1 mmol, 3.0 equiv.) in dioxane (60 mL) and toluene (30 mL) wereadded KF (1.4 g 24.1 mmol, 3.0 equiv.) and Pd(DPEphos)C12 (1.2 g, 1.7 mmol, 0.2 equiv.). The reaction mixture was purged with nitrogen three times, then heated to 90 °C and stirred for 16 hours under nitrogen. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel and then by prep-HPLC to afford U.8 (2.6 g, 3.2 mmol, 38.6%) as a yellow solid. LCMS (ESI) [M+l]+= 818.3.

[0362] Step 5: To a solution of U.8 (2.6 g, 3.2 mmol, 1.0 equiv.) in MeOH (100 mL) was added Pd / C (1.3 g). The suspension was stirred at rt for 16 h under H2. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel chromatography, eluting with a gradient of 0 to 10% MeOH in DCM to afford Int-U (2.1 g, 3.0 mmol, 93.8%) as a yellow solid. LCMS (ESI) [M+l]+= 684.2. Int-U was further purified by SFC to give a first eluting isomer Int-U-1 (500.0 mg, 0.7 mmol, 22.7%) and a second eluting isomer Int-U-2 (500.0 mg, 0.7 mmol, 22.7%) as a yellow solid. SFC was performed using the following method: Column: CHIRALPAK IE-3(IE30CE-QB017); Column size: 0.46 cm I. D. x 25 cm L; Injection: 5 μl; Mobile phase: Hexane / EtOH / DEA=50 / 50 / 0.1 (V / V / V); Flow rate: 1.0 ml / min; Wave length: UV 254 nm; Temperature: 35 °C; HPLC equipment: Shimadzu LC-20AD CP-HPLC-08. Int-U-1, retention time: 8.395 min; Int-U-2, retention time: 10.472 min.Preparation of Intermediate V (Int-V)

[0363] Step 1: To a solution of V.1 (32.0 g, 96.9 mmol, 1.0 equiv.) in THF (250.0 mL) was added DIEA(31.3 g, 242.2 mmol, 2.5 equiv.). The mixture was cooled to 0 °C, then V.2 (25.0 g, 96.9 mmol, 1.0 equiv.) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to 0 °C, poured into water and extracted with EA three times. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to afford V.3 (42.0 g, 75.9 mmol, yield: 83.6%) as a yellow solid. LCMS(ESI)[M+l]+= 554.3.

[0364] Step 2: To a solution of V.3 (42.0 g, 75.9 mmol, 1.0 equiv.) in DMA (400.0 mL) was added potassium fluoride (88.2 g, 1518.4 mmol, 20.0 equiv.), and the mixture was stirred at 120 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was cooled down, poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuum to afford crude V.4 (36.0 g, 67.1 mmol, 88.3%) as a yellow solid. LCMS(ESI)[M+1]+= 536.2.

[0365] Step 3: To a solution of V.4 (35.0 g, 65.2 mmol, 1.0 equiv.) and V.5 (7.5 g, 65.2 mmol, 1.0 equiv.) in 2-MeTHF (500.0 mL) was added t-BuONa (9.4 g, 97.8 mmol, 1.5 equiv.) at -10 °C, and the mixture was stirred at -10 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into NH4Cl aqueous and extracted with EA three times. The combinedorganic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 70% ethyl acetate in petroleum ether to afford V.6 (32 g, 50.6 mmol, yield: 77.7%) as yellow solid. LCMS(ESI)[M+1]+= 633.1.

[0366] Step 4: To a solution of V.6 (10.0 g, 15.8 mmol, 1.0 equiv.) in toluene (100.0 mL) and 1,4-dioxane (100.0 mL) were added V.7 (9.6 g, 23.7 mmol, 1.5 equiv.), Pd(DPEphos)Ch (2.3 g, 3.2 mmol, 0.2 equiv.), K3PO4 (10.1 g, 47.5 mmol, 3.0 equiv.) and potassium fluoride (2.8 g, 47.7 mmol, 3.0 equiv.). The mixture was stirred at 80 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was filtered, the filtrate was poured into water and extracted with EA three times. The combined organic layer was washed with brine, dried over anhydrous Na SCh, and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 6% methanol in DCM to give a crude product which was further purified by reversed phase CombiFlash® (40% MeOH in H2O (0.1% HCOOH)) to afford V.8 (5.0 g, 5.9 mmol, yield: 46.5%) as a yellow solid. LCMS(ESI)[M+1]+= 843.2.

[0367] Step 5: To a solution of V.8 (5.0 g, 5.9 mmol, 1.0 equiv.) in MeOH (50.0 mL) and DCM (10.0 mL) was added Pd / C (2.5 g), and the suspension was stirred at room temperature for 16 h under H2atmosphere. LCMS showed the reaction was complete. The reaction mixture was filtered and filtrate was concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 10% methanol in DCM to afford Int-V (2.2 g, 3.1 mmol, yield: 52.3%) as a yellow solid. LCMS(ESI)[M+1]+= 709.2.Preparation of Intermediate W (Int-W)

[0368] Step 1: To a solution of W.1 (5.0 g, 23.3 mmol, 1.0 equiv.) in THF (50.0 mL) were added DIEA(6.0 g, 46.7 mmol, 2.0 equiv.) and CbzCl (4.4 g, 25.7 mmol, 1.1 equiv.). The reaction was stirred at 90 °C for 16 h. LCMS showed the reaction was complete. The mixture was poured into water (200.0 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic phase was washed with brine (100.0 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1:1) to give W.2 (7.0 g, 20.1 mmol, yield: 86.1%) as a yellow solid. LCMS(ESI)[M+l-100]+= 249.1.

[0369] Step 2: To a solution of W.2 (7.0 g, 20.1 mmol, 1.0 equiv.) in DCM (50.0 mL) was added TFA (10.0 mL). The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give W.3 (4.5 g, 18.1 mmol, yield: 90.2%) as a white solid. LCMS(ESI)[M+1]+= 249.5.

[0370] Step 3: To a stirred solution of W.4 (7.0 g, 21.1 mmol, 1.0 equiv.) in THF (30.0 mL) was added a solution of W.3 (5.0 g, 21.1 mmol, 1.0 equiv.) and DIEA (13.0 g, 100.6 mmol, 5.0 equiv.) in THF (20.0 mL) dropwise at 0 °C under N2 atmosphere. After stirring at 0 °C for 1 h, LCMS showed the reaction was complete. The mixture was poured into water (100.0 mL) and extracted with EtOAc (30.0 mLx 3). The combined organic phase was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1) to give W.5 (8.0 g, 14.7 mmol, yield: 73.3%) as a white solid.

[0371] Step 4: To a solution of W.5 (8.0 g, 14.7 mmol, 1.0 equiv.) in DMA (100.0 mL) was added KF (12.8 g, 221.3 mmol, 15.0 equiv.). The reaction was stirred at 110 °C for 48 h. LCMS showed the reaction was complete. The mixture was poured into water (200.0 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic phase was washed with brine (100.0 mL), dried over anhydrous Na2SO4and concentrated under reduce pressure. The residue was purified bycolumn chromatography on silica gel (PE: EtOAc = 5:1) to give W.6 (5.0 g, 9.5 mmol, yield: 64.5%) as a yellow solid. LCMS(ESI)[M-1]’ = 523.

[0372] Step 5: To a solution of W.6 (5.0 g, 9.5 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (50.0 mL) were added W.7 (1.7 g, 10.5 mmol, 1.1 equiv.) and t-BuONa (0.9 g, 9.5 mmol, 1.0 equiv.) at -10 °C under N2 atmosphere. The reaction was stirred at -10 °C for 1 h. LCMS showed the reaction was complete. The mixture was poured into water (200.0 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic phases were washed with brine (100.0 mL), dried over anhydrous Na2SO4and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1) to give W.8 (3.5 g, 5.3 mmol, yield: 55.4%) as a yellow solid. LCMS(ESI)[M+1]+= 664.2 / 666.2.

[0373] Step 6: To a solution of W.8 (3.5 g, 5.3 mmol, 1.0 equiv.) in toluene (50.0 mL) were added W.9 (3.2 g, 7.9 mmol, 1.5 equiv), KF (5.9 g, 15.8 mmol, 3.0 equiv.), K3PO4 (3.4 g, 15.8 mmol, 3.0 equiv.) and Pd(DPEphos)C12 (1.5 g, 2.1 mmol, 0.4 equiv.). The mixture was backfilled with N2 for three times and stirred at 90 °C for 4 h under N2 atmosphere. LCMS showed the reaction was complete. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduce pressure to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 7:3) to give W.10 (1.2 g, 1.4 mmol, yield: 26.0%) as a white solid. LCMS(ESI)[M+1]+= 876.3.

[0374] Step 7: To a solution of W.10 (1.1 g, 1.3 mmol, 1.0 equiv.) in MeOH (10.0 mL) was added Pd / C (200 mg, 10wt%). The reaction was stirred at room temperature for 1 h under H2atmosphere. LCMS showed the reaction was complete. The mixture was filtered through Celite® and the filtrate was concentrated under reduce pressure to give Int-W (700.0 mg, 0.9 mmol, yield: 75.1%) as a white solid. LCMS(ESI)[M+1]+= 742.1.Preparation of Intermediate X-l (Int-X-1) and Intermediate X-2 (Int-X-2)Int-X-1 and Int-X-2

[0375] Step 1: To a solution of 1 (5.5 g, 26.6 mmol, 1.0 equiv.) in ethanol (50.0 mL) and water (10.0 mL) were added ammonium chloride (4.3 g, 79.2 mmol, 3.0 equiv.) and Fe (7.4 g, 132.7 mmol, 5.0 equiv.), and the mixture was stirred at 80°C for 10 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 2% methanol in DCM to afford 2 (4.1 g, 23.3 mmol, yield: 87.8%) as a black solid. LCMS(ESI)[M+1]+= 178.4, tR = 0.780 min.

[0376] Step 2: To a solution of 2 (3.0 g, 16.2 mmol, 1.0 equiv.) in toluene (100.0 mL) were added PPTS (816.0 mg, 3.2 mmol, 0.2 equiv.) and 3 (4.4 g, 16.2 mmol, 1.0 equiv.), and the mixture was stirred at 110°C overnight. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with 2% methanol in DCM to afford 4 (2.8 g, 6.9 mmol, yield: 42.3%) as a yellow solid.1HNMR (400 MHz, DMSO) 8 10.02 (s, 1H), 7.85 (d, J= 9.1 Hz, 1H), 7.45 (d, J= 8.9 Hz, 1H), 7.24 (s, 1H), 6.47 (s, 1H), 5.41 (s, 2H), 5.19 (s, 2H), 3.09 (t, J= 5.8 Hz, 2H), 2.95 (t, J= 5.8 Hz, 2H), 2.03 - 1.97 (m, 2H), 1.86 (dt, J= 14.1, 6.9 Hz, 2H), 0.88 (t, J= 7.3 Hz, 3H).

[0377] Step 3: To a solution of 4 (4.1 g, 10.1 mmol, 1.0 equiv.) in DMSO (120.0 mL) were added 5 (6.3 g, 27.4 mmol, 2.7 equiv.), Pd₂(dba)₃ (185.0 mg, 20.2 μmol, 0.02 equiv.) and L₁ (481.0 mg, 60.6 μmol, 0.06 equiv.), and the mixture was stirred at 30°C for 16 h. LCMS showed the reaction was complete. The reaction mixture was cooled down and poured into ice water. The suspension was filtered, the filter cake was purified using silica gel column chromatography, reversed phase combi flash (40% ACN in H2O (0.1% HCOOH)) and SFC to afford Int-X-1 (1.1 g, 2.0 mmol, yield: 19.9%) as a yellow solid and Int-X-2 (680.0 mg, 1.2 mmol, yield: 12.0%) as a yellow solid. Int-X-1: LCMS(ESI)[M+1]+= 559.3, tR= 1.856 min. ¹H NMR (400 MHz, DMSO) δ 7.98 (d, J = 9.3 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.27 (s, 1H), 6.49 (s, 1H), 6.15 (s, 1H), 5.86(s, 1H), 5.42 (s, 3H), 5.24 (s, 2H), 3.11 (d, J= 5.9 Hz, 2H), 3.04 (t, J= 6.0 Hz, 2H), 2.02 (d, J = 5.4 Hz, 2H), 1.87 (dq, J= 14.0, 7.1 Hz, 2H), 1.53 (d, J= 6.3 Hz, 3H), 1.43 (s, 9H), 0.88 (t, J= 7.3 Hz, 3H). Int-X-2: LCMS(ESI)[M+1]+= 559.3, tR= 1.884 min. ’H NMR (400 MHz, DMSO) 8 7.98 (d,.7= 9.3 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.27 (s, 1H), 6.49 (s, 1H), 6.14 (s, 1H), 5.85 (s, 1H), 5.42 (s, 3H), 5.23 (s, 2H), 3.12 (s, 2H), 3.04 (t, J= 5.9 Hz, 2H), 2.06 - 1.97 (m, 2H), 1.92 -1.82 (m, 2H), 1.53 (d, J= 6.3 Hz, 3H), 1.44 (s, 9H), 0.88 (t, J= 7.3 Hz, 3H). SFC Conditions: Column: ChiralPak AY, 250x20 mm I. D., 5 μm; Mobile phase: A for CO₂ and B for MeOH+33%ACN; Gradient: B 50%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 15 min; Eluted time: 10 h; Peak 1: Int-X-1, retention time: 2.581 min; Peak 2: Int-X-2, retention time: 4.449 min.Preparation of Intermediate Y-l (Int-Y-1) and Intermediate Y-2 (Int-Y-2)Int-Y-1 and Int-Y-2

[0378] Step 1: 1 (5.0 g, 30.5 mmol, 1.0 equiv.) was added to H₂SO₄ (80.0 mL) in a 3 neck round bottom flask. The mixture was stirred until all the solid had dissolved and then was cooled to 0-5°C. Then a solution of potassium nitrate (3.1 g, 30.5 mmol, 1.0 equiv.) in sulfuric acid (120 mL) was added at 0-5°C. The reaction mixture was stirred at 0-5°C until the reaction was complete. The reaction mixture was poured into ice water (250.0 mL) and the suspension was filtered, the cake was washed with water (50.0 mL) and dried in a vacuum oven for 2 h at 50°C. The crude solid was triturated with Et2O to give pure product 2 (5.0 g, 23.9 mmol, yield: 78.5%) as a white solid. LCMS(ESI)[M+1]+=210.18, tR=1.298 min.

[0379] Step 2: A solution of 2 (2.0 g, 9.6 mmol, 1.0 equiv.) in DMF (30.0 mL) were added DMBNH₂ (1.6 g, 9.6 mmol, 1.0 equiv.) and DIEA (3.7 g, 28.7 mmol, 3.0 equiv.) under N₂. The resulting mixture was stirred at 80°C for 2 hr. LCMS showed the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography to afford 3 (800.0 mg, 2.2 mmol, yield: 23.5%) as a brown solid. LCMS(ESI)[M+1]+=357.38, tR=1.579 min.

[0380] Step 3: To a stirred mixture of 3 (800.0 mg, 2.2 mmol, 1.0 equiv.) in DCM (9.0 mL) was added TFA (3.0 mL). The resulting mixture was stirred at rt for 1 hr. LCMS showed reaction was complete. The reaction mixture was concentrated under reduced pressure to afford 4 (420.0 mg, 2.0 mmol, yield: 90.7%) as a yellow solid. LCMS(ESI)[M+1]+=207.20, tR=0.964 min.

[0381] Step 4: To a stirred mixture of 4 (700.0 mg, 3.4 mmol, 1.0 equiv.) in dioxane (8.0 mL) were added DIEA (1316.3 mg, 10.2 mmol, 3.0 equiv.) and trichloromethyl [(trichloromethyl)oxy]methanoate (503.7 mg, 1.7 mmol, 0.5 equiv.) at 0 °C under N2. The resulting mixture was stirred at 100 °C for 10 min under N2. LCMS showed the reaction was complete. The resulting mixture was used directly in the next step. LCMS(ESI)[M+1]+=265.07, tR=1.109 min.

[0382] Step 5: To a stirred mixture of 5 (700.0 mg, 3.0 mmol, 1.0 equiv.) in dioxane (10.0 mL) was added L-1 (1557.6 mg, 9.0 mmol, 3.0 equiv.). The reaction mixture was stirred at 100 °C for 1 hr under N2. LCMS showed the reaction was complete. The resulting mixture was concentrated and purified by flash column chromatography on silica gel to give 7 (1.2 g, 3.0 mmol, yield: 98.4%) as a yellow solid. LCMS(ESI)[M+1]+=405.42, tR =1.760 min.

[0383] Step 6: To a stirred mixture of 7 (1.2 g, 3.0 mmol, 1.0 equiv.) in EtOH (15.0 mL) and H₂O (5.0 mL) were added Fe (1.0 g, 17.8 mmol, 6.0 equiv.) and NH₄Cl (1.6 g, 29.7 mmol, 10.0 equiv.). The resulting mixture was stirred at 80°C for 1 hr under N2. LCMS showed the reaction was complete. The reaction mixture was filtered, the filtrate was extracted with EA and the organic layer was concentrated under reduced pressure, the residue was purified by prep-HPLC to give 8 (750.0 mg, 2.0 mmol, yield: 67.5%) as a yellow solid. LCMS(ESI)[M+1]+=375.44, tR =1.560 min.

[0384] Step 7: To a stirred mixture of 8 (700.0 mg, 1.9 mmol, 1.0 equiv.) in toluene (30.0 mL) and o-cresol (1.0 mL) were added 9 (590.6 mg, 2.2 mmol, 1.2 equiv.) and PPTS (94.0 mg, 0.4 mmol, 0.2 equiv.). The resulting mixture was stirred at 120°C for 18 hr under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC and SFC to afford Int-Y-1 (160 mg, 0.3 mmol, yield: 22.8%) and Int-Y-2 (190.0 mg, 0.3 mmol, yield: 27.1%) as a yellow solid. LCMS(ESI)[M+1]+=602.66, tR =1.453 min. Column: CHIRALPAK IG (5.0 cm I. D. x 25 cm L; Mobile phase: MeOH / DCM=75 / 25 (V / V); Gradient: Isocratic elution; Flow rate: 60ml / min; Column temperature: 36°C; Wavelength: 214 nm; Injection volume: 6 ml; Sample dissolution solvent: MeOH / DCM=75 / 25 (V / V); Peak 1: Int-Y-1, retention time: 7.156 min; Peak 2: Int-Y-2, retention time: 8.732 min.Preparation of Intermediate Z-l (Int-Z-1) and Intermediate Z-2 (Int-Z-2)and Int-Z-2

[0385] Step 1: To a solution of 1 (10.0 g, 59.5 mmol, 1.0 equiv.) in DCM (300.0 mL) was added MnO₂ (77.5 g, 892.1 mmol, 15.0 equiv.), the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford 2 (9.0 g, 54.2 mmol, yield: 91.1%) as a yellow solid. LCMS(ESI)[M+1]+= 167.2, tR= 1.081 min. ¹H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.61 (d, J = 2.7 Hz, 1H), 8.20 (s, 2H), 8.12 (dd, J = 9.3, 2.7 Hz, 1H), 6.88 (d, J = 9.3 Hz, 1H).

[0386] Step 2: To a solution of 2 (5.0 g, 30.1 mmol, 1.6 equiv.) in HOAc (500.0 mL) and hydrogen chloride (100.0 mL) was added 3 (5.0 g, 19.0 mmol, 1.0 equiv.), the mixture was stirred at 120°C for overnight. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with 2% methanol in DCM to afford 4 (7.0 g, 17.8 mmol, yield: 93.7%) as a yellow solid. LCMS(ESI)[M+1]+= 394.2, tR= 1.101 min.

[0387] Step 3: To a solution of 4 (7.0 g, 17.8 mmol, 1.0 equiv.) in ethanol (50.0 mL) and water (2.0 mL) were added Fe (5.0 g, 89.0 mmol, 5.0 equiv.) and ammonium chloride (2.9 g, 53.4 mmol, 3.0 equiv.). The mixture was stirred at 80°C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 4% methanol in DCM to afford 5 (6.0 g, 15.0 mmol, yield: 84.4%) as a yellow solid. LCMS(ESI)[M+1]+= 364.2, tR= 1.432 min.

[0388] Step 4: To a solution of 5 (600.0 mg, 1.6 mmol, 1.0 equiv.) in 1,4-dioxane (12.0 mL) were added triphosgene (245.0 mg, 825.6 μmol, 0.5 equiv.) and DIEA (426.8 mg, 3.3 mmol, 2.0equiv.) at 0 °C. The mixture was stirred at 100 °C for 0.5 hours. LCMS showed the reaction was complete. The mixture was used directly to the next step without purification.

[0389] Step 5: To a solution of 6 (600.0 mg, 1.5 mmol, 1.0 equiv.) in 1,4-dioxane (12.0 mL) was added 7 (796.2 mg, 4.6 mmol, 3.0 equiv.). The mixture was stirred at 100 °C for 5 hours. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with 4% methanol in DCM to afford racemate which was further purified by SFC to give Int-Z-1 (155.0 mg, 276.0 μmol, yield: 17.9%) as a yellow solid and Int-Z-2 (164.0 mg, 292.0 μmol, yield: 18.9%) as a yellow solid. Int-Z-1: LCMS(ESI)[M+1]+= 562.3, tR= 1.517 min. Int-Z-2: LCMS(ESI)[M+1]+= 562.3, tR = 1.534 min. Column: ChiralPakOJ, 250x20 mm I. D., 5 μm; Mobile phase: A for Hexane and B for MeOH (0.1% 7 mol / L NH₃ in EtOH); Gradient: B 20%; Flow rate: 20 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle-time: 16 min; Run time: 20 min; Injection volume: 1.1 mL; Number of injection needles: 47; Eluted time: 5 H; 470 mg of sample was dissolved in 51 mL EtOH; Peak 1: Int-Z-1, retention time: 4.996 min; Peak 2: Int-Z-2, retention time: 6.250 min.Preparation of Intermediate AA-1 (Int-AA-1) and Intermediate AA-2 (Int-AA-2)

[0390] A mixture of 9 (890.0 mg, 2.4 mmol, 1.0 equiv.), 10 (639.0 mg, 2.4 mmol, 1.0 equiv.) and PPTS (61.0 mg, 240.0 μmol, 0.1 equiv.) in toluene (10.0 mL) was stirred at 110 °C for 80 mins. The reaction was concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM: MeOH = 15: 1) and prep-HPLC to give a mixture of Int-AA-1 and Int-AA-2 (450.0 mg, 0.8 mmol, yield: 31.2%) as a brown solid which was further purified by SFC to give Int-AA-1 (177.0 mg, 0.3 mmol, yield: 12.3%) & Int-AA-2 (190.0 mg, 0.3 mmol, yield: 13.2%). LCMS(ESI)[M+1]+= 594.3, tR= 1.500 min. Column: CHIRALCEL OJ; Column size: 2.5 cm I. D. × 25 cm L, 10 μm; Mobile phase: MeOH=100%; Flow rate: 30 ml / minWave length: UV 214 nm; Temperature: 38°C; Peak 1: Int-AA-1, retention time:3.560 min; Peak 2: Int-AA-2, retention time: 4.752 min.Preparation of Intermediate AB- 1 (Int-AB-1) and Intermediate AB-2 (Int-AB-2)

[0391] To a solution of 4 (500.0 mg, 0.9 mmol, 1.0 equiv.) in DCM (2.0 mL) / DMF (8.0 mL) were added L-7 (348.6 mg, 1.5 mmol, 1.6 equiv.) and DIEA (240.0 mg, 1.8 mmol, 2.0 equiv.). The mixture was stirred at rt for 1 h. LCMS showed the reaction was complete. The reaction mixture was diulted by EA and water, and the organic layer was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography and SFC to afford Int-AB-1 (200.0 mg, 271.7 μmol) and Int-AB-2 (198.0 mg, 269.0 μmol). LCMS(ESI) [M+1]+= 737.3, tR = 1.767 min. Column: ChiralPak IH, 250×30 mm I. D., 5 μm; Mobile phase: A for CO2 and B for MeOH; Gradient: B 20%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 8 min; Injection volume: 0.9 mL; Number of injection needles: 22; Eluted time: 3 h; Peak 1: Int-AB-1, retention time: 2.831 min; Peak 2: Int-AB-2, retention time: 3.264 min.Preparation of Intermediate AC-1 (Int-AC-1) and Intermediate AC-2 (Int-AC-2)

[0392] Step 1: To a stirred mixture of 5 (3.5 g, 12.5 mmol, 1.0 equiv.) in DCM (40.0 mL) were added DIEA(4.8 g, 37.5 mmol, 3.0 equiv.) and L-7 (2.9 g, 12.5 mmol, 1.0 equiv.). The resulting mixture was stirred under N2 at rt for 1 hr. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by silica gel column chromatography to afford 7 (4.5 g, 9.4 mmol, yield: 75.3%) as a white solid. LCMS(ESI)[M+1]+=479.54, tR=1.963 min.Step 2: To a stirred mixture of 7 (2 g, 4.2 mmol, 1.0 equiv.) in acetic acid (25.0 mL) was added 250-Int-4 (1.4 g, 5.0 mmol, 1.2 equiv.). The reaction mixture was stirred at 110°C for 4 hrs under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column and SFC to afford Int-AC-1 (350 mg, 0.6 mmol, yield: 35.0%) and Int-AC-2 (350.0 mg, 0.6 mmol, yield: 35.0%) as a light yellow solid. LCMS(ESI)[M+1]⁺ =578.65, tR =1.853 min, tR =1.848 min. Column: ChiralPak AD, 250×20 mm I. D., 5μm; Mobile phase: A for CO2 and B for MEOH; Gradient: B 50%; Flow rate: 30 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Run time: 20 min; Cycle-time: 20 min; Injection volume: 3 mL; Number of injection needles: 25; Eluted time: 10 h; Peak 1: Int-AC-1, retention time: 3.089 min; Peak 2: Int-AC-2, retention time: 5.151 min. Preparation of Intermediate AD-1 (Int-AD-1) and Intermediate AD-2 (Int-AD-2)

[0393] Step 1: To a solution of 1 (25.0 g, 95.0 mmol, 1.0 equiv.) and 2 (10.6 mL, 189.9 mmol, 2.0 equiv.) in DCM (1250 mL) was added TMSC1 (51.3 g, 474.8 mmol, 5.0 equiv.). The mixture was stirred at rt for 3 days. LCMS showed the reaction was complete. NaHCO₃ (42.0 g, 500 mmol) was added to the mixture and the mixture was stirred at rt for 30 min. Water (28 mL) was added to the mixture over 20 min and the mixture was stirred at rt for 30 min. The resulting mixture was diluted with water (500 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-3% DCM / MeOH) to give 3 (25 g, 81.3 mmol, yield: 85.7%) as a white solid. LCMS(ESI)[M+1]+= 308.2, tR= 1.245 min.

[0394] Step 2: To a solution of 3 (25.0 g, 81.3 mmol, 1.0 equiv.) in MeOH / THF / DCM (4 / 2 / 1, 350 mL) were added calcium chloride (11.7 g, 105.8 mmol, 1.2 equiv.) and NaBH₄ (3.4 g, 89.5 mmol, 1.1 equiv.) slowly. The mixture was stirred at rt for 2 h. LCMS showed the reaction was complete. The reaction was quenched by the addition of 1M HCl (100 mL) slowly. The mixture was stirred at rt for 30 min and then concentrated, and the residue was purified by flash column chromatography (DCM / MeOH from 0%-5%) to give 4 (22.0 g, 71.1 mmol, yield: 87.4%) as a white solid. LCMS(ESI)[M+1]+= 310.3, tR= 1.271 min.

[0395] Step 3: To a suspension of 4 (22.0 g, 71.1 mmol, 1.0 equiv.) in DCM (1000 mL) was added a solution of NaIO4 (30.4 g, 142.2 mmol, 2.0 equiv.) in water (600 mL) slowly. The mixture was stirred at rt for 3 h. LCMS showed the reaction was complete. The organic layer was concentrated and purified by flash column chromatography (98% EA with DCM as additive solution) to give 5 (19.0 g, 61.8 mmol, yield: 86.9%) as a white solid. LCMS(ESI)[M+1]+= 308.2, tR= 0.761 min.

[0396] Step 4: To a suspension of zinc(0) (32.3 g, 494.6 mmol, 8.0 equiv.) in tetrahydrofuran (200 mL) was added TMSC1 (0.2 g, 1.8 mmol, 0.3 equiv.). The mixture was stirred at rt for 20 min.6 (96.5 g, 494.6 mmol, 8.0 equiv.) was added slowly and the temperature was kept below 50 °C(exothermic). The mixture was stirred at 50 °C for 2 h. 5 (19.0 g, 61.8 mmol, 1.0 equiv.) was added and the mixture was stirred at 50 °C for another 3 h. LCMS showed the reaction was complete. The mixture was concentrated and diluted with DCM and water. The organic layer was concentrated and purified by flash column chromatography (0-3% DCM / MeOH) to give 7 (18.0 g, 45.5 mmol, yield: 73.6%) as a white solid. LCMS(ESI)[M+1]+= 396.3, tR = 2.296 min.

[0397] Step 5: A mixture of 7 (17.0 g, 43.0 mmol, 1.0 equiv.) in TFA (50 mL) was stirred at rt for 3 days. LCMS showed the reaction was complete. The mixture was diluted with EA (100 mL) and concentrated. The residue was triturated with DCM and filtered to give 7 g of Int-AD as an off-white solid. The mother liquid was concentrated and purified by flash column chromatography (DCM / EA from 20%-85%) to give 2.8 g of Int-AD as a white solid. 4.0 g Int-AD was separated by SFC to give 1.4 g of Int-AD-1 (first eluting isomer) and 1.4 g of Int-AD-2 (second eluting isomer). LCMS(ESI)[M+1]+= 378.1, tR = 0.400 min; Column: YMC-Triart C18, 50*4.6mm, 5um; Mobile Phase: Solvent A: H₂O / MeCN / FA = 90:10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL / min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B.1H NMR (400 MHz, DMSO-d6) 86.94 (s, 1H), 5.94 (s, 1H), 5.56 - 5.22 (m, 2H), 4.23 - 4.02 (m, 2H), 3.40 (d, J= 13.9Hz, 1H), 3.02 (d, J = 13.9 Hz, 1H), 2.92 -2.81 (m, 2H), 1.81 - 1.65 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H). SFC Conditions: Column: ChiralPak IC, 250×30mm I. D., 5μm; Mobile phase: A for CO2 and B for MeOH; Gradient: B 40%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 10 min; Eluted time: 20 h.Preparation of Intermediate AE-1 (Int-AE-1) and Intermediate AE-2 (Int-AE-2)Int-AE-1 and Int-AE-2

[0398] To a solution of 5 (63.4 mg, 114.8 μmol, 1.0 equiv.) in DCM (5.0 mL) were added TEA (28.9 mg, 286.8 μmol, 2.5 equiv.) and (Boc)₂O (37.5 mg, 172.1 μmol, 1.5 equiv.). The mixture was stirred at r.t for 1 h. LCMS showed the reaction was complete. The mixture was poured into H2O (10.0 mL) and extracted with DCM (5.0 mL x3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by flashchromatography (DCM / MeOH = 100:1 to 30:1) to give Int-AE (70.0 mg, 107.3 μmol, yield: 93.5%) as a yellow solid. LCMS(ESI)[M+1]+= 653.3, tR = 1.184 min. 70 mg of Int-AE was further purified by SFC (unstable during SFC) to give Int-AE-1 (5.0 mg, 10.0 μmol, yield: 7.1%) and Int-AE-2 (5.0 mg, 10.0 μmol, yield: 7.1%) as a solid. SFC method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak C-IC, 250x30 mm I. D., 5μm; Mobile phase: A for CO2 and B for IPA; Gradient: B 10%; Flow rate:30 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength:220 nm; Cycle-time: 15 min; Injection volume: 0.4 mL; Number of injection needles: 45; Eluted time: 10H; Peak 1: Int-AE-1, retention time: 2.742 min. Peak 2:Int-AE-2, retention time: 3.393 min.Preparation of Intermediate AF-1 (Int-AF-1) and Intermediate AF-2 (Int-AF-2)Int-AF-1 and Int-AF-28

[0399] Step J: To a solution of 1 (15.0 g, 45.4 mmol, 1.0 equiv.) in THF (500.0 mL) was added DIEA(17.6 g, 136.2 mmol, 3.0 equiv.), the mixture was cooled to 0°C, then 2 (10.0 g, 45.4 mmol, 1.0 equiv.) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to 0°C, poured into water and extracted with EA three times. The combined organic layer was washed with brine, dried over Na2SO4and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to afford 3 (20.0 g, 38.9 mmol, yield: 85.7%) as a yellow solid. LCMS(ESI)[M+1]+= 515.2, tR= 2.102 min.

[0400] Step 2: To a solution of 3 (20.0 g, 36.2 mmol, 1.0 equiv.) in DMA (200.0 mL) was added potassium fluoride (41.9 g, 723.1 mmol, 20.0 equiv.), and the mixture was stirred at 120°C for 72 h. LCMS showed the reaction was complete. The reaction mixture was cooled down, poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuum to afford crude 4 (17.0 g, 31.7 mmol, 87.6%) as a yellow solid. LCMS(ESI)[M+1]+= 499.1, tR= 1.901 min.

[0401] Step 3: To a solution of 4 (17.0 g, 34.2 mmol, 1.0 equiv.) and 5 (5.4 g, 34.2 mmol, 1.0 equiv.) in 2-MeTHF (200.0 mL) was added t-BuONa (4.9 g, 51.2 mmol, 1.5 equiv.) at -10°C, and the mixture was stirred at -10°C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into NH4Cl aqueous and extracted with EA three times. The combined organic layer was washed with brine, dried over Na2SO4and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 70% ethyl acetate in petroleum ether to afford 6 (15.0 g, 23.6 mmol, yield: 69.0%) as yellow solid. LCMS(ESI)[M+1]+= 638.2, tR= 1.204 min.

[0402] Step 4: To a solution of 6 (5.0 g, 7.9 mmol, 1.0 equiv.) in Toluene (100.0 mL) and 1,4-dioxane (100.0 mL) were added 7 (4.8 g, 11.8 mmol, 1.5 equiv), Pd(DPEphos)C12 (1.2 g, 1.6 mmol, 0.2 equiv.), K3PO4 (5.0 g, 23.6 mmol, 3.0 equiv.) and potassium fluoride (1.4 g, 23.6 mmol, 3.0 equiv.), and the mixture was stirred at 80°C for 16 h. LCMS showed the reaction was complete. The reaction mixture was filtered, the filtrate was poured into water and extracted with EA three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 6% methanol in DCM to give 8 (2.3 g, 2.7 mmol, yield: 34.5%) as a yellow solid. LCMS(ESI)[M+1]+= 848.3, tR= 1.833 min.

[0403] Step 5: To a solution of 8 (4.0 g, 4.7 mmol, 1.0 equiv.) in MeOH (40.0 mL) was added Pd / C (2.0 g), and the suspension was stirred at room temperature for 16 h under H2atmosphere. LCMS showed the reaction was complete. The reaction mixture was filtered and filtrate was concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 10% methanol in DCM to afford Int-AF (1.5 g, 2.1 mmol, yield: 44.5%) as a yellow solid. LCMS(ESI)[M+1]+= 714.2, tR= 0.883 min. SFC method: Preparative separation method: Column size: 0.46 cm ID. x 25 cm L; Injection: 10 ul; Mobile phase: Hexane / EtOH / DEA=70 / 30 / 0.1(V / V / V); Flow rate: 1.0 ml / min; Wave length: UV 254 nm; Temperature: 35 °C; HPLC equipment: Shimadzu LC-20AT CP-HPLC-07; Peak 1: Int-AF-1, retention time: 10.699 min. Peak 2: Int-AF-2, retention time: 12.282 min. Preparative separation method: Instrument: YMC, K-PreLAB 100S; Column: CHIRALPAK AD 5.0 cm I D. * 25 cm L; Mobile phase: Hexane / IPA / DEA=50 / 50 / 0.1(V / V / V); Gradient: Isocratic elution; Flow rate:60 ml / min; Column temperature: 38°C; Wavelength: 214 nm; Injection volume: 40 ml; Sample dissolution solvent: Hexane / IPA 50 / 50.Preparation of Intermediate AG-1 (Int-AG-1) and Intermediate AG-2 (Int-AG-2)ciC! - X CbzInt-AG-1 and Int-AG-2

[0404] Step 1: To a solution of 1 (25.0 g, 110.4 mmol) in DCM (30.0 mL) were added benzyl chloromethanoate (37.6 g, 220.9 mmol) and TEA (45.9 mL, 331.3 mmol) at 0°C. The mixture wasstirred at 20°C for 16 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with H2O (200.0 mL) and extracted with DCM (200.0 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 0-32% Ethyl acetate / Petroleum ethergradient 100 mL / min) to give 2 (30.0 g, 69.3 mmol, yield: 62.7 %) as a colorless oil. LCMS(ESI)[M-56]+= 305.3, tR = 1.775 min.

[0405] Step 2: To a solution of 2 (30.0 g, 83.2 mmol) in DCM (100.0 mL) was added TFA (50.0 mL, 83.2 mmol), the reaction mixture was stirred at room temperature for 4 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EA (30 mL), washed with sodium bicarbonate solution (10.0 mL*2) and saturated sodium chloride solution (10 mL), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to obtain 3 (20.0 g, 76.6 mmol, yield: 92.3%). LCMS(ESI)[M+1]+= 261.3, tR= 0.600 min.

[0406] Step 3: To a solution of 3 (20.0 g, 76.6 mmol, 1.1 equiv.) and TEA (22.9 g, 227.3 mmol, 3.0 equiv.) in THF (500.0 mL) was added 4 (25.0 g, 75.7 mmol, 1.0 equiv.) at 0°C. The mixture was stirred at rt for 1.5 h. LCMS showed the reaction was complete. The reaction mixture was quenched with water and extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with PE: DCM = 10:1 and filtered. The filter cake was further triturated with PE: EA = 20: 1 and filtered to afford 5 (36.0 g, 64.9 mmol, yield: 85.8%) as a white solid. LCMS(ESI)[M+1]+= 555.3, tR= 2.102 min.

[0407] Step 4: To a solution 5 (36.0 g, 67.9 mmol, 1.0 equiv.) in DMA (500.0 mL) was added potassium fluoride (113.0 g, 1948.6 mmol, 30.0 equiv.) at 25 °C under N2. The mixture was stirred at 120°C for 24 hrs. LCMS showed the reaction was complete. The reaction was quenched with water. The aqueous phase was extracted with EA for three times. The combined organic layers were dried over anhydrous. Na2SO4, filtered and concentrated under reduced pressure to give 6 (30.0 g, 55.8 mmol, yield: 85.8%) as yellow oil. LCMS(ESI)[M+1]+= 537.3, tR= 1.988 min.

[0408] Step 5: To a solution of 6 (30.0 g, 55.7 mmol, 1.0 equiv.) and 7 (8.8 g, 55.7 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (600.0 mL) was added t-BuONa (8.1g, 83.6 mmol, 1.5 equiv.) at -10 °C. The reaction was stirred at room temperature for 3 hours. LCMS showed the reactionwas complete. The reaction mixture was washed with NaHCO₃ solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a gradient of 20-30 % EtOAc in petroleum ether to afford 7 (26.0 g, 38.4 mmol, 68.5%) as a colorless oil. LCMS(ESI)[M+1]+= 678.4, tR= 1.237 min.

[0409] Step 6: To a mixture of 8 (10.0 g, 14.8 mmol, 1.0 equiv.), 9 (8.9 g, 22.2 mmol, 1.5 equiv.), K3PO4 (4.7 g, 22.2 mmol, 3.0 equiv.) in dioxane (80 mL) and Toluene (80 mL) were added KF (2.6 g 44.3 mmol, 3.0 equiv.), Pd(DPEphos)C12 (2.1 g, 2.9 mmol, 0.2 equiv.). The reaction mixture was backfilled with nitrogen three times, then heated to 90°C and stirred for 16 hours under nitrogen. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 10% MeOH in DCM to afford 10 (6.0 g, 6.8 mmol, 45.7%) as a yellow solid.

[0410] Step 7: To a solution of 10 (6.0 g, 17.4 mmol, 1.0 equiv.) in methanol (100 mL) was added Pd / C (3.0 g, 11.6 mmol). The mixture was stirred at 25°C for 16hours under H2 (25 Psi). The reaction was monitored by LCMS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 10% MeOH in DCM afford 2.5 g of a mixture of isomers (Int-AG). 1.5 g of mixture was purified by SFC to give Int-AG-1 (first eluting isomer, 650.0 mg, 6.3 mmol, 30.9%) and Int-AG-2 (second eluting isomer, 4.0 g, 6.3 mmol, 31.7 %) as a yellow solid. LCMS(ESI)[M+1]+= 754.5, tR= 1.087 min. LCMS(ESI)[M+1]+= 754.5, tR= 1.010 min. LCMS(ESI)[M+1]+= 888.4, tR= 1.819 min. Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPakC-IG, 250x20 mm I. D., 5 μm; Mobile phase: A for CO2and B for IPA (0.1 % 7 mol / L NH3in MeOH); Gradient: B 50 %; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 40 °C; Wavelength: 220 nm.Preparation of Intermediate AH-1 (Int-AH-1) and Intermediate AH-2 (Int-AH-2)Int-AH-1 and Int-AH-2

[0411] To a solution of 4 (1.5 g, 3.9 mmol, 1.0 equiv.) in DCM (10.0 mL) and NMP (10.0 mL) were added DIEA (1.5 g, 11.8 mmol, 3.0 equiv.) and 5 (1.5 g, 7.9 mmol, 2.0 equiv.). The reaction was stirred at rt for 16 h. LCMS showed the reaction was complete. The mixture was quenched by H2O and extracted with EA twice. The organic phase was dried and concentrated. The residue was purified using silica gel column chromatography eluting with 60% DCM in EA to afford Int-AH (1.0 g, 1.7 mmol, yield: 43.9%). LCMS(ESI)[M+1]+= 580.2, tR = 1.574 min. The mixture of isomers was further purified by SFC to give Int-AH-1 (400.0 mg, 0.7 mmol, 40.0%) and Int-AH-2 (350.0 mg, 0.7 mmol, 35.0%) as a yellow solid. Int-AH-1: LCMS(ESI)[M+1]+= 580.3, tR = 1.580 min. Int-AH-2: LCMS(ESI)[M+1]+=580.3, tR = 1.583 min. Preparative separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OJ, 250><20mm I. D., 5pm; Mobile phase: A for CO2 and B for MeOH; Gradient: B 50 %; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength:220 nm; Cycle-time:25 min; Run time: 25 min; Injection volume: 4.5 mL; Number of injection needles: 14; Eluted time: 2H. Peak 1: Int-AH-1, retention time: 3.968 min. Int-AH-2, retention time: 6.431 min.Preparation of Intermediate AI-1 (Int-AI-1) and Intermediate AI-2 (Int-AI-2)Int-AI-1 and Int-AI-2

[0412] To a solution of 7 (1.3 g, 2.7 mmol, 1.0 equiv.) in AcOH (15 mL) was added 8 (850.0 mg, 3.2 mmol, 1.2 equiv.). The mixture was stirred at 110°C for 6 h. LCMS showed the starting material was consumed, -50% of 9 and 50% of Int-AI (mixture of Int-AI-1 and Int-AI-2) were detected. The reaction mixture was concentrated and purified by flash to give 9 (250 mg, 0.3 mmol) and Int-AI (200.0 mg, 350.0 μmol) as yellow solid. LCMS(ESI) [M+1]+= 634.2, tR= 1.661 min. Int-AI (200.0 mg, 346.0 μmol) was purified by prep-HPLC to give Int-AI-1 (first eluting isomer, 30.0 mg, 52.0 μmol, yield: 15.0%) and Int-AI-2 (second eluting isomer, 15.0 mg, 26.0 μmol, yield: 7.5%) as a yellow solid. Instrument: E-Prep LC-024; Column: Welch Ultimate XS C18* 150 mm, 5 um; Temperature: 25 °C; Inject number:1; Wave length: 254 nm / 220 nm; phase A: H2O (0.1% TFA); phase B: MeOH.Preparation of Intermediate AJ-1 (Int-AJ-1) and Intermediate AJ-2 (Int-AJ-2)

[0413] A mixture of 1 (979.1 mg, 2.2 mmol, 1.0 equiv.) and Int-AD-1 (600 mg, 2.2 mmol, 1.0 equiv.) in AcOH (20 mL) was stirred at 115°C for 16h. LCMS showed the reaction was complete. The mixture was concentrated and purified by flash column chromatography (DCM / EA from 0% to 75%) to give Int-AJ (mixture of Int-AJ-1 and Int-AJ-2, 360 mg, yield: 28.0%) as a yellow solid. Int-AJ was separated by SFC to give Int-AJ-1 (90 mg) and Int-AJ-2 (110 mg). LCMS(ESI)[M+1]+= 594.2, tR = 1.406 min. Preparative separation method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPakIB, 250×30 mm I. D., 5μm; Mobile phase: A for CO2and B for MeOH; Gradient: B 50%; Flow rate:60 mL / min; Back pressure: 100 bar; Column temperature: 40°C; Wavelength: 220 nm; Cycle-time:5 min; Injection volume: 0.5 mL; Number of injection needles: 26; Eluted time: 3; The 350 mg sample was dissolved in 13 mL EtOH. Peak 1: Int-AJ-1, retention time: 3.535 min. Peak 2: Int-AJ-2, retention time: 3.997 min.Preparation of Intermediate AK (Int-AK)

[0414] Step 1: To a solution of 1 (7.0 g, 31.7 mmol, 1.0 equiv.) in ethanol (70.0 mL) was added NaBH4 (1.2 g, 31.7 mmol, 0.9 equiv.) at 0°C and the reaction mixture was stirred at rt for 1 h. TLC showed the reaction was complete. The solution was poured into water and extracted with EA three times, the combined organic layer was washed with water, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 2 (6.2 g, 27.8 mmol, yield: 87.8%) as a white solid.1H NMR (400 MHz, DMSO) δ 7.34 (td, J= 8.9, 3.0 Hz, 1H), 7.21 (dd, J= 9.5, 1.1 Hz, 1H), 5.70 (t, J= 5.7 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H).

[0415] Step 2: To a solution of 2 (6.2 g, 27.8 mmol, 1.0 equiv.) in DMF (30.0 mL) were added 4 (13.6 g, 69.5 mmol, 2.5 equiv.) and K2CO3(11.5 g, 83.4 mmol, 3.0 equiv.) and the reaction mixture was stirred at rt for 10 h. TLC showed the reaction was complete. The solution was poured into water and extracted with EA three times, the combined organic layer was washed with water, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4 (7.9 g, 23.4 mmol, yield: 84.3%).1H NMR (400 MHz, DMSO) δ 7.45 - 7.27 (m, 1H), 7.18 (t, J= 12.8 Hz, 1H), 4.57 (s, 2H), 4.11 (s, 2H), 1.35 (d, J= 9.9 Hz, 9H).

[0416] Step 3: To a solution of 4 (7.9 g, 23.4 mmol, 1.0 equiv.) in DCM (8.0 mL) was added TFA (4.0 mL) and the reaction mixture was stirred at rt for 1 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure to give 5 (6.1 g, 21.7 mmol, yield: 92.6%) as a white solid. LCMS(ESI) [M-l]’ = 278.9, tR= 1.272 min.

[0417] Step 4: To a solution of 5 (6.1 g, 21.7 mmol, 1.0 equiv.) and 6 (2.3 g, 23.9 mmol, 1.1 equiv.) in DMF (30.0 mL) were added HATU (9.2 g, 24.3 mmol, 1.12 equiv.) and DIEA (14.0 g, 108.5 mmol, 5.0 equiv.) and the reaction mixture was stirred at rt for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA three times, the combined organic layer was washed with water, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography onsilica gel to give 7 (7.0 g, 21.6 mmol, yield: 99.5%) as a white solid. LCMS(ESI) [M+1]+= 324.1, tR= 1.484 min.

[0418] Step 5: To a solution of 7 (7.0 g, 21.6 mmol, 1.0 equiv.) in THF (150.0 mL) was added n-BuLi (17.5 mL, 28.1 mmol, 1.3 equiv.) at -78°C and the reaction mixture was stirred at -78°C for 3 h. LCMS showed 40% of desired product was detected. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel to give 8 (2.5 g, 13.6 mmol, yield: 62.9%) as a white solid. LCMS(ESI) [M+1]+= 185.2, tR= 1.050 min.

[0419] Step 6: To a solution of 8 (3.0 g, 16.3 mmol, 1.0 equiv.) in H2SO4(20.0 mL) was added HNO3 (10.0 mL) at 0°C and the reaction mixture was stirred at 0°C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into ice-water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give 9 (2.9 g, 12.7 mmol, yield: 77.7%) as a white solid. LCMS(ESI) [M-l]’ = 228.0, tR= 1.236 min.1H NMR (400 MHz, DMSO) δ 7.86 (t, J= 11.1 Hz, 1H), 5.05 (s, 2H), 4.38 (s, 2H).19F NMR (377 MHz, DMSO) δ -98.14 (d, J= 19.6 Hz), -106.72 (d, J= 19.5 Hz).

[0420] Step 7: To a solution of 9 (2.9 g, 12.7 mmol, 1.0 equiv.) in EtOH (9.0 mL) and water (3.0 mL) were added NH4Cl (1.4 g, 25.3 mmol, 2.0 equiv.) and Fe (2.1 g, 37.9 mmol, 3.0 equiv.), and the reaction mixture was stirred at 80°C for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel to give 10 (1.5 g, 7.5 mmol, yield: 59.5%) as a yellow solid. LCMS(ESI) [M+1]+= 200.1, tR= 0.797 min.1H NMR (400 MHz, DMSO) δ 7.18 (s, 1H), 5.19 (s, 2H), 4.75 (s, 2H), 4.23 (s, 2H).19F NMR (377 MHz, DMSO) δ -119.87 (d, J= 5.7 Hz), -123.74 (d, J= 6.4 Hz).

[0421] Step 8: To a solution of 10 (1.5 g, 7.5 mmol, 1.0 equiv.) in DCM (20.0 mL) were added AcCl (1.1 mL, 15.1 mmol, 2.0 equiv.) and DIEA (2.9 g, 22.6 mmol, 3.0 equiv), and the reaction mixture was stirred at 0°C for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give 11 (1.5 g, 6.2 mmol, yield: 82.6%) as a white solid. LCMS(ESI) [M+1]+= 242.0, tR= 0.562 min.1H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 7.48 (s, 1H), 4.72 (s, 2H), 4.32(s, 2H), 2.09 (d, J= 2.8 Hz, 3H).19F NMR (377 MHz, DMSO) 8 -105.82 (d, J= 14.3 Hz), -109.13 (d, = 14.0 Hz).

[0422] Step 9: To a solution of 11 (100.0 mg, 410.0 pmol, 1.0 equiv.) in DMSO (1.5 mL) was added NH3H2O (2.4 mL) and the reaction mixture was stirred at 130°C for 6 h. LCMS showed the reaction was complete. The reaction mixture was purified by prep-HPLC to give 12 (30.0 mg, 130.0 pmol, yield: 30.4%) as a white solid. LCMS(ESI) [M+1]+= 239.1, tR = 0.581 min.

[0423] Step 10: To a solution of 12 (30.0 mg, 130.0 pmol, 1.0 equiv.) and 13 (36.5 mg, 140.0 pmol, 1.1 equiv.) in toluene (5.0 mL) was added PPTS (31.7 mg, 130.0 pmol, 1.0 equiv.) and the reaction mixture was stirred at 110°C for 5 h. LCMS showed the reaction was complete. The solution was filtered and the filter cake was dried under reduced pressure to give 14 (35.0 mg, 80.0 μmol, yield: 59.7%) as a black solid. LCMS(ESI) [M+1]+= 466.4, tR = 1.762 min.

[0424] Step 11: A solution of 14 (35.0 mg, 80.0 μmol, 1.0 equiv.) in HCl (2.0 mL) was stirred at 100°C for 20 min. LCMS showed the reaction was complete. The solution was purified by prep-HPLC to give Int-AK (4.0 mg, 10.0 pmol, yield: 12.6%) as a yellow solid. LCMS(ESI) [M+1]+= 424.2, tR = 1.386 min. Column: YMC-Triart C18, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O / CH3CN / FA = 90:10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL / min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'H NMR (400 MHz, DMSO) 87.70 (d, J= 12.6 Hz, 1H), 7.21 (s, 1H), 6.49 (s, 1H), 5.94 (s, 2H), 5.41 (s, 2H), 5.18 (s, 2H), 5.08 (s, 2H), 4.94 (s, 2H), 1.90 - 1.81 (m, 2H), 0.87 (t, J = 13 Hz, 3H).19F NMR (377 MHz, DMSO) 8 -123.69 (s). Preparation purifcation method: Column: YMC-Actus Triart C18 50 mm*70 cm *5 um; Temperature: RT; Inject number: 1; Wave length: 220 nm / 254 nm; phase A: H2O (0.1%FA); phase B: CH3CN; TIME: 17.5 min.Preparation of Intermediate AL (Int-AL)

[0425] Step 1: To a solution of 1 (25.0 g, 75.7 mmol, 1.0 equiv.) and DIEA (24.4 g, 189.2 mmol, 2.5 equiv.) in THF (130.0 mL) was added 2 (22.7 g, 113.5 mmol, 1.5 equiv.) at 0°C. The mixture was warmed to room temperature and stirred for 1 hr. LCMS showed the reaction was complete. The mixture was cooled to 0 °C, poured into water (100 ml) and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was recrystallized with PE: DCM = 10:1 and filtered. The filter cake was washed with a solution of PE: EA(20:l, 50 mLx 2), and dried in vacuum to afford 3 (36.5 g, 73.8 mmol, yield: 97.5%) as white solid. LCMS (ESI) [M+1]+= 415.6, tR= 2.096 min.

[0426] Step 2: To a solution of 3 (700.0 mg, 0.8 mmol, 1.0 equiv.) in DMF (10.0 mL) were added t-BuONa (104.2 mg, 1.1 mmol, 1.5 equiv.) and 4 (172.6 mg, 1.1 mmol, 1.5 equiv.). The mixture was stirred at 0°C for 2 hrs. LCMS showed the reaction was complete. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography and eluted with DCM: MeOH=l 0: 1to afford 5 (700.0 mg, 0.7 mmol, yeild: 66.6%) as a yellow solid. LCMS(ESI) [M+l]+= 538.4, tR= 1.696 min.

[0427] Step 3: To a mixture of 5 (1.0 g, 1.9 mmol, 1.0 equiv.) and 6 (1.1 g, 1.9 mmol, 1.0 equiv.) in dioxane: H2O= (15.0 mL: 2 mL) were added K3PO4(1.2 g, 5.6 mmol, 3.0 equiv.) and cataCXium A Pd G3 (270.0 mg, 0.4 mmol, 0.2 equiv.) at 90°C. The mixture was stirred at 90°C for 2 hrs. LCMS showed the reaction was complete. The solvent was poured into water and extracted with EtOAc twice. The organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash chromatography and eluted with DCM: MeOH =100:5 to afford 7 (900.0 mg, 1.0 mmol, yield: 51.4%) as a yellow solid. LCMS(ESI) [M+l]+= 945.2, tR = 0.915 min.

[0428] Step 4: To a solution of 7 (500.0 mg, 0.6 mmol, 1.0 equiv.) in DMF (10.0 mL) was added CsF (124.4 mg, 1.2 mmol, 2.0 equiv). The mixture was stirred at rt for 2 hrs. LCMS showed the reaction was complete. The mixture was poured into water (20 ml) and extracted with EtOAc (20 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with DCM: MeOH=10:1 to afford 8 (300.0 mg, 0.5 mmol, yeild: 80.4%) as a yellow solid. LCMS(ESI) [M+l]+= 788.7, tR= 1.582 min.

[0429] Step 5: To a solution of 7 (300.0 mg, 0.5 mmol, 1.0 equiv.) in DCM (10.0 mL) was added TFA (3.0 mL). The mixture was stirred at rt for 2 hrs. LCMS showed the reaction was complete. LCMS showed the reaction was complete. The reaction mixture was concentrated to give Int-AL (200.0 mg, 0.3 mmol, yield: 60.0%) as a yellow solid. LCMS(ESI) [M+l]+= 588.2, tR= 1.150 min.Preparation of Intermediate AM (Int-AM)

[0430] Step 1: To a solution of 1 (11.0 g, 35.1 mmol, 1.0 equiv.) and TEA (8.7 g, 87.6 mmol, 3.0 equiv.) in THF (110.0 mL) was added 2 (7.7 g, 38.5 mmol, 1.1 equiv.) at 0°C. The mixture was stirred at rt for 1.5 h. The reaction was monitored by LCMS. The reaction mixture was quenched with water and extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with PE: DCM = 10:1 and filtered. The filter cake was further triturated with PE: EA= 20:1 and filtered to afford 3 (15.0 g, 31.4 mmol, yield: 89.6 %) as a white solid. LCMS(ESI)[M+1] = 479.3, tR= 2.065 min.

[0431] Step 2: To a solution of 3 (15.7 g, 32.8 mmol, 1.0 equiv) and 4 (5.4 g, 34.5 mmol, 1.1 equiv) in THF (100.0 mL) and DMF (100.0 mL) were added Cs₂CO₃ (32.12 g, 98.5 mmol, 3.0 equiv) and 1, 4-diazabicyclo [2.2.2] octane (1.1 g, 9.8 mmol, 0.2 equiv). The reaction was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The reaction mixture was washed with NaHCO₃ solution, and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude product was purified by flash silica chromatography, eluting with a gradient of 20-30 % EtOAc in petroleum ether to afford 5 (18.0 g, 29.9 mmol, yield: 91.2 %) as a colorless oil. LCMS(ESI)[M+1]+= 602.4, tR= 1.448 min.

[0432] Step 3: To a mixture of 5 (3.0 g, 5.0 mmol, 1.0 equiv.), 6 (4.7 g, 7.5 mmol, 1.5 equiv.) and K3PO4 (3.2 g, 22.2 mmol, 3.0 equiv.) in H2O (6.0 mL) and toluene (30.0 mL) was added CataCXium A Pd G2(0.3 g, 0.5 mmol, 0.1 equiv.). The reaction mixture was backfilled with nitrogen three times, then heated to 80°C and stirred for 2 hours under nitrogen. The reaction was monitored by LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography, eluting with agradient of 0 to 10% MeOH in DCM. The desired fractions were evaporated to dryness to afford 7 (5.0 g, 6.8 mmol, yield: 97.6 %) as a yellow solid.

[0433] Step 4: To a solution of 7 (5.0 g, 4.8 mmol, 1.0 equiv.) in DMF (110.0 mL) were added K2CO3(3.4 g, 24.4 mmol, 5.0 equiv.) and CsF (1.4 g, 9.7 mmol, 2.0 equiv.). The mixture was stirred at 60 °C for 1.5 h. The reaction was monitored by LCMS. The reaction mixture was quenched with water and extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with PE: DCM = 10:1 and filtered. The filter cake was further triturated with PE: EA = 20: 1 and filtered to afford 8 (4.0 g, 4.6 mmol, yield: 94.4 %) as a white solid. LCMS(ESI)[M+1] = 869.4, tR= 1.754 min.

[0434] Step 5: To a solution of 8 (5.0 g, 4.8 mmol, 1.0 equiv.) in DMF (110...

Claims

CLAIMS1. A compound of Formula I:Ior 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 inhibitor payload moiety.

2. The compound of claim 1, wherein:L1is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-,-OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

4. The compound of claim 2, wherein L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-.

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

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

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

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

12. The compound of any one of claims 1-11, 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 of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Yis CR2orN;R1is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R2is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;R3is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R4is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;OK ^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 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 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; andeach m is independently 0, 1, or 2.

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

16. The compound of claim 14 or 15, wherein Y is CR2.

17. The compound of claim 16, wherein R2is halogen.

18. The compound of claim 14 or 15, wherein Y is N.

19. The compound of any one of claims 14-18, wherein R4is halogen.

20. The compound of any one of claims 14-19, wherein 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, -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.

21. The compound of claim 20, wherein R3is selected from:

22. The compound of any one of claims 14-21, wherein R5is -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.

23. The compound of claim 22, wherein R5is -O(Ci-4 alkylene)Cy2.

24. The compound of claim 22, wherein R5is selected from:

25. The compound of claim 22, wherein R6is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)2 or monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl.

26. The compound of claim 22, wherein Cy1is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

27. The compound of claim 22 or 23, wherein Cy2is an optionally substituted monocyclic 4-to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

28. The compound of any one of claims 14-27, 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.

29. The compound of claim 28, wherein Ring A is optionally substitutedV0A30. The compound of any one of claims 14-29, wherein L2is a covalent bond.

31. The compound of any one of claims 14-30, wherein L3is a covalent bond.

32. The compound of any one of claims 14-27, wherein a moietyselected from:

33. The compound of any one of claims 14-27, wherein the compound is a compound of Formula Il-b or Il-d:Il-b n-dor a pharmaceutically acceptable salt thereof, whereineach 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; andn is 0, 1, 2, 3, 4, 5, or 6.

34. The compound of claim 33, wherein each R7is independently optionally substituted Ci-6 alkyl.

35. The compound of claim 33, wherein 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.

36. The compound of any one of claims 33-35, wherein n is 0, 1, or 2.

37. The compound of any one of claims 1-36, wherein the compound is a compound of Formula III:IIIor 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 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;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 Ri, 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; Rjis 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; andeach 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 to form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

38. The compound of claim 37, wherein Z1is O.

39. The compound of any one of claims 1-36, wherein the compound is a compound of Formula IV: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 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, -C02Rbb, -C(0)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, -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; Rjis 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; andeach 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 to form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

40. The compound of any one of claims 37-39, wherein Z2is a covalent bond.

41. The compound of any one of claims 37-39, wherein Z2is -C(RC)2-.

42. The compound of any one of claims 37-41, wherein Rais Ci-6 alkyl.

43. The compound of any one of claims 37-42, wherein Rbis -OH.

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

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

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

47. The compound of any one of claims 37-46, 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 Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic.

48. The compound of any one of claims 37-46, wherein Rfis hydrogen, -CORbb, -C(NORbb)Rbb, -ORaa, -Si(Rbb)3, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic.

49. The compound of any one of claims 37-48, wherein Rgis hydrogen, halogen, -CN, -CORbb, -C(NORbb)Rbb, -NO2, or optionally substituted Ci-6 aliphatic.

50. The compound of any one of claims 37-46, wherein 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.

51. The compound of any one of claims 37-50, wherein Rhis hydrogen, halogen, -N(Raa)2, -ORaa, or optionally substituted Ci-6 aliphatic.

52. The compound of any one of claims 37-48, wherein 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.

53. The compound of any one of claims 37-52, wherein R1is hydrogen or halogen.

54. The compound of any one of claims 37-50, 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.

55. The compound of any one of claims 37-54, wherein Rjis hydrogen or halogen.

56. The compound of any one of claims 37-55, wherein each Raais Rbb.

57. The compound of any one of claims 37-56, wherein each Rbbis hydrogen or optionally substituted Ci-6 aliphatic.

58. The compound of any one of claims 37-57, wherein W is O.

59. The compound of any one of claims 37 or 42-58, wherein the compound is a compound of Formula Ill-b:Ill-bor a pharmaceutically acceptable salt thereof.

60. The compound of any one of claims 37 or 42-58, wherein the compound is a compound of Formulae Ill-d, Ill-e, Ill-f, or Ill-g:or a pharmaceutically acceptable salt thereof.

61. The compound of any one of claims 39-58, wherein the compound is a compound of Formula IV-a:or a pharmaceutically acceptable salt thereof.

62. The compound of any one of claims 39-58, wherein the compound is a compound of Formula IV-b:or a pharmaceutically acceptable salt thereof.

63. The compound of any one of claims 1-36, wherein the compound is a compound of Formula V: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 C1-6aliphatic; Rmis hydrogen or optionally substituted C1-6aliphatic;each Rnand Rpis independently hydrogen or optionally substituted C1-6aliphatic;each Rqis independently halogen, -ORcc, -N(Rcc)2, or optionally substituted C1-6aliphatic; each Rccis independently hydrogen or optionally substituted C1-6aliphatic;s is 0, 1, 2, 3, or 4; andt is 0, 1, 2, 3, or 4.

64. The compound of claim 63, wherein each Rkis independently halogen or -N(Rcc)2.

65. The compound of claim 63 or 64, wherein Rmis optionally substituted C1-6aliphatic.

66. The compound of any one of claims 63-65, wherein each Rnis hydrogen.

67. The compound of any one of claims 63-66, wherein each Rpis hydrogen.

68. The compound of any one of claims 63-67, wherein s is 0, 1, or 2.

69. The compound of any one of claims 63-68, wherein t is 0, 1, or 2.

70. The compound of any one of claims 63-69, wherein the compound is a compound of Formula V-a:V-aor a pharmaceutically acceptable salt thereof, wherein t is 0, 1, 2, or 3.

71. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VI:VIor 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-6aliphatic; Rsis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6aliphatic;each Rtis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted C1-6aliphatic, or two Rtcombine to form an optionally substituted C5-7carbocyclic 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 C1-6aliphatic;each Rddis independently hydrogen or optionally substituted C1-6aliphatic;u is 0, 1, 2, 3, or 4; andv is 0, 1, 2, 3, or 4.

72. The compound of claim 71, wherein each Rris independently -ORdd.

73. The compound of claim 71 or 72, wherein Rsis hydrogen.

74. The compound of any one of claims 71-73, wherein each Rtis independently -ORdd.

75. The compound of any one of claims 71-73, wherein two Rtcombine 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.

76. The compound of any one of claims 71-75, wherein Ruis optionally substituted C1-6 aliphatic.

77. The compound of any one of claims 71-76, wherein u is 0, 1, or 2.

78. The compound of any one of claims 71-77, wherein v is 0, 1, or 2.

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

80. A pharmaceutical composition, comprising the compound of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

81. A method of inhibiting topoisomerase I, comprising contacting the compound of any one of claims 1-79 or the composition of claim 80 with a KRAS protein (e.g., KRASG12C).

82. A method of releasing a topoisomerase 1 inhibitor payload (e.g., a topoisomerase 1 inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-79 or the composition of claim 80 with a KRAS protein (e.g., KRASG12C).

83. A method of delivering a topoisomerase 1 inhibitor payload (e.g., a topoisomerase 1 inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-79 or the composition of claim 80 with a KRAS protein (e.g., KRASG12C).

84. The method of any one of claims 81-83, wherein the contacting occurs in a cell harboring a KRASG12Cmutant protein.

85. The method of any one of claims 81-84, wherein the contacting occurs in a subject (e.g., a human subject).

86. A method, comprising administering the compound of any one of claims 1-79 or the composition of claim 80 to a subject in need thereof.

87. 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 1-79 or the composition of claim 80 to a subject in need thereof.

88. The method of claim 87, wherein the disease, disorder, or condition associated with KRAS is a cancer.

89. A method of treating cancer, comprising administering the compound of any one of claims 1-79 or the composition of claim 80 to a subject in need thereof.

90. The method of claim 88 or 89, wherein the cancer is non-small cell lung cancer or colorectal cancer.

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