Covalent-induced drug conjugates targeting KRAS and comprising a tubulin inhibitor payload

Abstract

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

Description

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

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 696,683, filed September 19, 2024; the contents of which is herein incorporated by reference.BACKGROUND

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

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

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

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

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

[0007] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0008] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, atropisomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0009] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

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

[0011] The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e g., Cue). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e g., C1.5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.

[0012] The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, Ci-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 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 7t electrons shared in a cyclic array; and having, in addition tocarbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 7- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

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

[0019] As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety or a 10- to 16-membered polycyclic (i.e., comprising three or more rings) moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, orpolycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic or polycyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 6- to 11 -membered spirocyclic bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic or polycyclic heterocyclic ring can also be a bridged ring system (e g., 6- to 11-membered bridged bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).

[0020] As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moi eties, as herein defined.

[0021] As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0022] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned bythis disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0023] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CH2)o 4R0; -(CH2)o-4OR°; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O 4CH(0RO)2; -(CH2)O^ISRC; -(CH2)o 4Ph, which may be substituted with R°; -(CH2)0 40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o 40(CH2)o 1 -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O4N(RO)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°;N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; - C(S)R°; -(CH2)O4C(O)ORO; -(CH2)O4C(O)SR°; -(CH2)O4C(O)OSiR°3; -(CH2)o4OC(O)R°; - OC(0)(CH2)o 4SR0; -(CH2)O4SC(O)RO; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; - SC(S)SR°, -(CH2)0 4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)o 4SSR0; -(CH2)0^S(O)2R°; -(CH2)o^S(0)2OR0; -(CH2)o4OS(O)2RO; - S(O)2NR°2; -(CH2)O4S(O)R°; -N(R°)S(O)2NRO2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; - (CH2)O4P(O)2R°; (CH2)O4P(O)RO2; (CH2)O4P(O)(ORO)2; (CH2)O4OP(O)RO2; (CH2)O4OP(O)(OR°)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or - (Ci^i straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[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)o2R*,-(haloR*), -(CH2)0 2OH, -(CH2)O 2OR*, -(CH2)O 2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)02C(O)R*, -(CH2)O 2C(O)OH, -(CH2)O 2C(O)OR*, -(CH2)O 2SR’, -(CH2)O-2SH, -(CH2)O 2NH2, - (CH2)0 2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR*. -(Ci-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 C i 4 aliphatic, - CH2Ph, -0(CH2)o-iPh, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

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

[0026] Suitable substituents on the aliphatic group of R include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R;, -NR‘:2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf,C(O)CH2C(O)Rt, -S(O)2RT, -S(O)2NRT2, -C(S)NRT2, -C(NH)NRt2, or -N(RT)S(O)2RT; wherein each R is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R' , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Suitable substituents on the aliphatic group of R:are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^t aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3-7- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.

[0030] In some embodiments, the term appears adjacent to a point of atropisomerism. In such cases, it is understood to denote either an “Ra” or “Sa” atropisomer, but the particular isomer was not determined.

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

[0032] In some embodiments, the present disclosure provides covalent-induced drug conjugates (CIDCs), as described further herein. Provided CIDCs are bifunctional compounds 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 ofcovalently interacting with the protein binding moiety, such as through a reactive cysteine residue; (ii) a payload moiety; and (iii) a linking moiety connecting the protein binding moiety to the payload moiety. Exemplary schemes are shown in FIG. lAand FIG. IB. First, the protein binding moiety (“R”) binds the oncogenic protein (“Target”), which bears a reactive cysteine residue. Then, the reactive cysteine residue covalently binds an a,|3-unsaturated carbonyl moiety (or other suitable Michael acceptor) of the CIDC, triggering cleavage of the linking moiety and release of the activated payload moiety (“Payload”).

[0033] CIDCs have the potential to reduce off-target side effects, because the cytotoxic payload is inactivated when it is part of the CIDC and is not released until the CIDC covalently binds an oncogenic target, meaning the payload is activated only upon delivery to a cancer cell expressing a particular oncogenic protein. Like antibody-drug conjugates (ADCs), the CIDC delivery mechanism allows for specific targeting of cancer cells; however, unlike ADCs, which target extracellular surface markers, CIDCs can also exploit intracellular proteins for precise payload delivery. Additionally, CIDCs are small molecules, in contrast to large-molecule ADCs, which makes CIDCs potentially amenable for oral administration.

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

[0035] In some embodiments, the present disclosure provides a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:KBM is a KRASG12Cbinding moiety;Rxis hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-6 aliphatic, C3.7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ryis hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rzis independently hydrogen, halogen, or optionally substituted C1-6 aliphatic;X is a covalent bond, -O-, -N(RW)-, or -S-;Rwis hydrogen or optionally substituted C1-6 aliphatic;L1is a covalent bond or a linking moiety; andTPM is a tubulin inhibitor payload moiety.

[0036] In some embodiments, the present disclosure provides a compound of Formula I-a:or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, X, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0037] In some embodiments, the present disclosure provides a compound of Formula I-b:Lb or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein: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 optionallyand independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0038] In some embodiments, the present disclosure provides a compound of Formula I-c:I-c or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lais a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-to 7-membered monocyclic heterocyclyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0039] In some embodiments, the present disclosure provides a compound of Formula I-d:I-d or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lhis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] In some embodiments, the present disclosure provides a compound of Formula I-e:or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0041] In some embodiments, the present disclosure provides a compound of Formula I-f:or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:Lbis a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-,-OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0042] In some embodiments, the present disclosure provides a compound of Formula I-g:I-g or a pharmaceutically acceptable salt thereof, wherein KBM, L1, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

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

[0044] In some embodiments, the present disclosure provides a compound of Formula I-h- 1 :I-h-1 or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-1, Rzis not hydrogen.

[0045] In some embodiments, the present disclosure provides a compound of Formula I-h-2:I-h-2 or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-2, Rzis not hydrogen.

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

[0047] In some embodiments of any Formulae described herein, Ryis hydrogen, halogen, cyano, or optionally substituted C1-6 aliphatic. In some embodiments, Ryis hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, Ryis hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Ryis an optionally substituted group selected from C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis an optionally substituted group selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis hydrogen. In some embodiments, Ryis halogen (e.g., fluoro). In some embodiments, Ryis cyano. In some embodiments, Ryis optionally substituted C1-6 aliphatic. In some embodiments, Ryis C1-6 aliphatic optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ryis Ci-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ryis Ci-6 alkyl. In some embodiments, Ryis -CH3. In some embodiments, Ryis Ci-6 aliphatic. In some embodiments, Ryis optionally substituted Ci-6 alkyl. In some embodiments, Ryis Ci-6 alkyl. Insome 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.

[0048] In some embodiments of any Formulae described herein, each Rzis independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each Rzis independently hydrogen or Ci-6 aliphatic. In some embodiments, each Rzis independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rzis independently hydrogen or C1-6 alkyl. In some embodiments, each Rzis hydrogen. In some embodiments, one Rzis hydrogen and the other Rzis optionally substituted C1-6 alkyl. In some embodiments, one Rzis hydrogen and the other Rzis C1-6 alkyl. In some embodiments, a Rzis hydrogen. In some embodiments, a Rzis halogen (e.g., fluoro). In some embodiments, a Rzis optionally substituted C1-6 aliphatic. In some embodiments, a Rzis C1-6 aliphatic optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), - NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rzis C1-6 aliphatic. In some embodiments, a Rzis optionally substituted C1-6 alkyl. In some embodiments, a Rzis Cue alkyl. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more halogen atoms. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more fluorine atoms. In some embodiments, a Rzis CF3. In some embodiments, a Rzis C1-6 alkyl optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), -NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rzis C1-6 alkyl.In some embodiments, a Rzis hydrogen, -CH3,. In some embodiments, one Rzis hydrogen, and one Rzis optionally substitutedCi-6 aliphatic.

[0049] In some embodiments of any Formulae described herein, X is -O- or -N(RW)-. In some embodiments, X is -O-. In some embodiments, X is -N(RW)-. In some embodiments, X is -N(H)- . In some embodiments, X is -N(CHs)-. In some embodiments, X is -S-. In some embodiments, X is a covalent bond. It will be appreciated that, in some embodiments, when X is a covalent bond, -i -TPM is a sufficient leaving group to result in release of the tubulin inhibitor payload upon binding of the compound to KRASG12C.

[0050] In some embodiments of any Formulae described herein, Rwis hydrogen. In some embodiments, Rwis optionally substituted Ci-6 aliphatic. In some embodiments, Rwis Ci-6 aliphatic. In some embodiments, Rwis optionally substituted Ci-6 alkyl. In some embodiments, Rwis Ci-6 alkyl (e.g., methyl).

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

[0052] In some embodiments of any Formulae described herein, L1is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S- , -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-, wherein each R is independently hydrogen or an optionallysubstituted 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.

[0053] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Cno hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0054] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-io hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)- , -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-.

[0055] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O- , -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(0)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0056] In some embodiments of any Formulae described herein, L1is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2- , 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 Ci- 6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N- , -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-.

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

[0059] In some embodiments of any Formulae described herein, L1isR, wherein Laand R are as defined above for Formula I-b and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-b.

[0060] In some embodiments of any Formulae described herein, L1is, whereinLais 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.

[0061] In some embodiments of any Formulae described herein, L1is, whereinLais as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0062] In some embodiments of any Formulae described herein,, wherein Laand R are as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0063] R v v

[0064] In some embodiments of any Formulae described herein, L1is O , whereinLband R are as defined above for Formula I-d and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-d.O

[0065] In some embodiments of any Formulae described herein, L1isRwherein Lband R are as defined above for Formula I-e and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-e.

[0066] In some embodiments of any Formulae described herein, L1is O , wherein Lband R are as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; and the L1moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-f.

[0067] In some embodiments of any Formulae described herein, L1is, whereinLbis as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0068] In some embodiments of any Formulae described herein, L1is R wherein Lbis as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached toTPM.

[0069] In some embodiments of any Formulae described herein, L1is 0

[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 ^4 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 A 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, L1is selected from: a covalent, p y p y substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.

[0076] In some embodiments of any Formulae described herein, L1is selected from: a covalentX; and the bond labeled B is attached to TPM.

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

[0078] 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 Ci-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lais an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0079] In some embodiments of any Formulae described herein, 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-, -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-

[0080] In some embodiments of any Formulae described herein, Lbis a covalent bond.

[0081] In some embodiments of any Formulae described herein, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0082] 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-, -0C(0)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lbis an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-

[0083] 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, Leis optionally substituted C1-3 alkylene. In some embodiments, Lcis Ci-6 alkylene. In some embodiments, Lcis C1-3 alkylene. In some embodiments, Leis -CH2- . In some embodiments, Lcis -CH2CH2-. In some embodiments, Lcis -CH2CH2CH2-.

[0084] 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 orCi-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 C1-6 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 C1-6 alkyl. In some embodiments, each R is hydrogen. In some embodiments, a R is hydrogen. In some embodiments, a R is optionally substituted C1-6 aliphatic. In some embodiments, a R is C1-6 aliphatic optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, an R is -CH2CH2N(CH3)2. In some embodiments, a R is optionally substituted Ci-6 alkyl. In some embodiments, a R is 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, a R is Ci-6 alkyl (e g., methyl). In some embodiments, an R is isopropyl. In some embodiments, an R is methyl. In some embodiments, a R is optionally substituted phenyl. In some embodiments, a R is optionally substituted C3-7 monocyclic carbocyclyl. In some embodiments, a R is optionally substituted C3-7 cycloalkyl (e.g., cyclopropyl). In some embodiments, a R is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a R is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments of any Formulae described herein, each Cy is independently an optionally substituted, mono- or multi cyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, phenylene, a bicyclic C9-10 arylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10- membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, phenylene, a monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, a bicyclic C9-10 arylene, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments of any Formulae described herein, a Cy is an optionally substituted monocyclic C3-7 carbocyclylene. In some embodiments, a Cy is an optionally substituted bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Cy is bivalent bicyclo[l. l. l]pentane. In some embodiments, a Cy is an optionally substituted phenylene. In some embodiments, a Cy is an optionally substituted bicyclic C9-10 arylene. In some embodiments, a Cy is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e g., a bivalent pyrrolidine). In some embodiments, a Cy is an optionally substituted bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Cy is an optionally substituted monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is bivalent tetrazole. In some embodiments, a Cy is an optionally substituted bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments of any Formulae described herein, -X-L1- forms a self- immolative or degradable linking moiety, such that upon binding of the compound to KRASG12C, the tubulin inhibitor payload is released from the compound. It will be appreciated therefore that, in some embodiments, when both X and L1are a covalent bond, TPM is a sufficient leaving group to result in release of the tubulin inhibitor payload upon binding of the compound to KRASG12C.KRABP12CBinding Moiety

[0088] As described and defined herein, KBM is a KRASG12Cbinding moiety, i.e., a moiety capable of binding KRASG12Cprotein. Typically, a KBM is considered to be capable of binding a KRASG12Cprotein if it specifically (or preferentially) associates with the KRASG12Cprotein when contacted with KRASG12Cprotein in the presence of at least one other protein. In some embodiments, a KBM is considered to be capable of binding KRASG12Cprotein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a KBM is considered capable of binding a KRASG12Cprotein if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less).

[0089] 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:Y is CR2or N;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;R5is hydrogen, -OR6, V°^^^Cy1, -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 heterocyclyl ene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

[0090] In some embodiments, the present disclosure provides a compound of Formula 11-a:Il-aor a pharmaceutically acceptable salt thereof, wherein L1, R2, 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-b:II-b or 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; and n is 0, 1, 2, 3, 4, 5, or 6.

[0092] In some embodiments, the present disclosure provides a compound of Formula II-c:II-C or a pharmaceutically acceptable salt thereof, wherein L1, 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.

[0093] In some embodiments, the present disclosure provides a compound of Formula Il-d:n-d or 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; and n is 0, 1, 2, 3, 4, 5, or 6.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] In some embodiments of any Formulae described herein, Y is CR2. In some embodiments, Y is N.

[0100] 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 Ci-6 aliphatic. In some embodiments, R1is Cue aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R1is Ci-6 aliphatic. In some 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 Ci-6 alkyl (e.g., -CH3). In some embodiments, R1is optionally substituted C3-7 cycloaliphatic. In some embodiments, R1is C3-7 cycloaliphatic. In some embodiments, R1is optionally substituted C3-7 cycloalkyl. In some embodiments, R1is C3-7 cycloalkyl (e.g., cyclopropyl).

[0101] 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 Ci-6 aliphatic. In some embodiments, R2is Ci-6 aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R2is Ci-6 aliphatic. In some embodiments, R2is optionally substituted Ci-6 alkyl. In some embodiments, R2is Ci-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).

[0102] 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-6alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3).

[0103] 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 a 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 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.

[0104] 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 Ci-6 haloaliphatic (e.g., -CF3).

[0105] 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 Ci-6 haloaliphatic (e.g., -CF3).

[0106] 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, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-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 Ci-6haloaliphatic (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 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 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).

[0107] 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, C1-6 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, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 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, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3is optionally substituted benzothiophenyl, optionally substituted benzothiazolyl, optionally substituted benzimidazolyl, or optionally substituted indazolyl. In some embodiments, R3is benzothiophenyl 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 benzothiazolyl 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).

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

[0109] In some embodiments of any Formulae described herein, R3is a 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).

[0110] In some embodiments of any Formulae described herein, R3is selected from:[0U1] In some embodiments of any Formulae described herein, R3is selected from:some embodiments,some embodiments,

[0112] 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). y°'^ /

[0113] In some embodiments of any Formulae described herein, R5is -OR6,Cy1, -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. In some embodiments, R is -OR6,, or -O(Ci-4 alkylene)Cy2. In some embodiments, R5is y° / hydrogen. In some embodiments, R5is -OR6. In some embodiments, R5isCy1. In some embodiments, R5is -O(Ci-4 alkylene)Cy2. In some embodiments, R5is -OCFFCy2. 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, R' is an optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is azetidinyl optionally substituted with -N(CI-6 alkyl^).

[0114] In some embodiments of any Formulae described herein, R?is selected from hydrogen,some embodiments, R5isIn some embodiments, R5isembodiments, R isIn some embodiments, R5isembodiments,some embodiments, R5is. In some embodiments, R5isIn some embodiments,some embodiments, R5isIn some embodiments,some embodiments, R5isIn some embodiments, R5isIn some embodiments, R5isIn some embodiments, R5is

[0115] In some embodiments of any Formulae described herein, R6is optionally substitutedCi-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)2. In some embodiments, R6is -CH2CH2N(CH.3)2. In some embodiments, R6is optionally substituted Ci-6 alkyl. In some embodiments, R6is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)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 1-2heteroatoms 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)? or 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl.

[0116] 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.

[0117] 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 heteroatomsindependently 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.

[0118] 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.

[0119] In some embodiments of any Formulae described herein, Cy1is an optionally substituted ring selected from:

[0120] In some embodiments of any Formulae described herein, Cy1is selected from:

[0121] 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.

[0122] 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.

[0123] 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 some embodiments, Cy2is a bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or Ci-6 alkyl. In some embodiments, Cy2is an optionallysubstituted 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.

[0124] In some embodiments of any Formulae described herein, Cy2is an optionally substituted ring selected from:

[0125] In some embodiments of any Formulae described herein, Cy2is selected from:embodiments, Cy2isIn some embodiments,some embodiments,some embodiments, Cy2iss, y .

[0126] 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.

[0127] 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.

[0128] 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 optionally substituted monocyclic 4- to 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring A is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur(e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring A is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more Ci-6 alkyl or -CH2CN). In some embodiments, Ring A is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0129] 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 optionally substituted 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.

[0130] In some embodiments of any Formulae described herein, Ring A is optionally substituted 0A

[0131] In some embodiments of any Formulae described herein, Ringwherein R7and n are as defined herein for Formula Il-b and described in classes and subclasses herein, both singly and in combination.

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

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

[0134] In some embodiments of any Formulae described herein, Ring A is selected from:

[0135] In some embodiments of any Formulae described herein, Ring A is selected from:

[0136] 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.

[0137] 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.

[0138] 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-.

[0139] 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’)-.

[0140] 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.

[0141] 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’)-.

[0143] In some embodiments of any Formulae described herein, a moietyis selected from:

[0144] In some embodiments of any Formulae described herein, a moietyis selected from:

[0145] In some embodiments, KBM is a KRASG12Cbinding moiety (e.g., a moiety that binds and / or inhibits KRASG12C). The present disclosure encompasses the recognition that i) KRASG12Cinhibitor compounds generally comprise an a,P-unsaturated carbonyl moiety (or other suitable Michael acceptor) at a suitable position to interact with a cysteine of KRASG12C, and ii) a KRASG12Cbinding moiety in the CIDCs described herein can be made by installing a linking moiety bound to a tubulin inhibitor payload moiety, as defined herein (e.g.,such suitable position where an a, [3 -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,0-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;WO20 16 / 044772; WO2016 / 049524; WO2016 / 164675; WO2016 / 168540; W02017 / 058805;WO2017 / 015562; WO2017 / 058728; WO2017 / 058768; WO2017 / 058792; WO2017 / 058805;W02017 / 058807; W02017 / 058902; WO2017 / 058915; WO2017 / 087528; W02017 / 100546;W02017 / 201161; WO2018 / 064510; WO2018 / 068017; WO2018 / 119183; W02018 / 140512;WO2018 / 140513; W02018 / 140514; WO2018 / 140598; WO2018 / 140599; WO2018 / 140600;WO2018 / 143315; WO2018 / 206539; WO2018 / 218070; WO2018 / 218071; WO2019 / 099524;W02019 / 110751; W02019 / 141250; W02019 / 150305; WO2019 / 155399; WO2019 / 213516;WO2019 / 213526; WO2019 / 217307; WO2019 / 217691; WO2019 / 232419; W02020 / 050890;W02020 / 035031; W02020 / 047192; W02020 / 081282; W02020 / 086739; W02020 / 106640;W02020 / 113071; WO2021 / 055728; W02021 / 058018; WO2021 / 086833; WO2022 / 083569;WO2022 / 087375; WO2022 / 087371; WO2022 / 093856; WO2022 / 109487; WO2022 / 109485;WO2022 / 119748; WO2022 / 152233; WO2022 / 221528; WO2022 / 232318; WO2022 / 232320;WO2022 / 269508; WO2022 / 269525; WO2023 / 225252; WO2023 / 133181; W02023 / 004102;WO2023 / 283213; WO2023 / 284730; WO2023 / 287896; WO2023 / 284537; WO2023 / 283933;W02023 / 001141; W02023 / 018809; W02023 / 018699; W02023 / 034290; W02023 / 030495;W02023 / 030517; W02024 / 050640; W02023 / 039240; WO2023 / 049697; WO2023 / 046135;WO2023 / 056421; WO2023 / 057985; WO2023 / 064857; W02023 / 081840; WO2023 / 086341;WO2023 / 086383; WO2023 / 097227; WO2023 / 101928; WO2023 / 099623; WO2023 / 099612;WO2023 / 099592; WO2023 / 105491; WO2023 / 114733; WO2023 / 125627; WO2023 / 133183;W02023 / 141300; WO2023 / 150284; WO2023 / 154766; WO2023 / 152255; WO2023 / 159086;WO2023 / 159087; WO2023 / 173014; WO2023 / 172737; WO2023 / 183755; WO2023 / 179703;WO2023 / 183585; WO2023 / 205719; WO2023 / 212548; WO2023 / 212549; WO2023 / 215801;WO2023 / 213269; WO2023 / 219941; WO2023 / 220421; WO2023 / 225302; W02023 / 230190;WO2023 / 240263; WO2023 / 240189; WO2023 / 240188; WO2023 / 244604; WO2023 / 244599;WO2023 / 244615; WO2023 / 244713; WO2023 / 246777; W02024 / 008610; W02024 / 008068;W02024 / 009191; W02024 / 008179; W02024 / 008834; W02024 / 015262; W02024 / 015731;W02024 / 030647; W02024 / 030633; W02024 / 036270; W02024 / 032703; W02024 / 032704;W02024 / 032702; W02024 / 040109; W02024 / 040131; WO2024 / 041621; WO2024 / 041573;WO2024 / 047135; WO2024 / 054926; WO2024 / 051721; WO2024 / 054647; WO2024 / 064353;WO2024 / 076674; W02024 / 076670; WO2024 / 085661; WO2024 / 083168; WO2024 / 083246;W02024 / 091409; WO2024 / 097559; W02024 / 103010; WO2024 / 107686; WO2024 / 112654;WO2024 / 120419; WO2024 / 153116; WO2024 / 155706; WO2024 / 153119; WO2024 / 158778;WO2024 / 159471 ; WO2024 / 159470; WO2024 / 173842; WO2024 / 178304; WO2024 / 178313;WO2024 / 179546; WO2024 / 192424; WO2024 / 197503; WO2024 / 206747; WO2024 / 206766;WO2024 / 209339; WO2024 / 213979; WO2024 / 215754; WO2024 / 220532; WO2024 / 220645;WO2024 / 218686; WO2024 / 227091; WO2024 / 229317; WO2024 / 229442; WO2024 / 229444;WO2024 / 229447; WO2024 / 230734; WO2024 / 233776; WO2024 / 236452; WO2024 / 238343;WO2024 / 238633; WO2024 / 235286; WO2024 / 243025; WO2024 / 241248; WO2024 / 246099;WO2024 / 259169; WO2024 / 255795; W02025 / 006704; W02025 / 007000; W02025 / 006962;W02025 / 006720; W02025 / 123007; WO2025 / 122619; WO2025 / 123318; WO2025 / 124415;WO2025 / 137519; WO2025 / 151765; WO2025 / 151738; WO2025 / 151594; WO2025 / 153038;WO2025 / 163494; WO2025 / 165972; WO2025 / 170938; WO2025 / 171055; WO2025 / 168072;WO2025 / 179058; WO2025 / 184572; and WO2025 / 188668.

[0146] In some embodiments, KBM is a means for binding KRASG12C. In some embodiments, KBM is a means for targeting KRASG12C.Tubulin Inhibitor Payload Moiety

[0147] As described and defined herein, TPM is a tubulin inhibitor payload moiety, i.e., a moiety capable of binding and / or inhibiting tubulin protein. Typically, a TPM is considered to be capable of binding a tubulin protein if it specifically (or preferentially) associates with the tubulin protein when contacted with tubulin protein in the presence of at least one other protein or DNA. In some embodiments, a TPM is considered to be capable of binding tubulin protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a TPM is considered capable of binding a tubulin protein if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 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 tubulin 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).

[0148] In some embodiments, the present disclosure provides a compound of Formula III:Ill or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Rais independently halogen, -OR33, -N(Raa)2, or optionally substituted Ci-6 aliphatic; each Rbis independently halogen, -OR33, -NQ3^, or optionally substituted Ci-6 aliphatic;Rcand Rdare each independently hydrogen, halogen, or optionally substituted Ci-6 aliphatic; each R33is independently hydrogen or optionally substituted Ci-6 aliphatic; a is 0, 1, 2, 3, 4, or 5; and b is 0, 1, 2, 3, 4, or 5.

[0149] In some embodiments, the present disclosure provides a compound of Formula IILa:Ill-a or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rx, Ry, Rz, X, a, 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-b :or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Rx, Ry, Rz, X, b, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination; and a is 0, 1, 2, 3, or 4.

[0151] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Rc, Rd, a, and b are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0152] In some embodiments of any Formulae described herein, TPM is:wherein Raand a are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0153] In some embodiments of any Formulae described herein, TPM is:wherein Ra, Rb, Re, Rd, a, and b are as defined in Formula Ill-b and described in classes and subclasses herein, both singly and in combination.

[0154] In some embodiments of any Formulae described herein, each Rais independently halogen, -ORaa, -N(Raa)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rais independently -ORaaor -N(Raa)2. In some embodiments, each Rais independently -ORaa(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rais -OH. In some embodiments, Rais -OCH3. In some embodiments, a Rais halogen. In some embodiments, a Rais -ORaa(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rais -N(Raa)2. In some embodiments, a Rais -N(H)(Raa).In some embodiments, a Rais optionally substituted Ci-6 aliphatic. In some embodiments, a Rais Ci-6 aliphatic. In some embodiments, a Rais optionally substituted Ci-6 alkyl. In some embodiments, a Rais Ci-6 alkyl. In some embodiments, Rais the point of attachment to the rest of the molecule.

[0155] In some embodiments of any Formulae described herein, each Rbis independently halogen, -ORaa, -N(Raa)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rbis independently -ORaaor -N(Raa)2. In some embodiments, each Rbis independently -ORaa(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRbis halogen. In some embodiments, a Rbis -ORaa(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rbis -N R^. In some embodiments, a Rbis -N(H)(Raa). In some embodiments, a Rbis optionally substituted C1-6 aliphatic. In some embodiments, a Rbis C1-6 aliphatic. In some embodiments, a Rbis optionally substituted Ci-6 alkyl. In some embodiments, a Rbis C1-6 alkyl.

[0156] In some embodiments of any Formulae described herein, a moietyis

[0157] In some embodiments of any Formulae described herein, Rcis hydrogen, halogen, or optionally substituted Ci-6 alkyl. In some embodiments, Reis hydrogen. In some embodiments, Rcis halogen. In some embodiments, Rcis optionally substituted C1-6 aliphatic. In some embodiments, Reis Ci-6 aliphatic. In some embodiments, Rcis optionally substituted Ci-6 alkyl. In some embodiments, Rcis Ci-6 alkyl.

[0158] 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.

[0159] In some embodiments of any Formulae described herein, each Raais independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Raais hydrogen. In some embodiments, each Raais independently optionally substituted Ci-6 aliphatic. In someembodiments, each Raais independently Ci-6 aliphatic. In some embodiments, each Raais independently optionally substituted Ci-6 alkyl. In some embodiments, each Raais independently Ci-6 alkyl. In some embodiments, a Raais hydrogen. In some embodiments, a Raais optionally substituted Ci-6 aliphatic. In some embodiments, a R33is Ci-6 aliphatic. In some embodiments, a Raais optionally substituted Ci-6 alkyl. In some embodiments, a Raais Ci-6 alkyl (e g., methyl).

[0160] In some embodiments of any Formulae described herein, a is 0, 1, 2, or 3. In some embodiments, a is 0, 1, or 2. In some embodiments, a is 1, 2, or 3. In some embodiments, a is 0 or 1. In some embodiments, a is 1 or 2. In some embodiments, a is 2 or 3. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4. In some embodiments, a is 5.

[0161] In some embodiments of any Formulae described herein, b is 0, 1, 2, or 3. In some embodiments, b is 0, 1, or 2. In some embodiments, b is 1, 2, or 3. In some embodiments, b is 0 or 1. In some embodiments, b is 1 or 2. In some embodiments, b is 2 or 3. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4. In some embodiments, b is 5.

[0162] In some embodiments, the present disclosure provides a compound of Formula IV:IV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic,or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently halogen or optionally substituted Ci-6 aliphatic, each Rgis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic; each Rbbis independently hydrogen or optionally substituted Ci-6 aliphatic; e is 0, 1, 2, 3, 4, or 5; f is 0, 1, 2, or 3; and g is 0, 1, 2, 3, 4, or 5.

[0163] In some embodiments, the present disclosure provides a compound of Formula IV-a:or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, Ring Z, e, f, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0164] In some embodiments, the present disclosure provides a compound of Formula IV-b:IV-b or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, e, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and f is 0 or 1.

[0165] In some embodiments, the present disclosure provides a compound of Formula IV-c:or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, e, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and f is 0 or 1.

[0166] In some embodiments, the present disclosure provides a compound of Formula IV-d:IV-d or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rx, Ry, Rz, X, e, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0167] In some embodiments, the present disclosure provides a compound of Formula IV-e:IV-e or a pharmaceutically acceptable salt thereof, wherein L1, Re, R1, Rx, Ry, Rz, X, Ring Z, f, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, or 3.

[0168] In some embodiments, the present disclosure provides a compound of Formula IV-f:IV-f or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rg, Rx, Ry, Rz, X, Ring Z, f, g, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, 3, or 4.

[0169] In some embodiments, the present disclosure provides a compound of Formula IV-g:or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, Ring Z, f, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, or 3.

[0170] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0171] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Ring Z, e, and f are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0172] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, e, and f are as defined in Formula IV-b and described in classes and subclasses herein, both singly and in combination.

[0173] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, e, and f are as defined in Formula IV-c and described in classes and subclasses herein, both singly and in combination.

[0174] In some embodiments of any Formulae described herein, TPM is:wherein Reand e are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0175] In some embodiments of any Formulae described herein, TPM is:wherein Re, R1, e, and f are as defined in Formula IV-e and described in classes and subclasses herein, both singly and in combination.

[0176] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV-f and described in classes and subclasses herein, both singly and in combination.

[0177] In some embodiments of any Formulae described herein, TPM is:wherein Re, Rf, Ring Z, e, and f are as defined in Formula IV-g and described in classes and subclasses herein, both singly and in combination.

[0178] In some embodiments of any Formulae described herein, Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a oxazole, isoxazole, or triazole. In some embodiments, Ring Z is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-membered heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0179] In some embodiments of any Formulae described herein, Ring Z is selected from:wherein each ring is substituted with / instances of Rf.

[0180] In some embodiments of any Formulae described herein, Ring Z substituted with f instances of Rfis selected from:

[0181] In some embodiments of any Formulae described herein, each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic. In some embodiments, each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Reis independently -ORbbor -N(Rbb)2. In some embodiments, each Reis independently -ORbb(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Reis -OCH3. In some embodiments, a Reis halogen. In some embodiments, a Reis -ORbb(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Reis -N(Rbb)2. In some embodiments, a Reis -N(H)(Rbb). In some embodiments, a Reis optionally substituted C1-6 aliphatic. In some embodiments, a Reis Ci- 6 aliphatic. In some embodiments, a Reis optionally substituted Ci-6 alkyl. In some embodiments, a Reis Ci-6 alkyl. In some embodiments, each Reis independently -ORbb(e.g., -O(Ci-6 alkyl), e.g., -OCH3), or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Reis independently -ORbb(e.g., -O(Ci-6 alkyl), e.g., -OCH3), or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Reare takentogether with the atoms to which they are attached to form an optionally substituted 5- to 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted imidazole ring. In some embodiments, two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Reis the point of attachment to the rest of the molecule. In some embodiments, the ring formed by taking two Retogether is the point of attachment to the rest of the molecule.

[0182] In some embodiments of any Formulae described herein, each Rfis independently halogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rfis independently halogen. In some embodiments, each R1is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rfis independently Ci-6 aliphatic. In some embodiments, each Rfis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rfis independently Ci-6 alkyl. In some embodiments, a R* is halogen. In some embodiments, a R1is optionally substituted Ci-6 aliphatic. In some embodiments, a Rfis Ci-6 aliphatic. In some embodiments, a Rfis optionally substituted Ci-6 alkyl. In some embodiments, aR1is Ci-6 alkyl.

[0183] In some embodiments of any Formulae described herein, each Rgis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rgis independently -ORbbor -N(Rbb)2. In some embodiments, each Rgis independently -ORbb(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRgis halogen. In some embodiments, a Rgis -ORbb(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rsis -N(Rbb)2. In some embodiments, a Rgis -N(H)(Rbb). In some embodiments, a Rgis optionally substituted C1-6 aliphatic. In some embodiments, a Rgis C1-6 aliphatic. In some embodiments, a Rgis optionally substituted C1-6 alkyl. In some embodiments, a R8is C1-6 alkyl.

[0184] In some embodiments of any Formulae described herein, a moiety

[0185] In some embodiments of any Formulae described herein, each Rbbis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rbbis hydrogen. In some embodiments, each Rbbis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rbbis independently Ci-6 aliphatic. In some embodiments, each Rbbis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rbbis independently Ci-6 alkyl. In some embodiments, a Rbbis hydrogen. In some embodiments, a Rbbis optionally substituted Ci-6 aliphatic. In some embodiments, a Rbbis Ci-6 aliphatic. In some embodiments, a Rbbis optionally substituted Ci-6 alkyl. In some embodiments, a Rbbis Ci-6 alkyl (e.g., methyl).

[0186] In some embodiments of any Formulae described herein, e is 0, 1, 2, 3, or 4. In some embodiments, e is 0, 1, 2, or 3. In some embodiments, e is 0, 1, or 2. In some embodiments, e is 1, 2, or 3. In some embodiments, e is 0 or 1. In some embodiments, e is 1 or 2. In some embodiments, e is 2 or 3. In some embodiments, e is 0. In some embodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, e is 4. In some embodiments, e is 5.

[0187] In some embodiments of any Formulae described herein, f is 0, 1, or 2. In some embodiments, f is 0 or 1. In some embodiments, f is 1 or 2. In some embodiments, f is 2 or 3. In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3.

[0188] In some embodiments of any Formulae described herein, g is 0, 1, 2, or 3. In some embodiments, g is 0, 1, or 2. In some embodiments, g is 1, 2, or 3. In some embodiments, g is 0 or 1. In some embodiments, g is 1 or 2. In some embodiments, g is 2 or 3. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5.

[0189] In some embodiments, the present disclosure provides a compound of Formula V:V or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:the bracketed moiety is attached to the rest of the molecule at any suitable position;Z’ is NH, O, or S; each Rhis independently halogen, -ORCC, -N(R“)2, or optionally substituted Ci-6 aliphatic;R1is hydrogen, halogen, optionally substituted Ci-6 aliphatic, or optionally substituted phenyl; each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rccis independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

[0190] In some embodiments, the present disclosure provides a compound of Formula V-a:V-a or a pharmaceutically acceptable salt thereof, wherein L1, Rh, R>, Rx, Ry, Rz, X, h, and KBM are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0191] In some embodiments, the present disclosure provides a compound of Formula V-b:V-b or a pharmaceutically acceptable salt thereof, wherein L1, Rh, R', Rk, Rx, Ry, Rz, X, h, k, and KBM are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0192] In some embodiments of any Formulae described herein, TPM is:wherein Rh, Rj, Rk, Z1, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0193] In some embodiments of any Formulae described herein, TPM is:wherein Rh, R>, and h are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0194] In some embodiments of any Formulae described herein, TPM is:wherein Rh, Rj, Rk, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0195] In some embodiments, the present disclosure provides a compound of Formula V’:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination; and wherein: each Rhis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rkis independently halogen, -ORce, -N(Rec)2, or optionally substituted Ci-6 aliphatic; each Rccis independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

[0196] In some embodiments, the present disclosure provides a compound of Formula V’-a:V’-a or a pharmaceutically acceptable salt thereof, wherein L1, Rh, Rx, Ry, Rz, X, h, and KBM are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.

[0197] In some embodiments of any Formulae described herein, TPM is:wherein Rhand h are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.

[0198] In some embodiments of any Formulae described herein, TPM is:wherein Rk, Rh, k, and h are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.

[0199] In some embodiments of any Formulae described herein, Z1is NH. In some embodiments, Z1is O. In some embodiments, Z1is S. In some embodiments, Z1is the point of attachment to the rest of the molecule.

[0200] In some embodiments of any Formulae described herein, each Rhis independently halogen, -ORce, -N(Rec)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rhis independently -ORCCor -N(RCC)2. In some embodiments, each Rhis independently -ORCC(e.g., - O(Ci-6alkyl), e.g., -OCH3). In some embodiments, Rhis -OCH3. In some embodiments, a Rhis halogen. In some embodiments, a Rhis -ORec(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rhis -N(RCC)2. In some embodiments, a Rhis -N(H)(R“). In some embodiments, a Rhis optionally substituted C1-6 aliphatic. In some embodiments, a Rhis C1-6 aliphatic. In some embodiments, a Rhis optionally substituted C1-6 alkyl. In some embodiments, Rhis methyl. In some embodiments, a Rhis C1-6 alkyl. In some embodiments, Rhis the point of attachment to the rest of the molecule.

[0201] In some embodiments of any Formulae described herein, Rjis hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted phenyl. In some embodiments, R> is optionally substituted C1-6 aliphatic or optionally substituted phenyl. In some embodiments, ' is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, R1is hydrogen. In some embodiments, R) is halogen. In some embodiments, R> is optionally substituted C1-6 aliphatic. In some embodiments, R' is C1-6 aliphatic. In some embodiments, R' is optionally substituted C1-6 alkyl. In some embodiments, R' is C1-6 alkyl (e.g., methyl). In some embodiments, R' is methyl. In some embodiments, R' is optionally substituted phenyl (e.g., phenyl optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), or C1-6 alkyl). In some embodiments, R1is phenyl.

[0202] In some embodiments of any Formulae described herein, each Rkis independently halogen, -ORce, -N(Rec)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rkis independently -ORCCor -N(Rec)2. In some embodiments, each Rkis independently -ORCC(e.g., - O(Ci-6alkyl), e.g., -OCH3). In some embodiments, Rkis -OCH3. In some embodiments, a Rkis halogen. In some embodiments, a Rkis -ORec(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rkis -N(RCC)2. In some embodiments, a Rkis -N(H)(RCC). In some embodiments, a Rkis optionally substituted C1-6 aliphatic. In some embodiments, a Rkis C1-6 aliphatic. In some embodiments, a Rkis optionally substituted C1-6 alkyl. In some embodiments, a Rkis Ci-6 alkyl.

[0203] In some embodiments of any Formulae described herein, a moiety if J“(Rk)kis

[0204] 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 Ci-6 aliphatic. In some embodiments, each Rccis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rccis independently Ci-6 alkyl. In some embodiments, a Rccis hydrogen. In some embodiments, a Rceis optionally substituted Ci-6 aliphatic. In some embodiments, a Rccis Ci-6 aliphatic. In some embodiments, a Recis optionally substituted Ci-6 alkyl. In some embodiments, a Rccis Ci-6 alkyl (e.g., methyl).

[0205] In some embodiments of any Formulae described herein, h is 0, 1, 2, or 3. In some embodiments, h is 0, 1, or 2. In some embodiments, h is 0 or 1 . In some embodiments, h is 1 or 2.In some embodiments, h is 2 or 3. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4.

[0206] In some embodiments of any Formulae described herein, k is 0, 1, 2, or 3. In some embodiments, k is 0, 1, or 2. In some embodiments, k is 1, 2, or 3. In some embodiments, k is 0 or 1. In some embodiments, k is 1 or 2. In some embodiments, k is 2 or 3. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5.

[0207] In some embodiments, the present disclosure provides a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z2is CH or N;Ring Y is phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Q is -CH2- or -C(O)-;W is -CH2-, -CHOH-, -C(O)-, -NH-, or -O-;Rmis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rnis independently halogen or optionally substituted Ci-6 aliphatic; each Rpis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rddis independently hydrogen or optionally substituted Ci-6 aliphatic; n4 is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

[0208] In some embodiments, the present disclosure provides a compound of Formula Vl-a:VLaor a pharmaceutically acceptable salt thereof, wherein L1, Rm, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0209] In some embodiments, the present disclosure provides a compound of Formula Vl-b:VI-b or a pharmaceutically acceptable salt thereof, wherein L1, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0210] In some embodiments, the present disclosure provides a compound of Formula VI-c:VI-c or a pharmaceutically acceptable salt thereof, wherein L1, Rm, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0211] In some embodiments of any Formulae described herein, TPM is:wherein Rm, Rn, Rp, Q, W, Z2, Ring Y, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0212] In some embodiments of any Formulae described herein, TPM is:wherein Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0213] In some embodiments of any Formulae described herein, TPM is:wherein Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0214] In some embodiments of any Formulae described herein, TPM is:wherein Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0215] In some embodiments of any Formulae described herein, Z2is CH. In some embodiments, Z2is N.

[0216] In some embodiments of any Formulae described herein, Ring Y is phenyl or a 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is phenyl. In some embodiments, Ring Y is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a furan, thiophene, pyrrole, or isoxazole). In some embodiments, Ring Y is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine). In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring Y is a 5- to 6- membered carbocyclic ring. In some embodiments, Ring Y is a 5-membered carbocyclic ring. In some embodiments, Ring Y is a 6-membered carbocyclic ring. In some embodiments, Ring Y is a C3-7 cycloalkyl ring. In some embodiments, Ring Y is a C5-6 cycloalkyl ring. In some embodiments, Ring Y is a C5 cycloalkyl ring. In some embodiments, Ring Y is a C& cycloalkyl ring. In some embodiments, Ring Y is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0217] In some embodiments of any Formulae described herein, Q is -CH2-. In some embodiments, Q is -C(O)-.

[0218] In some embodiments of any Formulae described herein, W is -CH2-. In some embodiments, W is -CHOH-. In some embodiments, W is -C(O)-. In some embodiments, W is - NH-. In some embodiments, W is -O-. In some embodiments, W is the point of attachment to the rest of the molecule.

[0219] In some embodiments of any Formulae described herein, Q is -C(O)- and W is -NH-. In some embodiments, Q is -CH2- and W is -CH2. In some embodiments, Q is -CH2- and W is - C(O)-. In some embodiments, Q is -CH2- and W is -CHOH-. In some embodiments, Q is -CH2- and W is -O-.

[0220] In some embodiments of any Formulae described herein, Rmis hydrogen, halogen, - ORdd, -N(Rdd)2, or optionally substituted C1-6 alkyl. In some embodiments, Rmis halogen, -N(Rdd)2, or optionally substituted C1-6 aliphatic. In some embodiments, Rmis halogen, -N(Rdd)2, or C1-6 alkyl. In some embodiments, Rmis hydrogen. In some embodiments, Rmis halogen. In some embodiments, Rmis -ORdd(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rmis - N(Rdd)2. In some embodiments, Rmis -N(H)(Rdd) (e.g., -NH(CI-6 alkyl), e.g., -N(H)CH3). In someembodiments, Rmis -N(H)CH3. In some embodiments, Rmis optionally substituted Ci-6 aliphatic. In some embodiments, Rmis Ci-6 aliphatic. In some embodiments, Rmis optionally substituted Ci- 6 alkyl. In some embodiments, Rmis Ci-6 alkyl. In some embodiments, Rmis the point of attachment to the rest of the molecule.

[0221] In some embodiments of any Formulae described herein, each Rnis independently halogen or optionally substituted Ci-6 alkyl. In some embodiments, a Rnis halogen. In some embodiments, a Rnis optionally substituted Ci-6 aliphatic. In some embodiments, a Rnis Ci-6 aliphatic. In some embodiments, a R11is optionally substituted Ci-6 alkyl. In some embodiments, a Rnis Ci-6 alkyl.

[0222] In some embodiments of any Formulae described herein, each Rpis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rpis independently -ORddor -N(Rdd)2. In some embodiments, each Rpis independently -ORdd(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rpis -OCH3. In some embodiments, a Rpis halogen. In some embodiments, a Rpis -ORdd(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rpis -N(Rdd)2. In some embodiments, a Rpis -N(H)(Rdd). In some embodiments, a Rpis optionally substituted Ci-6 aliphatic. In some embodiments, a Rpis Ci-6 aliphatic. In some embodiments, a Rpis optionally substituted Ci-6 alkyl. In some embodiments, a Rpis Ci-6 alkyl.

[0223] In some embodiments of any Formulae described herein, each Rddis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rddis hydrogen. In some embodiments, each Rddis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rddis independently Ci-6 aliphatic. In some embodiments, each Rddis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rddis independently Ci-6 alkyl. In some embodiments, a Rddis hydrogen. In some embodiments, a Rddis optionally substituted Ci-6 aliphatic. In some embodiments, a Rddis Ci-6 aliphatic. In some embodiments, a Rddis optionally substituted Ci-6 alkyl. In some embodiments, a Rddis Ci-6 alkyl (e.g., methyl).

[0224] In some embodiments of any Formulae described herein, n4 is 0, 1, 2, or 3. In some embodiments, n4 is 0, 1, or 2. In some embodiments, n4 is 1, 2, or 3. In some embodiments, n4 is 0 or 1. In some embodiments, n4 is 1 or 2. In some embodiments, n4 is 2 or 3. In some embodiments, n4 is 0. In some embodiments, n4 is 1. In some embodiments, n4 is 2. In some embodiments, n4 is 3. In some embodiments, n4 is 4. In some embodiments, n4 is 5.

[0225] In some embodiments of any Formulae described herein, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0226] In some embodiments, the present disclosure provides a compound of Formula VII:VII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rqis independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci-6 aliphatic; each Rris independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci.6 aliphatic; each Rsis independently halogen or optionally substituted Ci-6 aliphatic;Rlis -N(Ree)(Ci-4 alkylene)CN; each Reeis independently hydrogen or optionally substituted Ci-6 aliphatic; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, or 4; and s is 0, 1, or 2.

[0227] In some embodiments, the present disclosure provides a compound of Formula Vll-a:\TI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rq, Rr, Rl, Rx, Ry, Rz, X, q, r, and KBM are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.

[0228] In some embodiments, the present disclosure provides a compound of Formula Vll-b:VILb or a pharmaceutically acceptable salt thereof, wherein L1, Rq, Rr, Rs, R Rx, Ry, Rz, X, q, r, s, and KBM are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination; and q is 0, 1, 2, 3, or 4.

[0229] In some embodiments of any Formulae described herein, TPM is:wherein Rq, Rr, Rs, Rl, Ring X, q, r, and s are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.

[0230] In some embodiments of any Formulae described herein, TPM is:wherein Rq, Rr, R q, and r are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.

[0231] In some embodiments of any Formulae described herein, TPM is:wherein Rq, Rr, Rs, R\ q, r, and s are as defined in Formula VH-b and described in classes and subclasses herein, both singly and in combination.

[0232] In some embodiments of any Formulae described herein, Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring X is an oxadiazole (e.g., a 1,2,5-oxadiazole). In some embodiments,Ring X is

[0233] In some embodiments of any Formulae described herein, each Rqis independently halogen, -ORCC, -N(Rec)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rqis independently -OReeor -N(Ree)2. In some embodiments, each Rqis independently -ORee(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRqis halogen. In some embodiments, a Rqis -ORee(e.g., -O(Ci-6alkyl), e.g., -OCH3). In some embodiments, a Rqis -N(Ree)2. In some embodiments, a Rqis -N(H)(Ree). In some embodiments, a Rqis optionally substituted C1-6 aliphatic. In some embodiments, a Rqis C1-6 aliphatic. In some embodiments, a Rqis optionally substituted C1-6 alkyl. In some embodiments, a Rqis C1-6 alkyl. In some embodiments, a Rqis the point of attachment to the rest of the molecule.

[0234] In some embodiments of any Formulae described herein, each Rris independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rris independently -OReeor -N(Ree)2. In some embodiments, each Rris independently -ORee(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rris halogen. In some embodiments, a Rris -ORee(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rris -N(Ree)2. In some embodiments, a Rris -N(H)(Ree). In some embodiments, a Rris optionally substituted C1-6 aliphatic. In some embodiments, a Rris C1-6 aliphatic. In some embodiments, a Rris optionally substituted C1-6 alkyl. In some embodiments, a Rris Ci-6 alkyl.

[0235] In some embodiments of any Formulae described herein, each Rsis independently halogen or optionally substituted Ci-6 alkyl. In some embodiments, a Rsis halogen. In some embodiments, a Rsis optionally substituted Ci-6 aliphatic. In some embodiments, a Rsis Ci-6 aliphatic. In some embodiments, a Rsis optionally substituted Ci-6 alkyl. In some embodiments, a Rsis Ci-6 alkyl.

[0236] In some embodiments of any Formulae described herein, Rlis -N(H)(CI-4 alkylene)CN. In some embodiments, R‘ is -N(Ree)(Ci-2 alkylene)CN. In some embodiments, Rlis -N(H)(CI-2 alkylene)CN. In some embodiments, R‘ is -N(Ree)CH2CH2CN. In some embodiments, Rlis - N(H)CH2CH2CN.

[0237] In some embodiments of any Formulae described herein, each Reeis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Reeis hydrogen. In some embodiments, each Reeis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Reeis independently Ci-6 aliphatic. In some embodiments, each Reeis independently optionally substituted Ci-6 alkyl. In some embodiments, each Reeis independently Ci-6 alkyl. In some embodiments, a Reeis hydrogen. In some embodiments, a Reeis optionally substituted Ci-6 aliphatic. In some embodiments, a Reeis Ci-6 aliphatic. In some embodiments, a Reeis optionally substituted Ci-6 alkyl. In some embodiments, a Reeis Ci-6 alkyl (e.g., methyl).

[0238] In some embodiments of any Formulae described herein, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.

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

[0240] In some embodiments of any Formulae described herein, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0241] In some embodiments, the present disclosure provides a compound of Formula VIII:VIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;M is a covalent bond or Ci-4 alkylene; each Ruis independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 aliphatic; each Rvis independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 aliphatic; each Rffis independently hydrogen or optionally substituted Ci-6 aliphatic;Rsgis hydrogen or optionally substituted Ci-6 aliphatic; u is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, 3, or 4.

[0242] In some embodiments, the present disclosure provides a compound of Formula Vlll-a:VUI-a or a pharmaceutically acceptable salt thereof, wherein L1, Ru, Rv, Rx, Ry, Rz, Rff, X, u, v, and KBM are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0243] In some embodiments, the present disclosure provides a compound of Formula Vlll-b:vni-b or a pharmaceutically acceptable salt thereof, wherein L1, M, Ru, Rv, Rx, Ry, Rz, Rfl, Rgg, X, u, v, and KBM are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0244] In some embodiments, the present disclosure provides a compound of Formula VIII-c:VIII-c or a pharmaceutically acceptable salt thereof, wherein L1, Ru, Rv, Rx, Ry, Rz, Rff, X, u, v, and KBM are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0245] In some embodiments of any Formulae described herein, TPM is:wherein M, Ru, Rv, Rfl, Rgg, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0246] In some embodiments of any Formulae described herein, TPM is:wherein Ru, Rv, Rft, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0247] In some embodiments of any Formulae described herein, TPM is:wherein M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0248] In some embodiments of any Formulae described herein, TPM is:wherein Ru, Rv, Rff, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0249] In some embodiments of any Formulae described herein, M is a covalent bond. In some embodiments, M is Ci-4 alkylene. In some embodiments, M is C1-2 alkylene. In some embodiments, M is -CH2-.

[0250] In some embodiments, a moiety

[0251] In some embodiments of any Formulae described herein, each Ruis independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Ruis independently -ORffor -N(Rff)2. In some embodiments, each Ruis independently -ORff(e.g., - O(Ci-6alkyl) or -OH). In some embodiments, a Ruis halogen. In some embodiments, a Ruis -ORff(e.g., -O(Ci-6 alkyl) or -OH). In some embodiments, a Ruis -N(Rff)2. In some embodiments, a Ruis -N(H)(Rff). In some embodiments, a Ruis optionally substituted Ci-6 aliphatic. In some embodiments, a Ruis Ci-6 aliphatic. In some embodiments, a Ruis optionally substituted Ci-6 alkyl. In some embodiments, a Ruis Ci-6 alkyl. In some embodiments, a Ruis the point of attachment to the rest of the molecule.

[0252] In some embodiments of any Formulae described herein, each Rvis independently halogen, -ORff, -N(Rft)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rvis independently -ORflor -N(Rff)2. In some embodiments, each Rvis independently -ORfl(e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRvis halogen. In some embodiments, a Rvis -ORff(e.g., -O(Ci-6alkyl), e.g., -OCH3). In some embodiments, a Rvis -N(Rff)2. In some embodiments, a Rvis -N(H)(Rff). In some embodiments, a Rvis optionally substituted Ci-6 aliphatic. In some embodiments, a Rvis Ci-6 aliphatic. In some embodiments, a Rvis optionally substituted Ci-6 alkyl. In some embodiments, a Rvis Ci-6 alkyl.

[0253] In some embodiments of any Formulae described herein, each Rffis independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rffis hydrogen. In some embodiments, each Rffis independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rffis independently Ci-6 aliphatic. In some embodiments, each Rffis independently optionally substituted Ci-6 alkyl. In some embodiments, each Rffis independently Ci-6 alkyl. In some embodiments, a Rflis hydrogen. In some embodiments, a Rflis optionally substituted Ci-6 aliphatic. In some embodiments, a Rffis Ci-6 aliphatic. In some embodiments, a Rffis optionally substituted Ci-6 alkyl. In some embodiments, a Rffis Ci-6 alkyl (e.g., methyl).

[0254] In some embodiments of any Formulae described herein, Rggis hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Rggis hydrogen. In some embodiments, Rggis optionally substituted Ci-6 aliphatic. In some embodiments, Rggis Ci-6 aliphatic. In some embodiments, Rggis optionally substituted Ci-6 alkyl. In some embodiments, Rggis Ci-6 alkyl.

[0255] In some embodiments of any Formulae described herein, u is 0, 1, 2, or 3. In some embodiments, u is 0, 1, or 2. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 0 or1 . In some embodiments, u is 1 or 2. In some embodiments, u is 2 or 3. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

[0256] In some embodiments of any Formulae described herein, v is 0, 1, 2, or 3. In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0 or 1. In some embodiments, v is 1 or 2. In some embodiments, v is 2 or 3. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4.

[0257] In some embodiments, TPM is a tubulin inhibitor payload moiety (e g., a moiety that binds and / or inhibits tubulin). In some embodiments, TPM is a tubulin inhibitor payload moiety targeting the colchicine binding site. The present invention encompasses the recognition that a tubulin inhibitor payload moiety in the CIDCs described herein can be made by installing a linking moiety bound to a KRASG1Cbinding moiety, as defined hereinany suitable position on a tubulin inhibitor compound. In some embodiments, TPM is a tubulin inhibitor (e.g., a radical of such inhibitor compound) selected from ABT-751, avanbulin, BNC105P, cabazitaxel, colchicine, combretastatin A-4, combretastatin A-l, docetaxel, dolastatin 10, EAPB0203, EAPB02303, EAPB0503, epothilone A, eribulin, fosbretabulin, ixabepilone, KX2-361, lisavanbulin, monomethyl auristatin E, A-acetylcolchicinol, ombrabulin, Oxi4503, paclitaxel, plinabulin, tesetaxel, sabizabulin, verubulin, vinblastine, and vincristine. In some embodiments, TPM is a tubulin inhibitor (e.g., a radical of such inhibitor compound) described in Hawesh, M. Biomolecules 2022, 12, 1843; Weng, H., et al., Future Med. Chem. 2023, 15(1), 73- 95; Beale, T. M., et al., ACS Med. Chem. Lett. 2012, 3, 177-181; Liou, J.-P., et al., J. Med. Chem. 2004, 47, 2897-2905; Patinote, C., et al., Eur. J. Med. Chem. 2021, 212, 113031; Pochampally, S., et al., ACS Pharmacol. Transl. Sci. 2023, 6, 526-45; Prota, A. E., et al., J. Mol. Biol. 2014, 426, 1848-60; Sun, C.-M., et al., Bioorg. Med. Chem. Lett. 2007, 17, 1078-81; Zhou, J. et al., Eur. J. Med. Chem. 2013, 68, 222-32; WO1996 / 030355; WO1998 / 045301; WO 1999 / 002514; W02002 / 056872; US2003 / 0195244; W02004 / 054498; W02005 / 054199; US2005 / 0065595; WO20 12 / 027481; or WO2012 / 106522.

[0258] In some embodiments, TPM is a means for binding tubulin. In some embodiments, TPM is a means for inhibiting tubulin. In some embodiments, TPM is a means for inhibiting tubulin at the colchicine binding site.Exemplary Compounds of the Disclosure

[0259] In some embodiments, the present disclosure provides a compound of Formula IX:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.

[0260] In some embodiments, the present disclosure provides a compound of Formula IX-a:IX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R?, 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, Rh, Rc, Rd, a, and b are as defined in Formula Ill-b and described in classes and subclasses herein, both singly and in combination.

[0261] In some embodiments, the present disclosure provides a compound of Formula IX-al :IX-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula Ill-b and described in classes and subclasses herein, both singly and in combination.

[0262] In some embodiments, the present disclosure provides a compound of Formula X:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R?, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, R1, Rg, Ring Z, e, f, and g are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.

[0263] In some embodiments, the present disclosure provides a compound of Formula X-a:X-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, 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 Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV-f and described in classes and subclasses herein, both singly and in combination.

[0264] In some embodiments, the present disclosure provides a compound of Formula X-al :X-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV-f and described in classes and subclasses herein, both singly and in combination.

[0265] In some embodiments, the present disclosure provides a compound of Formula X-b:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes andsubclasses herein, both singly and in combination; and Re, R1, Ring Z, e, and f are as defined in Formula IV-g and described in classes and subclasses herein, both singly and in combination.

[0266] In some embodiments, the present disclosure provides a compound of Formula X-bl :X-bl or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Ring Z, e, and f are as defined in Formula IV-g and described in classes and subclasses herein, both singly and in combination.

[0267] In some embodiments, the present disclosure provides a compound of Formula XI:or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R3, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rh, Rj, Rk, Z1, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0268] In some embodiments, the present disclosure provides a compound of Formula Xl-a:Xl-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; 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 Rh, R', Rk, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0269] In some embodiments, the present disclosure provides a compound of Formula XI-al :XI-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rh, R>, Rk, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.

[0270] In some embodiments, the present disclosure provides a compound of Formula XII:XII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Q, Rm, R11, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0271] In some embodiments, the present disclosure provides a compound of Formula Xll-a:XII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, 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 Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0272] In some embodiments, the present disclosure provides a compound of Formula Xll-al :Xll-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0273] In some embodiments, the present disclosure provides a compound of Formula Xll-b:XILb or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R\ Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0274] In some embodiments, the present disclosure provides a compound of Formula Xll-bl :Xll-bl or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.

[0275] In some embodiments, the present disclosure provides a compound of Formula XIII:XIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R', Ring X, q, r, and s are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.

[0276] In some embodiments, the present disclosure provides a compound of Formula XIILa:Xlll-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R3, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Vll-b and described in classes and subclasses herein, both singly and in combination.

[0277] In some embodiments, the present disclosure provides a compound of Formula XIII- al :XIILal or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Vll-b and described in classes and subclasses herein, both singly and in combination.

[0278] In some embodiments, the present disclosure provides a compound of Formula XIV:XIV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, 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 M, Ru, Rv, Rff, Rsg, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0279] In some embodiments, the present disclosure provides a compound of Formula XlV-a:XlV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, 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 M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula Vlll-b and described in classes and subclasses herein, both singly and in combination.

[0280] In some embodiments, the present disclosure provides a compound of Formula XIV- al :XlV-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rss, u, and v are as defined in Formula Vlll-b and described in classes and subclasses herein, both singly and in combination.

[0281] In some embodiments, the present disclosure provides a compound of Formula XlV-b:XlV-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R?, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rfl, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0282] In some embodiments, the present disclosure provides a compound of Formula XIV- bl :XIV-bl or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0283] In some embodiments, the present disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.Table 1. Exemplary Compounds of the DisclosurePreparing Provided Compounds

[0284] Provided compounds generally can be prepared using the processes described in the ensuing schemes and examples.

[0285] 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 coupling 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.

[0286] 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, L RX, 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 coupling agent and optionally in the presence of a suitable base.

[0287] In some embodiments, provided compounds (e.g., compounds wherein X is not a covalent bond) are prepared according to the following Scheme:A.4 B.3 C.4 wherein KBM, TPM, L1, Rx, Ry, Rz, and X are as defined in Formulae herein; and LG1is a suitable leaving group (e.g., Br or OMs). 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.

[0288] 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.6 wherein KBM, TPM, Cy, L1, Rx, Ry, Rz, and X are as defined in Formulae herein; and LG2is 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 coupling agent and optionally in the presence of a suitable base.Compositions

[0289] 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.

[0290] 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, Il-a, Il-b, II-c, ILd, III, Ill-a, IILb, IV, IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, V, V-a, V-b, V’, V’-a, VI, VI-a, Vl-b, VLc, VII, VILa, VILb, VIII, Vlll-a, VIILb, VIILc, IX, IX-a, IX-al, X, X-a, X- al, X-b, X-bl, XI, Xl-a, XLal, XII, Xll-a, XILal, XILb, Xll-bl, XIII, XIILa, XIILal, XIV, XIV- a, XlV-al, XlV-b, and XlV-bl).

[0291] 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, I-h-1, 1-h-2, II, ILa, Il-b, II-c, ILd, III, Ill-a, Ill-b, IV, IV-a, IV-b, IV-c, IV- d, IV-e, IV-f, IV-g, V, V-a, V-b, V’, V’-a, VI, VI-a, Vl-b, VI-c, VII, Vll-a, VILb, VIII, Vlll-a, VIII- b, VIILc, IX, IX-a, IX-al, X, X-a, X-al, X-b, X-bl, XI, XLa, Xl-al, XII, Xll-a, Xll-al, XILb, Xll-bl, XIII, XIILa, XIILal, XIV, XlV-a, XlV-al, XlV-b, and XlV-bl) and further comprises a pharmaceutically acceptable carrier.

[0292] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.

[0293] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0294] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predeterminedquantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0295] 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.

[0296] 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

[0297] 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.

[0298] In some embodiments, provided compounds are useful as covalent-induced drug conjugates, e.g., CIDCs targeting cells expressing mutant KRAS (e.g., KRASG12C).

[0299] In some embodiments, the present disclosure provides methods of inhibiting tubulin, comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C) in the presence of tubulin. In some embodiments, contacting occurs in a cell. In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0300] In some embodiments, the present disclosure provides methods of releasing a tubulin inhibitor payload (e.g., a tubulin inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C). In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0301] In some embodiments, the present disclosure provides methods of delivering a tubulin inhibitor payload (e.g., a tubulin inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C). In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0302] 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).

[0303] 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 selected from 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.

[0304] 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 moreregimens 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.

[0305] 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

[0306] 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 B (Int-B)

[0307] 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, PMBCI (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 Na2SCU 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.

[0308] Step 2: To a solution of B.l (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.l (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 Na2SC>4 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.

[0309] 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 Na2SO4 and 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=l :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.

[0310] 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 Na2SO4 and 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.

[0311] 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)2Ch (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 Na2SC>4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography eluted with DCM:MeOH=10: l to afford B.8 (1.3 g, 1.4 mmol, yield: 74.5%) as a yellow solid. LCMS(ESI) [M+l]+= 909.4.

[0312] 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+l]+= 808.6.Preparation of Intermediate D (Int-D)D.2

[0313] 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 (21.2g, 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.

[0314] 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 to the reaction mixture, and the resulting solution was extracted with ethyl acetate, the organic layer was dried over anhydrous Na2SC>4, 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.

[0315] 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 Na2SC>4, 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.

[0316] 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.

[0317] 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 NaHCOs(aq) and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SC>4, 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 N (Int-N)

[0318] Step 1: To a solution of N.I (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 Na2SC>4 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.

[0319] 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 Na2SC>4 and 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.

[0320] 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.

[0321] 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 Na2SC>4, 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.

[0322] 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 Na2SC>4 and 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 R (Int-R)lnt-R-1 and lnt-R-2

[0323] Step 1: To a solution of R.1 (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 Na2SC>4 and 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) 5 7.35 (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).

[0324] Step 2: 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 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, 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.

[0325] 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.

[0326] 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 NH4CI 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.

[0327] 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 MgSO4, 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 a yellow solid. LCMS (ESI) [M+l]+= 862.6. 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 H2 atmosphere (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)

[0328] 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 Na2SO4 and 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.

[0329] 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 over Na2SO4 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.

[0330] 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 NH4CI 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.

[0331] 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.

[0332] 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 pl; Mobile phase: EtOH / TFA / DEA= 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 L-5rt, 48 hrs0°C L-5

[0333] Step 1: To a solution of / c / 7-butyl acrylate (56.6 mL, 390.1 mmol, 1.0 equiv.) in dioxane / IbO (250.0 mL) was added DABCO (131.2 g, 1.1 mol, 3.0 equiv.) and formaldehyde (95.1 mL, 1.1 mol, 3.0 equiv.). The reaction was stirred at rt for 48 hrs. TLC showed the reaction was completed. The mixture was extracted with EA, washed with water and brine. The organic layer was dried by Na2SC>4, purified by silica gel chromatography (20% EA in PE) to give L-4 (22.0 g, 139.0 mmol, yield: 35.6%) as a yellow oil. ’H NMR (400 MHz, MeOD) 5 6.13 (dd, J = 3.1, 1.5 Hz, 1H), 5.79 (q, J= 1.8 Hz, 1H), 4.84 (s, 1H), 4.21 (t, J= 1.5 Hz, 2H), 1.49 (s, 9H).

[0334] Step 2: To a solution of L-4 (10.0 g, 63.3 mmol, 1.0 equiv.) in Et20 (100.0 mL) was added PB (11.9 g, 44.4 mmol, 0.7 equiv.) at -10 °C, the reaction was stirred at 0 °C for 5 hrs. TLC showed the reaction was completed. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography to give L-5 (9.2 g, 41.8 mmol, yield: 66.1%) as a yellow oil. ' H NMR (400 MHz, CDCh) 8 6.23 (d, J = 0.9 Hz, 1H), 5.86 (d, J= 0.8 Hz, 1H), 4.15 (d, J = 0.7 Hz, 2H), 1.52 (s, 9H).Preparation of Intermediate L-680 C, 16 h

[0335] Step 1: To a solution of acetaldehyde (51.0 mL, 908.0 mmol, 1.0 equiv.) in H2O (45.0 mL) and dioxane (45.0 mL) were added tert-butyl acrylate (174.5 g, 1.3 mol, 1.5 equiv.) and DABCO (101.8 g, 908.0 mmol, 1.0 equiv.) at rt under N2. The reaction mixture was stirred at rt for 48 h under N2. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE / EA=10 / l) to afford L-1 (50.0 g, 290.3 mmol, yield: 31.9%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) 5 5.96 (dd, J= 2.0, 1.0 Hz, 1H), 5.76 (dd, J = 3.4, 1.6 Hz, 1H), 4.95 (d, J= 4.8 Hz, 1H), 4.42 (dd, J = 6.2, 5.1 Hz, 1H), 1.44 (s, 9H), 1.17 (d, J= 6.4 Hz, 3H).

[0336] Step 2: To a solution of NBS (15.5 g, 87.0 mmol, 1.5 equiv.) in DCM (100.0 mL) was added dimethylsulfane (7.3 mL, 98.7 mmol, 1.7 equiv.) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h under N2. Then L-1 (10.0 g, 58.0 mmol, 1.0 equiv.) was added in the solution at 0 °C. The reaction mixture was stirred at rt for 16 h under N2. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product L-2 (13.0 g, 55.2 mmol, yield: 95.2%) as a yellow oil which was used to next step.

[0337] Step 3: To a solution of Na2HPC>4 (12.0 g, 85.0 mmol, 2.0 equiv.) and NaH2PO4 (12.2 g, 85.0 mmol, 2.0 equiv.) in DMPU (80.0 mL) and H2O (40.0 mL) was added L-2 (10.0 g, 42.5 mmol, 1.0 equiv.) at rt under N2. The reaction mixture was stirred at 100 °C overnight under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE / EA=10 / l) to afford L-6 (3.0 g, 17.420 mmol, yield: 40.9%) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 6.72 (q, J= 7.2 Hz, 1H), 4.55 (t,J= 5.5 Hz, 1H), 4.10 (d, J= 5.5 Hz, 2H), 1.82 (d, J= 7.2 Hz, 3H), 1.43 (s, 9H).Preparation of Intermediate L-7, L-7

[0338] To a solution of L-1 (50.0 g, 290.3 mmol, 1.0 equiv.), DMAP (14.1 g, 116.1 mmol, 0.4 equiv.) and pyridine (23.4 mL, 290.3 mmol, 1.0 equiv.) in DCM (500.0 mL) was added methyl chloromethanoate (33.6 mL, 435.4 mmol, 1.5 equiv.) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. The reaction mixture was washed with a Nal ICCh solution, the organic layer was dried over anhydrous ISfeSCh, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0~10% EtOAc in petroleum ether to afford L-7 (30.0 g, 130.2 mmol, yield: 44.8%) as a colorless oil. ’H NMR (400 MHz, CDC13) 8 6.22 (s, 1H), 5.78 (s, 1H), 5.56 (q, J = 6.4 Hz, 1H), 3.79 (s, 1H), 1.50 (s, 9H), 1.44 (d, J = 6.5 Hz, 3H).Preparation of Intermediate L-81 ? 1 / TriphosgeneH° l! " TEA Pentane, rt, 16h * L-1

[0339] To a solution of ISfeCCh (24.6 g, 232.3 mmol, 2.0 equiv.) and triphosgene (25.2 g, 84.8 mmol, 0.7 equiv.) in pentane (200 mL) was added TEA (1.6 mL, 11.6 mmol, 0.1 equiv.) at 0°C. The mixture was stirred for 30 min under N2. Then L-1 (20.0 g, 116.1 mmol, 1.0 equiv.) was added and the reaction was stirred at rt for 16 h. TLC showed a new spot. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography to give L-8 (11.5 g, 49.0 mmol, yield: 42.2%) as a yellow oil. 1H NMR (400 MHz, CDCh) 86.25 (s, 1H), 5.75 (s, 1H), 5.68 (q, .7= 6.5 Hz, 1H), 1.44 Cd, 2.2 Hz, 12H).Preparation of Provided CompoundsExample 1: Preparation of Compound 1

[0340] Step 1: To a solution of compound 1.1 (600.0 mg, 1.7 mmol, 1.0 equiv.) in DMF (10.0 mL) were added K2CO3 (709.9 mg, 5.1 mmol, 3.0 equiv.) and compound 1.2 (402.6 mg, 1.7 mmol, 1.0 equiv.). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous NasSCL and concentrated to dryness. The mixture was purified by prep-HPLC to give compound 1.3 (50.0 mg, 0.1 mmol, yield: 5.9%) as a yellow solid. LCMS(ESI)[M+1]+= 505.3.

[0341] Step 2: To a solution of compound 1.3 (50.0 mg, 0.1 mmol, 1 .0 equiv.) in DCM (10.0 mL) and TFA (3.0 mL). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated to give compound 1.4 (35.0 mg, 0.1 mmol, yield: 87.3%) as a white solid.

[0342] Step 3: To a solution of 1.3 (35.0 mg, 0.1 mmol, 1.0 equiv.) in DMF (5.0 mL) were added 1.5 (59.4 mg, 0.1 mmol, 1.0 equiv.), DIEA (45.9 mg, 0.3 mmol, 3.0 equiv.), and I 3P (58.0 mg, 0.2 mmol, 1.2 equiv.). The reaction was stirred at 0 °C for 1 hour. 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 Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 1 : 2) to give 1.6 (20.0 mg, 50.0 pmol, yield: 19.6%) as a yellow solid. LCMS(ESI)[M+1]+= 1031.3.

[0343] Step 4: To a solution of compound 1.6 (20.0 mg, 50.0 pmol, 1.0 equiv.) in DCM (2.0 mL) was added HCl / MeOH (2.0 mL). The resulting mixture was stirred at 0 °C for 1 h under N2 atmosphere. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC to give Compound 1 (3.0 mg, 3.0 pmol, yield: 5.6%) as a white solid. Prep-HPLC was performed using a E-Prep LC 012 LH-40 with the following conditions: Column: XBring Prep Phenyl 19*250mm; Temperature: 25 °C; Inject number: 1; Wave length: 254nm / 220nm; phase A: H2O (0.1%TFA); phase B: CH3CN; Gradient(%B / time): 15% B 0.01 min; 15% B 4.00 min; 80% B 25.00 min; 95% B 28.00 min; 95% B 34.00. LCMS(ESI)[M+1]+= 987.3. ’H NMR (400 MHz, DMSO-de) 8 10.76 (s, 1H), 10.21 (s, 1H), 9.59 (s, 1H), 9.14 (s, 1H), 8.06 - 7.93 (m, 1H), 7.71 (s, 1H), 7.50 (m, J= 22.9, 13.8 Hz, 2H), 7.43 - 7.29 (m, 3H), 7.16 (t, J= 27.9 Hz, 3H), 6.96 (d, J = 12.9 Hz, 2H), 5.68 - 5.53 (m, 2H), 5.27 (s, 1H), 4.66 (dd, J = 66.8, 49.3 Hz, 7H), 3.88 (s, 3H), 3.31 (s, 2H), 3.12 (s, 4H), 2.36 - 2.00 (m, 6H), 1.87 (d, J= 60.8 Hz, 5H), 1.54 (s, 3H), 1.24 (s, 1H).Example 2: Preparation of Compound 22.7 .

[0344] Step 1: To a solution of compound 2.1 (10.0 g, 50.2 mmol, 1.0 equiv.) in DMF (100 mL) was added ammonium carbonate (24.1 g, 251.2 mmol, 5.0 equiv.). The reaction was stirred at 80 °C for 16 h. LCMS showed the reaction was completed. The mixture was poured into water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 3 : 1) to give compound 2.2 (5.0 g, 27.8 mmol, yield: 55.4%) as a white solid. LCMS(ESI) [M+l]+= 180.2.

[0345] Step 2: To a solution of compound 2.2 (5.0 g, 27.8 mmol, 1.0 equiv.) in THF (50.0 mL) and H2O (50.0 mL) was added compound 2.3 (16.5 g, 83.5 mmol, 3.0 equiv.). The reaction was stirred at 75 °C for 16 h. LCMS showed the reaction was completed. The mixture poured into water (150 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by columnchromatography on silica gel (PE : EtOAc = 3 : 1) to give compound 2.4 (3.5 g, 17.2 mmol, yield: 61.7%) as a yellow solid. LCMS(ESI) [M+l]+= 204.0.

[0346] Step 3: To a solution of compound 2.4 (3.5 g, 17.2 mmol, 1.0 equiv.) in DMF (40 mL) were added methanamine (1.5 g, 34.4 mmol, 2.0 equiv.) and DIEA (6.7 g, 51.5 mmol, 3.0 equiv.). The reaction was stirred at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture poured into water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 3 : 1) to give compound 2.5 (2.0 g, 10.1 mmol, yield: 58.7%) as a white solid. LCMS(ESI)[M+1]+= 199.1.

[0347] Step 4: To a solution of compound 2.5 (2.0 g, 10.1 mmol, 1.0 equiv.) in CHCh (20 mL) was added NBS (2.2 g, 12.1 mmol, 1.2 equiv.) at 0 °C. The reaction was stirred at 60 °C for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated and purified by column chromatography on silica gel to give compound 2.6 (2.0 g, yield: 80.0%) as a yellow solid. LCMS(ESI) [M+l]1= 278.9.

[0348] Step 5: To a solution of compound 2.7 (10.0 g, 90.8 mmol, 1.0 equiv.) in acetone (200.0 mL) were added chloro(methoxy)methane (7.3 g, 90.8 mmol, 1.0 equiv.) and K2CO3 (37.6 g, 272.5 mmol, 3.0 equiv.). The reaction was stirred at 25 °C for 24 hours. The mixture poured into water (1000 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were purified by column chromatography on silica gel (PE : EtOAc = 5 : 1) to give compound 2.8 (5.0 g, 25.2 mmol, yield: 27.8%) as yellow oil.

[0349] Step 6: To a solution of compound 2.8 (5.0 g, 32.5 mmol, 1.0 equiv.) in DMF (100.0 mL) was added NBS (5.8 g, 32.5 mmol, 1.0 equiv.). The reaction was stirred at 0 °C for 30 minutes. The mixture poured into water (1000 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 3 : 1) to give compound 2.9 (2.5 g, 232.5 mmol, yield: 41.7%) as a yellow solid. LCMS(ESI) [M+l]+= 231.2.

[0350] Step 7: To a solution of compound 2.9 (2.5 g, 10.7 mmol, 1.0 equiv.) in dioxane (50.0 mL) were added compound 2.10 (3.3 g, 12.8 mmol, 1.2 equiv.), KO Ac (3.2 g, 32.2 mmol, 3.0 equiv.) and Pd(dppf)C12 (0.8 g, 1.1 mmol, 0.1 equiv.). The reaction was stirred at 85 °C for 1 hour. The mixture poured into water (100.0 mL) and extracted with EtOAc (30.0 mLx 3). The combinedorganic phases were purified by column chromatography on silica gel (PE : EtOAc = 5 : 1) to give compound 2.11 (2.0 g, 7.1 mmol, yield: 66.6%) as a yellow solid.

[0351] Step 8: To a solution of compound 2.6 (2.0 g, 7.2 mmol, 1.0 equiv.) in dioxane (20 mL) and H2O (5.0 mL) were added compound 2.11 (2.0 g, 7.2 mmol, 1.0 equiv.), K2CO3 (3.0 g, 21.6 mmol, 3.0 equiv.) and Pd(dppf)Ch (0.5 g, 0.7 mmol, 0.1 equiv ). The mixture was degassed for three times under N2 atmosphere and stirred at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give compound 2.12 (600.0 mg, 1.7 mmol, yield: 23.7%) as a yellow solid. LCMS(ESI) [M+l]+= 351.2.

[0352] Step 9: To a solution of compound 2.12 (600.0 mg, 1.7 mmol, 1.0 equiv.) in DMF (10.0 mL) were added K2CO3 (709.9 mg, 5.1 mmol, 3.0 equiv.) and compound 2.13 (402.6 mg, 1.7 mmol, 1.0 equiv.). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 1 : 1) to give compound 2.14 (500.0 mg, 1.0 mmol, yield: 57.9%) as a yellow solid. LCMS(ESI) [M+l]+= 505.3.

[0353] Step 10: To a solution of compound 2.14 (500.0 mg, 1.0 mmol, 1.0 equiv.) in DCM (10.0 mL) and TFA (3.0 mL). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated to give compound 2.15 (350.0 mg, 0.9 mmol, yield: 87.3%) as a white solid. LCMS(ESI) [M+l]+= 405.2.

[0354] Step 11: To a solution of compound 2.15 (100.0 mg, 0.3 mmol, 1.0 equiv.) in DMF (5.0 mL) were added compound 2.16 (159.4 mg, 0.3 mmol, 1.0 equiv.), DIEA(95.9 mg, 0.7 mmol, 2.5 equiv.) and T3P (118.0 mg, 0.4 mmol, 1.2 equiv.). The reaction was stirred at 0 °C for 1 hour. 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 Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 1 : 2) to give compound 2.17 (50.0 mg, 0.1 mmol, yield: 19.6%) as a yellow solid. LCMS(ESI) [M+l]+= 1031.3.

[0355] Step 12: To a solution of compound 2.17 (50.0 mg, 0.1 mmol, 1 .0 equiv.) in DCM (2.0 mL) was added HCl / MeOH (2.0 mL). The resulting mixture was stirred at 0 °C for 1 h under N2 atmosphere. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC to give Compound 2 (3.0 mg, 3.0 pmol, yield: 0.3%) as a white solid. Prep-HPLC was performed using a E-Prep LC 012 LH-40 with the following conditions: Column: XBring Prep Phenyl 19*250mm; Temperature: 25 °C; Inject number: 1; Wave length: 254nm / 220nm; phase A: H2O (0.1%TFA); phase B: CH3CN; Gradient(%B / time): 15% B 0.01 min; 15% B 4.00 min; 80% B 25.00 min; 95% B 28.00 min; 95% B 34.00. LCMS(ESI) [M / 2]+= 494.3. ’H NMR (400 MHz, DMSO-d6) 6 11.52 (s, 1H), 10.22 (s, 1H), 9.76 (s, 1H), 9.10 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.98 (dd, J= 9.2, 6.0 Hz, 1H), 7.67 (s, 1H), 7.50 - 7.36 (m, 4H), 7.25 (dt, J= 6.1, 3.1 Hz, 3H), 7.03 - 6.97 (m, 2H), 6.20 (q, J = 6.8 Hz, 1H), 5.58 (d, J = 53.7 Hz, 1H), 4.91 (s, 2H), 4.78 - 4.44 (m, 6H), 3.97 (s, 1H), 3.78 (dd, J= 26.1, 17.2 Hz, 6H), 3.31 (d, J= 3.4 Hz, 6H), 2.66 - 2.53 (m, 1H), 2.32 (d, J= 9.3 Hz, 1H), 2.17 (dd, J= 18.4, 9.2 Hz, 2H), 2.06 (d, J = 10.2 Hz, 1H), 1.93 (d, J = 7.0 Hz, 4H), 1.79 (s, 2H).Example 3: Preparation of Compound 3Compound 3

[0356] Step 7: To a solution of [(2S)-l-methylpyrrolidin-2-yl]methanol (229 mg, 1.991 mmol) in THF (5 mL) was added NaH (60% dispersion in oil) (191 mg, 7.960 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2 atmosphere. Then, tert-butyl (2S)-4-(7-bromo-6- chloro-2,8-difluoro-quinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (1.0 g, 1.991 mmol) in THF (5 mL) was added the mixture The reaction mixture was stirred at 25 °C for 1 hour under N2 atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dry over Na2SO4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=10:l) to give tert-butyl (2S)-4-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l-carboxylate (600 mg, 1.00 mmol, 50.45% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+599.3.

[0357] Step 2'. To a solution of tert-butyl (2S)-4-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-l - methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l -carboxylate (310 mg, 0.518 mmol) in dioxane (10 mL) were added K2CO3 (215 mg, 1.561 mmol), tert-butyl N-[3- cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (377 mg, 0.933 mmol), and di chloropalladium; [1 -(2-diphenylphosphanyl-l-naphthyl)-2-naphthyl]- diphenyl-phosphane (83 mg, 0.104 mmol). The reaction mixture was stirred at 105 °C for 16 hours under N2 atmosphere. Then, the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=10: 1) to give tert-butyl (2S)-4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4- yl]-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-2- (cyanomethyl)piperazine-l -carboxylate (300 mg, 0.370 mmol, 71.49% yield) as a dark red oil. LCMS (ESI) m / z: [M+H]+810.1.

[0358] Step 3: To a solution of tert-butyl (2S)-4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7- fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l -carboxylate (200 mg, 0.247 mmol) in DCM (4 mL) was added TFA (1.5 g, 13.071 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Cis reverse column chromatography (ACN:H2O=2: 1) to give 2-amino-4-[6- chloro-4-[(3S)-3-(cyanomethyl)piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (120 mg, 0.197 mmol, 79.72% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+610.1.

[0359] Step 4: To a solution of 2-(hydroxymethyl)prop-2-enoic acid (50 mg, 0.492 mmol) in DCM (5 mL) were added DIEA (106 mg, 0.821 mmol), T4P (177 mg, 0.493 mmol), and 2-amino- 4-[6-chloro-4-[(3S)-3-(cyanomethyl)piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (100 mg, 0.164 mmol). The reaction mixture was stirred at 25 °C for 15 minutes under air atmosphere. Then the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=8: l) to give 2-amino-4-[6-chloro-4-[(3S)-3- (cyanomethyl)-4-[2-(hydroxymethyl)prop-2-enoyl]piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (15 mg, 0.021 mmol, 13.18% yield) as white solid. LCMS (ESI) m / z: [M+H]+694.2.

[0360] Step 5: To a solution of 2-amino-4-[6-chloro-4-[(3S)-3-(cyanomethyl)-4-[2- (hydroxymethyl)prop-2-enoyl]piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (70 mg, 0.101 mmol) in DCM (5 mL) were added DIEA (39 mg, 0.303 mmol) and methanesulfonic anhydride (53 mg, 0.303 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=8: l) to give 2-[(2S)-4-[7-(2-amino-3-cyano-7-fluoro- benzothiophen-4-yl)-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]quinazolin-4- yl]-2-(cyanomethyl)piperazine-l-carbonyl]allyl methanesulfonate (20 mg, 0.026 mmol, 25.68% yield) as white solid. LCMS (ESI) m / z: [M+H]+771.4.

[0361] Step 6: To a solution of 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol (7 mg, 0.021mmol) in DMF (2 mL) was added CS2CO3 (0.019 mg, 0.058 mmol). The reaction mixture was stirred at 25 °C for 10 minutes under air atmosphere. Then, 2-[(2S)-4-[7-(2-amino-3- cyano-7-fluoro-benzothiophen-4-yl)-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l-carbonyl]allyl methanesulfonate (15 mg, 0.019 mmol) was added. The mixture was stirred at 35 °C for 2 h. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=7:l) to give 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)-4-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((S)-l-methylpyrrolidin- 2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1.6 mg, 0.001 mmol, 8.30% yield) as white solid. 'H NMR (400 MHz, DMSO-d6) 8 8.12 (s, 3H), 7.29 - 7.21 (m, 1H), 7.16 (td, J = 9.0, 3.1 Hz, 1H), 6.90 (d, J = 6.0 Hz, 3H), 6.60 - 6.44 (m, 4H), 5.70 - 5.24 (m, 2H), 4.88 (d, J = 64.5 Hz, 1H), 4.56 (s, 2H), 4.38 (s, 1H), 4.21 (d, J = 10.7 Hz, 3H), 3.73 (s, 3H), 3.63 (d, J = 9.3 Hz, 9H), 2.94 (d, J = 8.6 Hz, 2H), 2.63 - 2.56 (m, 1H), 2.36 (s, 3H), 2.20 - 2.15 (m, 1H), 1.95 (dd, J = 11.0, 6.9 Hz, 1H), 1.72 - 1.60 (m, 3H). LCMS (ESI) m / z: [M+H]+991.5.Example 4: Preparation of Compound 4Boc

[0362] Step 1 To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (4.5 g, 13.620 mmol) in dioxane (15 mL) were added tert-butyl (S)-2-(cyanomethyl)piperazine-l-carboxylate (3.4 g, 14.980 mmol) and DIPEA (5.3 g, 40.860 mmol). The reaction solution was stirred at rt for0.5 hr. The reaction mixture was purified by flash chromatography (eluting with DCM:EtOAc=100:0 to 85: 15) to give tert-butyl (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin- 4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (9.5 g, 12.810 mmol, 94.03% yield, 70% purity) as a yellow solid. LCMS (ESI) m / z: [M+H]+520.2.

[0363] Step 2: To a solution of tert-butyl (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4- yl)-2-(cyanomethyl)piperazine-l -carboxylate (8.0 g, 15.410 mmol) in DMA (160 m ) was added KF (35.8 g, 616.340 mmol), and the reaction solution was stirred at 120 °C for 18 h under N2. The reaction was quenched with NaCl aq. and extracted with DCM, the organic layer was concentrated under reduce pressure, and the residue was purified by flash chromatography (eluting with DCM:EtOAc=100:0 to 70:30) to give tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin- 4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (5.4 g, 10.740 mmol, 69.71% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+504.1.

[0364] Step 3 To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (238 mg, 1.490 mmol) in THF (3 m ) was added NaH (60% dispersion in oil) (159 mg, 3.980 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2 atmosphere. Then, tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (500 mg, 0.995 mmol) in THF (5 mL) was added the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 10 minutes under N2 atmosphere. The mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM:MeOH=15: l) to give tert-butyl (S)-4- (7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (500 mg, 0.779 mmol, 78.32% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+643.3.

[0365] Step 4 A solution of tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine- 1-carboxylate (500 mg, 0.779 mmol) in dioxane (8 mL) were added tert-butyl (3-cyano-4-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (340 mg, 0.841 mmol), dichloropalladium; [l-(2-diphenylphosphanyl-l-naphthyl)-2-naphthyl]-diphenyl- phosphane (75 mg, 0.093 mmol), and K2CO3 (194 mg, 1.400 mmol). The reaction was stirred at 105 °C for 16 h under N2. The reaction mixture was concentrated to provide a residue, which waspurified by filtering with (DCM:MeOH=15: l) to give tert-butyl (2S)-4-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (480 mg, 0.562 mmol, 72.37% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+853.3.

[0366] Step 5: To a solution of tert-butyl (2S)-4-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano- 7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (480 mg, 0.562 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to provide a residue, which was purified by Cis column to give2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (250 mg, 0.383 mmol, 68.05% yield) as a white solid. LCMS (ESI) m / z: [M+H]+653.3.

[0367] Step 6: To a solution of 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)piperazin-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7- fluorobenzo[b]thiophene-3-carbonitrile (250 mg, 0.383 mmol) in DCM (5 mL) were added 2- (hydroxymethyl)prop-2-enoic acid (117 mg, 1.148 mmol), DIPEA(198 mg, 1.531 mmol), and T4P (276 mg, 0.766 mmol). The mixture was stirred at 25 °C for 10 minutes. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (DCM:MeOH=10:l) to give 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)-4-(2-(hydroxymethyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (200 mg, 0.271 mmol, 70.88% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+737.3.

[0368] Step 7 A solution of 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)-4-(2- (hydroxymethyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (200 mg, 0.271 mmol) in DCM (4 mL) were added DIPEA (140 mg, 1.084 mmol) and methyl sulfonyl methanesulfonate (142 mg, 0.814 mmol). The reaction was stirred at 25 °C for 16 h. The reaction mixture was concentrated to provide a residue which was purified by filtering with (DCM:MeOH=10:l) to give 2-((2S)-4-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-2-(cyanomethyl)piperazine-l-carbonyl)allyl methanesulfonate (100 mg, 0.123 mmol, 45.21% yield) as white solid. LCMS (ESI) m / z: [M+H]+815.4.

[0369] Step 8: To a solution of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (39 mg, 0.123 mmol) in DMF (3 mL) was added CS2CO3 (120 mg, 0.368 mmol). The mixture was stirred at 25 °C for 1 h. Then, 2-((2S)-4-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2- (cyanomethyl)piperazine-l-carbonyl)allyl methanesulfonate (100 mg, 0.123 mmol) in DMF (1 mL) was added to the mixture. The mixture was stirred at 35 °C for 2 h. The mixture was concentrated to provide a residue which was purified by Prep-TLC (DCM:MeOH=10: 1) to give crude product. The crude product was purified by Prep-HPLC to give 2-amino-4-(6-chloro-4-((S)- 3-(cyanomethyl)-4-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene- 3-carbonitrile (4.8 mg, 0.005 mmol, 3.69% yield) as a white solid.(400 MHz, DMSO- d6) 8 8.13 (s, 2H), 8.01 (s, 1H), 7.29 - 7.21 (m, 1H), 7.20 - 7.11 (m, 1H), 6.95 - 6.85 (m, 3H), 6.61 - 6.44 (m, 4H), 5.67 - 5.18 (m, 3H), 5.05 - 4.72 (m, 1H), 4.55 (d, J = 16.0 Hz, 2H), 4.44 - 4.16 (m, 2H), 4.16 - 3.99 (m, 3H), 3.74 (s, 4H), 3.63 (d, J = 8.0 Hz, 11H), 3.15 - 2.95 (m, 5H), 2.86 - 2.77 (m, 1H), 2.18 - 1.97 (m, 3H), 1.88 - 1.71 (m, 3H). LCMS (ESI) m / z: [M+H]+1035.6.Example 5: Preparation of Compound 5Compound 5

[0370] Step . To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.1 g, 4.221 mmol) in DCM (16 mL) was added DIEA (1.8 mL, 10.541 mmol) at -40 °C. The mixture was stirred at -40 °C for 15 min. Then tert-butyl (S)-2-(cyanomethyl)piperazine-l -carboxylate (950 mg, 4.221 mmol) (dissolved in DCM (4 mL) was added and stirred at -40 °C for 1 h. The reaction mixture was diluted with DCM (40 mL) quenched with water (40 mL), washed with brine (40 mL), and dried over anhydrous Na2SO4. The combined organic layers were concentrated under reduced pressure to give tert-butyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)piperazine-l-carboxylate (1.8 g, 96%) as a yellow solid. LCMS (ESI) m / z: [M+H]+441.1.

[0371] Step 2: To a mixture of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (649 mg, 4.081 mmol) in THF (8 mL) was added NaH (326 mg, 8.162 mmol, 60% purity) at 0 °C. The mixture was stirred at rt for 15 min to give mixture A. To a mixture of tertbutyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-l- carboxylate (1.8 g, 4.081 mmol) in THF (40 mL) was added mixture A at 0 °C. The mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), washed with brine (50 mL), and dried over anhydrous Na2SO4. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (DCM) to give tert-butyl (S)-4-(7-chloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 2-(cyanomethyl)piperazine-l -carboxylate (1.7 g, 73%) as a yellow solid. LCMS (ESI) m / z: [M+Na]+564.3.

[0372] Step 3: To a solution of tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (900 mg, 1.601 mmol) in MeOH (10 mL) was added HC1 (4 M, 15 mL). The mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjust to pH 8 with NaHCCh, then was concentrated under reduced pressure to give another residue. The residue was dissolved with DCM and filtered. The filtrate was concentrated in vacuo to afford 2-((S)-4-(7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (700 mg, 94%) as a yellow solid. LCMS (ESI) m / z: [M+H]+464.3.

[0373] Step 4: To a mixture of 2-((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (700 mg, 1.512 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)naphthalen-l -yl)ethynyl)triisopropylsilane (1.0 g, 1.963 mmol) in dioxane (20 mL) and water (8 mL) were added CS2CO3 (1.5 g, 4.531 mmol) and Pd(dppf)Ch.CH2C12 (185 mg, 0.226 mmol) . The mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (5% MeOH in DCM(0.5% TEA)) to give 2-((S)-4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (300 mg, 24%) as a yellow solid. LCMS (ESI) m / z: [M+H]+814.2.

[0374] Step 5: To a solution of 2-((S)-4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (250 mg, 0.307 mmol) in THF (4 mL) was added TBAF (1 M, 0.921 mmol, 0.9 mL). The mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (6% MeOH in DCM) to give 2-((S)-4- (7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile (200 mg, 99%) as a yellow solid. LCMS (ESI) m / z: [M+H]+658.4.

[0375] Step 6: To a solution of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (150 mg, 0.228 mmol) and 2-(hydroxymethyl)acrylic acid (70 mg, 0.684 mmol) in DCM (5 mL) were added DIEA (118 mg, 0.912 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (164 mg, 0.456 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was quenched with water, extracted with ethyl acetate (3 x 15 mL), washed with brine (30 mL), dried over anhydrous Na2SO4. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (8% MeOH in DCM) to give 2-((S)-4-(7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2- (hydroxymethyl)acryloyl)piperazin-2-yl)acetonitrile (110 mg, 65%) as a yellow solid. LCMS (ESI) m / z: [M+H]+742.5.

[0376] Step 7: To a solution of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-(hydroxymethyl)acryloyl)piperazin-2- yl)acetonitrile (90 mg, 0.121 mmol) in DCM (4 mL) were added TEA (37 mg, 0.364 mmol), pyridine (29 mg, 0.364 mmol) and DMAP (15 mg, 0.121 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure to give 2-((S)-2- (cyanomethyl)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R,7aS)-2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazine-l-carbonyl)allyl methanesulfonate (90 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H]+820.5.

[0377] Step 8: To a mixture of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (52 mg, 0. 165 mmol) in ACN (3 mL) was added CS2CO3 (107 mg, 0.329 mmol). The mixture was stirred at rt for 30 min. Then 2-((S)-2-(cyanomethyl)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- I-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperazine-l-carbonyl)allyl methanesulfonate (90 mg, 0.110 mmol) was added and stirred at 60 °C for 1 h. The mixture was fdtered and the fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (MeOH / DCM=l / 15) to give 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-((2-methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-2- yl)acetonitrile (60 mg, 52%) as a yellow solid. LCMS (ESI) m / z: [M+H]+1040.6.

[0378] Step 9: To a solution of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-2-yl)acetonitrile (60 mg, 0.058 mmol) in formic acid (3 mL) was stirred at rt for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2-((S)-4-(7-(8-ethynyl- 7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-2-yl)acetonitrile (18.1 mg) as a light yellow solid. ‘HNMR (400 MHz, DMSO-d6) 5 10.20 (s, 1H), 9.12 (s, 1H), 7.99 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.20 (t, J = 3.2 Hz, 1H), 6.96 - 6.86 (m, 3H), 6.61 - 6.43 (m, 4H), 5.74 - 5.19 (m, 3H), 5.00 - 4.75 (m, 1H), 4.66 - 4.34 (m, 4H), 4.30 - 3.89 (m, 4H), 3.86 - 3.67 (m, 5H), 3.63 (s, 10H), 3.20 - 2.98 (m, 5H), 2.90 - 2.79 (m, 1H), 2.16 - 2.11 (m, 1H), 2.08 - 1.98 (m, 2H), 1.88 - 1.74 (m, 3H). LCMS (ESI) m / z: [M+H]1996.6.Example 6: Preparation of Compound 6

[0379] Step 1 To a solution of 5-bromo-2-iodo-phenol (3.0 g, 10.040 mmol) in THF (40 mL) at 0 °C was added NaH (60% dispersion in oil) (802 mg, 20.070 mmol). The mixture was stirred at 0 °C for 15 min, and bromo(methoxy)methane (1.6 g, 13.050 mmol) was added dropwise at 0 °C. The mixture was stirred for 30 min at 0 °C, quenched with water (10 mL), and extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (30 mL) three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 98:2) to give 4-bromo-l-iodo-2- (methoxymethoxy)benzene (3.4 g, 9.910 mmol, 98.78% yield). *HNMR (400 MHz, Chloroform- d) 8 7.54 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 5.16 (s, 2H), 3.45 (s, 3H).

[0380] Step 2: To a solution of 4-bromo-l-iodo-2-(meth oxymethoxy )benzene (3.5 g, 10.210 mmol), 2-trimethylsilylethanol (6.0 g, 51.030 mmol), Cui (388 mg, 2.040 mmol), 1,10- phenanthroline (735 mg, 4.080 mmol), and CS2CO3 (10.0 g, 30.620 mmol) in toluene (30 mL). The reaction was submitted to microwave irradiation for 60 minutes at 120 °C. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 98:2) to give 2-[4-bromo-2-(methoxymethoxy)phenoxy]ethyl-trimethyl -silane (1.2 g, 3.600 mmol, 35.28% yield). 'H NMR (400 MHz, Chloroform-d) 8 7.21 - 7.16 (m, 1H), 7.00 (dd, J = 8.6, 2.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.11 (s, 2H), 4.06 - 3.95 (m, 2H), 3.43 (s, 3H), 1.14 - 1.04 (m, 2H).

[0381] Step 3: To a solution of 2-[4-bromo-2-(methoxymethoxy)phenoxy]ethyl-trimethyl- silane (1.6 g, 4.80 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.8 g, 7.200 mmol), cyclopentyl(diphenyl)phosphane;dichloropalladium; iron (526 mg, 0.720 mmol) and KOAc (2.8 g, 28.080 mmol) in dioxane (20 mb). The resulting mixture was refluxed for 12 h. The solid was removed through a Celite® pad and washed with EtOAc (3 mb x 3). The filtrate and washings were combined and evaporated to give a yellow oil, which was chromatographed on SiCh (15 g, n-hexane / acetone = 5 / 1) to give (2-(2- (methoxymethoxy)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)ethyl)trimethylsilane (900 mg, 2.370 mmol, 49.29% yield). ’H NMR (400 MHz, Chloroform-d) 8 7.42 (d, J = 1.6 Hz, 1H), 7.40 - 7.35 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.15 (s, 2H), 3.45 (s, 3H), 1.24 (s, 13H), 1.20 - 1.09 (m, 5H), 0.01 (s, 9H).

[0382] Step 4: To a solution of 2-imidazol-l-ylaniline (1.0 g, 6.280 mmol) and CDI (1.1 g, 6.910 mmol) in 1,2-di chlorobenzene (16 mb). The reaction was irradiated in the microwave at 180 °C for 30 min. The reaction solution was cooled to 0 °C and filtrated. The filter cake was washed with toluene, PE and water and then dried over in vacuum to provide 5H-imidazo[l,2- a]quinoxalin-4-one (1.0 g, 5.400 mmol, 85.96% yield). LCMS (ESI) m / z: [M+H]+186.24.

[0383] Step 5: To a solution of 5H-imidazo[l,2-a]quinoxalin-4-one (300 mg, 1.620 mmol) in POC13 (5 mb). The reaction was stirred in 110 °C for 16 h. The reaction solution was concentrated under vacuum , washed with DCM, and filtrated. The filtrate was concentrated under reduced pressure to give 4-chloroimidazo[l,2-a]quinoxaline (300 mg, 1.470 mol, 90.94% yield). LCMS (ESI) m / z: [M+H]+204.22.

[0384] Step 6: To a solution of 4-chloroimidazo[l,2-a]quinoxaline (400 mg, 1.960 mmol) and methylamine (1.2 g, 39.290 mmol) in EtOH (5 mb). The reaction was submitted to microwave irradiation for 30 minutes at 100 °C. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc =70:30) to give N- methylimidazo[l,2-a]quinoxalin-4-amine (200 mg, 1.010 mmol, 51.36% yield). LCMS (ESI) m / z: [M+H]+199.31.

[0385] Step 7: To a solution of N-methylimidazo[l,2-a]quinoxalin-4-amine (180 mg, 0.908 mmol) and NBS (129 mg, 0.726 mmol) in chloroform (5 mL) . The reaction was stirred at reflux for 40 min. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate, washed twice with a saturated aqueous NH4CI solution, saturated aqueous NaHCO.i solution, distilled water, brine, then dried over Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 70:30) to give l-bromo-N-methyl-imidazo[l,2-a]quinoxalin-4-amine (100 mg, 0.360 mmol, 39.74% yield). LCMS (ESI) m / z: [M+H]+277.21.

[0386] Step 8: To a solution of 2-[2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy]ethyl-trimethyl-silane (82 mg, 0.217 mmol), 1-bromo-N-methyl- imidazo[l,2-a]quinoxalin-4-amine (50 mg, 0.180 mmol), Na2CC>3 (38 mg, 0.360 mmol), and palladium;triphenylphosphine (21 mg, 0.018 mmol) in H2O (2 mL) and DME (2 mL). The reaction was irradiated in a microwave at 120 °C for 1 h. The reaction solution was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 60:40) to give l-(3-(methoxymethoxy)-4-(2-(trimethylsilyl)ethoxy)phenyl)-N-methylimidazo[l,2-a]quinoxalin-4-amine (30 mg, 0.066 mmol, 36.90% yield). LCMS (ESI) m / z: [M+H]+451.56.

[0387] Step 9: To a solution of l-(3-(methoxymethoxy)-4-(2-(trimethylsilyl)ethoxy)phenyl)- N-methylimidazo[l,2-a]quinoxalin-4-amine (30 mg, 0.066 mmol) in THF was added TBAF (1.0 M in THF) (26 mg, 0.099 mmol). The reaction was stirred in 25 °C for 2 h. The resulting mixture was quenched with water and extracted with EtOAc (30 mL * 3). The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PE: EtOAc = 50:50) to obtain 2-(methoxymethoxy)-4-(4-(methylamino)imidazo[ 1,2- a]quinoxalin-l-yl)phenol (20 mg, 0.057 mmol, 85.74% yield). LCMS (ESI) m / z: [M+H]+351.49.

[0388] Step 10: To a solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl methanesulfonate (6.13) (45 mg, 0.056 mmol) in ACN (5 mL) was added CS2CO3 (73 mg, 0.223 mmol). Compound 6.13 was prepared from Int-D in the same manner as 5.12 was prepared from 5.9. The mixture was stirred at 25 °C for 10 minutes. Then 2-(methoxymethoxy)-4-(4-(methylamino)imidazo[ 1,2- a]quinoxalin-l-yl)phenol (20 mg, 0.056 mmol) in ACN (2 mL) was added to the mixture. Themixture was stirred at 60 °C for 3 h. The reaction solution was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH=90: 10) to give l-(3-(7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2-((2-(methoxymethoxy)-4-(4-(methylamino)imidazo[l,2- a]quinoxalin-l-yl)phenoxy)methyl)prop-2-en-l-one (45 mg, 0.042 mmol, 76.04% yield). LCMS (ESI) m / z: [M+H]+1061.6.

[0389] Step 11: To a solution of l-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2-(methoxymethoxy)-4-(4- (methylamino)imidazo[l,2-a]quinoxalin-l-yl)phenoxy)methyl)prop-2-en-l-one (45 mg, 0.042 mmol) in formic acid (5 mL). The reaction was stirred in 25 °C for 3 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give the residue which was further purified by Prep-HPLC to give l-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2-hydroxy-4-(4-(methylamino)imidazo[l,2-a]quinoxalin- l-yl)phenoxy)methyl)prop-2-en-l-one (13 mg, 0.013 mmol, 30.69% yield). 'H NMR (400 MHz, DMSO-de) 8 9.61 (s, 1H), 9.06 (s, 1H), 7.98 (dd, J= 9.2, 6.0 Hz, 1H), 7.75 - 7.66 (m, 1H), 7.59 (dd, J = 8.1, 1.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.35 - 7.26 (m, 2H), 7.22 - 7.15 (m, 2H), 7.02 - 6.93 (m, 3H), 5.85 (s, 1H), 5.64 (s, 1H), 5.39 - 5.17 (m, 1H), 4.89 (s, 2H), 4.84 - 4.41 (m, 4H), 4.13 (d, J = 10.4 Hz, 1H), 4.07 - 3.88 (m, 3H), 3.67 (s, 2H), 3.11 - 3.03 (m, 5H), 3.01 (s, 1H), 2.88 - 2.78 (m, 1H), 2.18 - 2.08 (m, 1H), 2.07 - 1.94 (m, 3H), 1.90 - 1.73 (m, 6H). LCMS (ESI) m / z: [M+H]+973.6.Example 7: Preparation of Compound 7

[0390] Step 1 To a solution of 7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-l,3-dihydroquinoxalin-2-one (750 mg, 2.310 mmol) and tert-butyl 2-bromoacetate (674 mg, 3.460 mmol) in DMF (15 mb) was added K2CO3 (955 mg, 6.920 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The mixture was concentrated and purified by silica gel chromatography (eluting with 1 / 7 MeOH / DCM) to afford tert-butyl 2-[7-methoxy-4- [2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l- yl]acetate (370 mg, 0.841 mmol, 36.52% yield). LCMS (ESI) m / z: [M+H]+440.3.

[0391] Step 2: To a solution of tert-butyl 2-[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]acetate (370 mg, 0.841 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise. The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum and purified on a Biotage Isolera One (Cl 8 column, eluting with 5% to 95% ACN / H2O) to afford 2-[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]acetic acid (150 mg, 0.391 mmol, 46.47% yield). LCMS (ESI) m / z: [M+H]+384.2.

[0392] Step 3 A mixture of 2-[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]acetic acid (150 mg, 0.391 mmol), tertbutyl 2-(hydroxyrnethyl)prop-2-enoate (185 mg, 1.170 mmol), DPPA (194 mg, 0.704 mmol), and TEA (79 mg, 0.782 mmol) in toluene (6 mL) was heated at 85 °C for 3 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was purified by silica gel chromatography (eluting with 3 / 97 MeOH / DCM) to afford tert-butyl 2-[[7-methoxy-4-[2-(methylamino)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l- yl]methylcarbamoyloxymethyl]prop-2-enoate (90 mg, 0.167 mmol, 42.71% yield). LCMS (ESI) m / z: [M+H]+539.4.

[0393] Step 4 A solution of tert-butyl 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoate (90 mg, 0.167 mmol) in formic acid (3 mL) was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum and purified on a Biotage Isolera One (C 18 column, eluting with 5% to 95% ACN / H2O) to afford 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoic acid (35 mg, 0.072 mmol, 43.41% yield). LCMS (ESI) m / z: [M+H]1483.3.

[0394] Step 5 To a solution of 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoic acid (35 mg, 0.072 mmol) in DCM (3 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en- 1-amine (39 mg, 0.290 mmol). The resulting mixture was stirred at rt for 1 hour. The reaction was quenched with MeOH. The mixture was concentrated and used directly in the next step. LCMS (ESI) m / z: [M+ Na]+497.4.

[0395] Step 6: To a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-l-yl]-2-[[(2S)- l-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (53 mg, 0.093 mmol) in DCM were added 2-chlorocarbonylallyl N-[[7-methoxy-4-[2- (methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l- yl]methyl]carbamate (36 mg, 0.072mmol) and 2,6-lutidine (23 mg, 0.215 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 5 min. The crude product was purified by silica gel chromatography (eluting with 1 / 8 MeOH / DCM) and prep-HPLC to afford 2-((3S)-4-(7-(6-amino- 4-methyl-3-(tri fluoromethyl )pyri din-2 -yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-l-carbonyl)allyl ((7 -methoxy -4-(2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxo-3,4-dihydroquinoxalin- l(2H)-yl)methyl)carbamate (3 mg, 0.003 mmol, 4.45% yield).1H NMR (400 MHz, DMSO-de) 58.11 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 6.93 - 6.74 (m, 3H), 6.61 (m, 2H), 6.50 (s, 1H), 5.49 (s, 1H), 5.28 (m, 3H), 4.67 (s, 3H), 4.46 (s, 2H), 4.38 (m, 1H), 4.17 (m, 2H), 3.95 (m, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 2.94 (m, 1H), 2.77 (m, 3H), 2.60 - 2.52 (m, 4H), 2.36 (m, 6H), 2.17 (m, 1H), 1.96 (m, 3H), 1.67 (m, 5H), 1.24 (m, 3H). LCMS (ESI) m / z: [M+H]+1032.6.Example 8: Preparation of Compound 8Corapotffid 8

[0396] Step I To a solution of l-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-(hydroxymethyl)prop-2-en-l-one (100 mg, 0.137 mmol) in DCM (3 mL) were added TEA (42 mg, 0.411 mmol), pyridine (33 mg, 0.412 mmol), DMAP (17 mg, 0.137 mmol), and methanesulfonyl chloride (62.87 mg, 0.548 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under air atmosphere. Then the mixturewas diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over NajSCL, filtered and concentrated to provide a residue which was used for next step. LCMS (ESI) m / z: [M+H]‘ 807.5.

[0397] Step 2'. To a solution of 2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5-yl]phenol (22 mg, 0.062 mmol) in ACN (1 m ) was added CS2CO3 (50 mg, 0.154 mmol). The reaction mixture was stirred at 25 °C for 15 minutes under air atmosphere. Then 2-[3-[7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carbonyl]allyl methanesulfonate (50 mg, 0.062 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours under N2 atmosphere. Then the mixture was filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=10: 1) to give l-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2R,8S)-2- fhioro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octan-8-yl]-2-[[2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5- yl]phenoxy]methyl]prop-2-en-l-one (40 mg, 0.037 mmol, 60.38% yield) as white solid. LCMS (ESI) m / z: [M+H]+209.1.

[0398] Step 3 To l-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[[2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5- yl]phenoxy]methyl]prop-2-en-l-one (40 mg, 0.037 mmol) was added formic acid (1.2 g, 26.491 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep-HPLC to give l-[3- [7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]-2-[[2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5-yl]phenoxy]methyl]prop-2-en-l-one (15 mg, 0.014 mmol, 39.37% yield) as white solid. 'H NMR (400 MHz, DMSO-d6) 8 10.17 (s, 1H), 9.05 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 7.01 (s, 2H), 5.66 (s, 1H), 5.54 (s, 1H), 5.39 - 5.18 (m, 1H), 4.80 - 4.37 (m, 6H), 4.09 (dd, J = 37.8, 10.4 Hz, 2H), 3.93 (s, 1H), 3.83 (d, J = 26.4 Hz, 1H), 3.75 (d, J = 1.7 Hz, 12H), 3.67 (s, 1H), 3.08 (dd, J = 24.2, 13.6 Hz,3H), 2.83 (dd, J = 15.3, 8.0 Hz, 1H), 2.14 (d, J = 5.2 Hz, 1H), 2.09 - 1.99 (m, 2H), 1.82 (dd, J =22.3, 12.6 Hz, 7H). LCMS (ESI) m / z: [M+Hf 1025.6.Example 9: Preparation of Compound 9

[0399] Step 1: To a solution of (6-methoxy-2-methyl-lH-indol-3-yl)-(3,4,5- trimethoxyphenyl)methanone (880 mg, 2.480 mmol) in DMF (10 mL) were added tert-butyl 2- bromoacetate (628 mg, 3.220 mmol) and K2CO3 (684 mg, 4.950 mmol). The mixture was stirred at 60 °C for 2 h. The mixture was quenched by sat. aq. citric acid (150 mL), and extracted with DCM (containing 10% methanol, 150 mLx4). The combined organic layers were dried by Na2SO4, filtered and concentrated under reduce pressure to give residue. The residue was purification by flash silica gel (80 g, EtOAc / PE=0~50%) to give tert-butyl 2-[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]acetate (800 mg, 1.700 mmol, 68.81% yield). LCMS (ESI) m / z: [M+H-56]+470.3.

[0400] Step 2: To a solution of tert-butyl 2-[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]acetate (800 mg, 1.700 mmol) in DCM and TFA. The reaction was stirred in 25 °C for 1 h. The mixture was concentrated and purified by reversed-phase column(Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 80% in 30 min) and the fractions containing the product were combined and lyophilized to give 2-[6-methoxy-2- methyl-3-(3,4,5-trimethoxybenzoyl)indol-l-yl]acetic acid (350 mg, 0.846 mmol, 49.69% yield). LCMS (ESI) m / z: [M+H-56]+414.2.

[0401] Step 3 To a stirred solution of 2-[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]acetic acid (100 mg, 0.242 mmol), tert-butyl 2- (hydroxymethyl)prop-2-enoate (115 mg, 0.726 mmol), TEA (49 mg, 0.484 mmol), and DPPA(120 mg, 0.435 mmol) in toluene (5 mL) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 85 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography (DCM:MeOH= 98:2) to give tert-butyl 2-[[6-methoxy-2- methyl-3-(3,4,5-trimethoxybenzoyl)indol-l-yl]methylcarbamoyloxymethyl]prop-2-enoate (120 mg, 0.211 mmol, 87.25% yield). LCMS (ESI) m / z: [M+H]+569.4.

[0402] Step 4.' To a solution of tert-butyl 2-[[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]methylcarbamoyloxymethyl]prop-2-enoate (60 mg, 0.106 mmol) in formic acid (5 mL). The reaction was stirred in 25 °C for 3 h. The mixture was purified by reversed-phase column (Mobile phase: A: 0.5% Formic acid in water, B Acetonitrile; B from 5% to 80% in 30 min) and the fractions containing the product were combined and lyophilized to give 2-[[6-m ethoxy -2-methyL3-(3, 4, 5-trimethoxybenzoyl)indol-l- yl]methylcarbamoyloxymethyl]prop-2-enoic acid (30 mg, 0.058 mmol, 55.47% yield). LCMS (ESI) m / z: [M+H]+513.3.

[0403] Step 5: To a solution of 2-[[6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)indol-l- yl]methylcarbamoyloxymethyl]prop-2-enoic acid (60 mg, 0.117 mmol) in DCM (3 mL) was added a solution of l-chloro-N,N,2-trimethylpropenylamine (31 mg, 0.234 mmol) in DCM (2 mL) at 0 °C slowly. The reaction was stirred in 25 °C for 1 hour under N2. The mixture was used to next step without further work-up.

[0404] Step 6: To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (73 mg, 0.113 mmol) and 2,6-dimethylpyridine (12 mg, 0.113 mmol) in DCM (4.99 mL) was added 2-chlorocarbonylallyl N-[[6-methoxy-2-methyl- 3-(3,4,5-trimethoxybenzoyl)indol-l-yl]methyl]carbamate (60 mg, 0.113 mmol). The reaction was stirred in 25 °C for 1 h. The mixture was purified by silica gel column chromatography (MeOH:DCM=10: l) to give 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l -yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl ((6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)-lH-indol-l-yl)methyl)carbamate (40 mg, 0.035 mmol, 31.07% yield) as a white solid. LCMS (ESI) m / z: [M+H]+1139.6.

[0405] Step 7: To a solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl ((6-methoxy-2-methyl-3- (3,4,5-trimethoxybenzoyl)-lH-indol-l-yl)methyl)carbamate (40 mg, 0.035 mmol) in formic acid (5 mL). Th reaction was stirred in 25 °C for 3 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give the residue, which was further purified by Prep- HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carbonyl)allyl ((6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)- lH-indol-l-yl)methyl)carbamate (9 mg, 0.008 mmol, 23.67% yield) as a white solid.!H NMR (400 MHz, DMSO-d6) 8 10.25 (s, 1H), 9.01 (s, 1H), 8.69 - 8.55 (m, 1H), 8.01 - 7.88 (m, 1H), 7.46 (d, J = 12.0 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.34 (s, 1H), 7.29 - 7.19 (m, 2H), 6.92 (s, 2H), 6.72 (d, J= 8.7 Hz, 1H), 5.62 (s, 1H), 5.57 - 5.38 (m, 3H), 5.27 (d, J= 54.3 Hz, 1H), 4.92 - 4.16 (m, 6H), 4.11 (d, .7 = 8.0 Hz, 1H), 4.O1 (d, J= 12.0 Hz, 1H), 3.91 (s, 1H), 3.80 (s, 3H), 3.74 (d, 7= 4.3 Hz, 9H), 3.62 (s, 2H), 3.14 - 3.06 (m, 3H), 3.05 - 2.98 (m, 2H), 2.89 - 2.78 (m, 1H), 2.16 - 1.94 (m, 4H), 1.89 - 1.72 (m, 3H), 1.62 (s, 4H). LCMS (ESI) m / z: [M+H]+1095.6.Example 10: Preparation of Compound 10

[0406] Step 7: To a mixture of l-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(hydroxymethyl)prop-2-en-l-one (100 mg, 0.137 mmol), TEA (42 mg, 0.411 mmol), pyridine (32 mg, 0.411 mmol), and DMAP (16 mg, 0.137 mmol) in DCM (5 mL) under N2 was added methanesulfonyl chloride (62 mg, 0.548 mmol), and the mixture was stirred at 25 °C for 1 h. Then the mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl methanesulfonate (95 mg, 0.117 mmol, 85.81% yield) as a white solid. LCMS (ESI) m / z: [M+H]+807.27.

[0407] Step 2'. To a solution of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (55 mg, 0.176 mmol) in ACN (5 mL) was added CS2CO3 (153 mg, 0.470 mmol). The mixture was stirred at 25 °C for 10 minutes. Then 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl methanesulfonate (95 mg, 0.117 mmol) in ACN (2 mL) was added above the mixture. The mixture was stirred at 60 °C for 3 h. Theresidue was purified by silica gel column chromatography (2% MeOH in DCM). The residue was further purified by prep-HPLC to give l-(3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2- methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (35 mg, 0.034 mmol, 28.94% yield) as a white solid. LCMS (ESI) m / z: [M+H]+1027.41.

[0408] Step 3: To l-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- Iluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (35 mg, 0.034 mmol) was added FA (2 mL). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep-HPLC to give l-(3-(7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen- l -yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-l H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2- methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (8.8 mg, 0.009 mmol, 26.27% yield) as a white solid.(400 MHz, DMSO-d6) 5 10.29 (s, 1H), 9.05 (s, 1H), 8.04 - 7.92 (m, 1H), 7.52 - 7.34 (m, 2H), 7.19 (s, 1H), 6.96 - 6.83 (m, 3H), 6.62 - 6.42 (m, 4H), 5.62 (s, 1H), 5.51 (s, 1H), 5.40 - 5.18 (m, 1H), 4.80 - 4.35 (m, 6H), 4.19 - 4.10 (m, 1H), 4.09 - 4.00 (m, 1H), 3.97 - 3.78 (m, 2H), 3.68 (s, 3H), 3.64 (s, 3H), 3.63 - 3.59 (m, 6H), 3.48 - 3.41 (m, 1H), 3.15 - 3.06 (m, 2H), 3.02 (s, 1H), 2.88 - 2.80 (m, 1H), 2.17 - 2.10 (m, 1H), 2.09 - 1.98 (m, 2H), 1.96 - 1.73 (m, 7H). LCMS (ESI) m / z: [M+H]+983.6.Example 11: Preparation of Compound 11

[0409] Step 1 To an ice-cooled, stirred solution of 4-(lH-benzimidazol-2-yl)-l,2,5-oxadiazol- 3-amine (3.0 g, 14.910 mmol) in pyridine (20 mL) was added sodium methoxide (1.5 g, 26.840 mmol) and subsequently prop-2-enenitrile (1.1 g, 19.390 mmol). The reaction mixture is stirred at room temperature overnight. The residue was suspended in 100 mL of water and extracted with 4x100 mL of ethyl acetate. The combined organic layers were washed with 2 x 500 mL of brine, dried over Na2SO4, concentrated under vacuum and purified by silica gel column chromatography (PE:EtOAc=3:l) to give 3-((4-(lH-benzo[d]imidazol-2-yl)-l,2,5-oxadiazol-3- yl)amino)propanenitrile (2.5 g, 9.83 mmol, 65.94% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+255.09.

[0410] Step 2 To a solution of 3-((4-(lH-benzo[d]imidazol-2-yl)-l ,2,5-oxadiazol-3- yl)amino)propanenitrile (2.5 g, 9.830 mmol) in DMF (50 mL) were added K2CO3 (2.72 g, 19.670 mmol) and 2-bromo-l-(4-nitrophenyl)ethanone (2.9 g, 11.800 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water and extracted with EtOAc, dried over Na2SO4, concentrated under vacuum and purified by silica gel column chromatography (PE / EA=3 : 1) to 3- ((4-(l-(2-(4-nitrophenyl)-2-oxoethyl)-lH-benzo[d]imidazol-2-yl)-l,2,5-oxadiazol-3- yl)amino)propanenitrile (3.0 g, 7.19 mmol, 73.10% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+418.12.

[0411] Step 3: To a solution of 3-((4-(l-(2-(4-nitrophenyl)-2-oxoethyl)-lH-benzo[d]imidazol- 2-yl)-l,2,5-oxadiazol-3-yl)amino)propanenitrile (2.5 g, 5.990 mmol) in DCM (20 mL) was added zinc (3.9 g, 59.900 mmol) and AcOH (2 mL) at 25 °C. The reaction mixture was stirred at rt for 5 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 5:95) to afford 3-((4-(l- (2-(4-aminophenyl)-2-oxoethyl)-lH-benzo[d]imidazol-2-yl)-l,2,5-oxadiazol-3- yl)amino)propanenitrile (1.5 g, 3.870 mmol, 64.64% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+388.14.

[0412] Step 4: A mixture of 3-((4-(l-(2-(4-aminophenyl)-2-oxoethyl)-lH-benzo[d]imidazol- 2-yl)-l,2,5-oxadiazol-3-yl)amino)propanenitrile (310 mg, 0.800 mmol), tert-butyl 2- (hydroxymethyl)prop-2-enoate (379 mg, 2.40 mmol) and triphosgene (308 mg, 1.040 mmol) in DCM (5 mL) was stirred at 0 °C for 5 min. Then, triphosgene (308.70 mg, 1.04 mmol) in DCM (5 mL) was added slowly at 0 °C. The mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1 / 2 EtOAc / PE) to afford tert-butyl 2-((((4- (2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l- yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylate (220 mg, 0.384 mmol, 48.10% yield). LCMS (ESI) m / z: [M+H]+572.22.

[0413] Step 5: To a solution of tert-butyl 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5- oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylate (310 mg, 0.542 mmol) was added DCM (3 mL) and TFA (1 mL), and the reaction was stirred at 25 °C for 30 min. After completion of the reaction (as monitored by LC-MS), the mixture was concentrated under vacuum afford crude 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylic acid (220 mg, 0.426 mmol, 78.69% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+516.16.

[0414] Step 6: To a solution of 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)- lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylic acid (100 mg, 0.194 mmol) in DCM (6 mL) was added a solution of l-chloro-N,N,2-trimethylprop-l-en-l -amine (155 mg, 1.160 mmol) in DCM (6 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min and then quenched with MeOH. The reaction mixture used in the next step without further purification. LCMS (ESI) m / z: [M+H]+534.12.

[0415] Step 7: To a solution of 2-(chlorocarbonyl)allyl (4-(2-(2-(4-((2-cyanoethyl)amino)- l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (100 mg, 0.187 mmol) in DCM (3 mL) were added 2,6-lutidine (60 mg, 0.561 mmol) and 6-(6-chloro-8-fluoro-4- ((S)-2-methylpiperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4- methyl-5-(trifluoromethyl)pyridin-2-amine (106 mg, 0.187 mmol) at 0 °C. The reaction was stirred at 25 °C for 0.5 h. The residue was purified by silica gel column chromatography (2% MeOH in DCM) to give a residue. The residue was purified by prep-HPLC to give 2-((3S)-4-(7- (6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3 -methylpiperazine- l-carbonyl)allyl (4-(2-(2- (4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l- yl)acetyl)phenyl)carbamate (2.2 mg, 0.002 mmol, 1.10% yield) as a white solid. ' H NMR (400 MHz, DMSO-d6) 8 10.40 (s, 1H), 8.18 - 8.12 (m, 2H), 7.95 (dd, J = 6.7, 2.3 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.53 - 7.43 (m, 3H), 6.90 (s, 2H), 6.56 (s, 1H), 6.38 (s, 2H), 5.72 (s, 1H), 5.50 (s, 1H), 5.04 - 4.89 (m, 2H), 4.79 (s, 1H), 4.49 - 4.07 (m, 5H), 3.78 - 3.71 (m, 3H), 3.22 - 3.13 (m, 1H), 3.03 - 2.96 (m, 3H), 2.66 - 2.61 (m, 1H), 2.45 - 2.42 (m, 3H), 2.41 - 2.39 (m, 3H), 2.25 - 2.18 (m, 1H), 2.04 - 1.95 (m, 1H), 1.77 - 1.65 (m, 3H), 1.43 - 1.35 (m, 3H). LCMS (ESI) m / z: [M+H]+1065.6.Example 12: Preparation of Compound 12

[0416] Step 1 To a solution of 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoic acid (20 mg, 0.041 mmol) in DCM (3 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en- 1 -amine (22 mg, 0.166 mmol). The resulting mixture was stirred at 25 °C for 1 hour. The mixture was concentrated and used directly in the next step. LCMS (ESI) m / z: [M+ Na]+497.4.

[0417] Step 2: To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-[8-ethynyl-7-fluoro-3- (methoxy methoxy)- 1 -naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidine (38 mg, 0.059 mmol) in DCM (5 mL) was added 2- chlorocarbonylallyl N-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methyl]carbamate (20 mg, 0.039 mmol) and 2,6-lutidine (13 mg, 0.119 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 5 min. The crude product was purified by silica gel chromatography (eluting with 1 / 8 MeOH / DCM) to afford 2-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methyl]carbamate (19 mg, 0.017 mmol, 42.91% yield). LCMS (ESI) m / z: [M+H]+1109.6.

[0418] Step 3: A solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl ((7-methoxy-4-(2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxo-3,4-dihydroquinoxalin- l(2H)-yl)methyl)carbamate (19 mg, 0.017mmol) in formic acid (3 mL) was stirred at 25 °C for 3 hours. The mixture was concentrated under vacuum and purified by prep-HPLC to afford 2-(3-(7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carbonyl)allyl ((7-methoxy-4-(2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2- oxo-3, 4-dihydroquinoxalin-l(2H)-yl)methyl)carbamate (5 mg, 0.005 mmol, 27.40% yield).!H NMR (400 MHz, DMSO-d6) 8 10.24 (s, 1H), 9.05 (s, 1H), 8.14 (m, 1H), 7.98 (m, 1H), 7.47 (m, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.61 (m, 2H), 5.54 (d, J = 32.1 Hz, 2H), 5.28 (m, 3H), 4.58 (d, J = 97.6 Hz, 8H), 4.17 - 4.00 (m, 2H), 3.92 (s, 1H), 3.78 (s, 3H), 3.69 (s, 2H), 3.13 - 3.06 (m, 2H), 3.02 (s, 1H), 2.84 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.58 (m, 2H), 2.13 (d, J = 4.5 Hz, 1H), 2.03 (m, 4H), 1.89 - 1.63 (m, 9H). LCMS (ESI) m / z: [M+H]+1065.7.Example 13: Preparation of Compound 13

[0419] Step 1 To a solution of 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol (300 mg, 0.948 mmol) in DMF (6 mL) were added bis(4-nitrophenyl) carbonate (720 mg, 2.380 mmol) and DIEA (368 mg, 2.840 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. Then the mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL><3) and the combined organic layers were washed with brine, dried over Na2SC>4. The obtained crude product was subjected to silica gel column chromatography (PE / EtOAc=3:l) to give [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl](4- nitrophenyl) carbonate (400 mg, 0.830 mmol, 87.61% yield) as a yellow oil. LCMS (ESI) m / z: [M+H]+482.3.

[0420] Step 2: To a solution of [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] (4-nitrophenyl) carbonate (500 mg, 1.040 mmol) in DCM (5 mL) were added tert-butyl (2S)-2- (methylaminomethyl)pyrrolidine-l -carboxylate (289 mg, 1.350 mmol) and DIEA (403 mg, 3.120mmol, 0.542 ml) at 25 °C. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (PE / EtOAc =3: 1) to give tert-butyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (500 mg, 0.898 mmol, 86.49% yield) as a transparent oil. LCMS (ESI) m / z: [M+H]+556.6.

[0421] Step 3: To a suspension of tert-butyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (500 mg, 0.898 mmol) in DCM (3 mb) was added TFA (1.49 g, 13.070 mmol, 1 m ). The reaction mixture was stirred at 25 °C for 1 h. The crude product was purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give [2-methoxy-5-[(Z)-2- (3,4,5-trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (278 mg, 0.609 mmol, 67.79% yield) as white solid. LCMS (ESI) m / z: [M+H]+457.3.

[0422] Step 4'. To a suspension of tert-butyl 2-(hydroxymethyl)prop-2-enoate (322 mg, 2.040 mmol) in DCM (5 mb) was added TEA (137 mg, 1.360 mmol, 0.189 mb). The reaction mixture was stirred at 25 °C for 1 h, and then [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (310 mg, 0.679 mmol) was added. The reaction mixture was stirred at 25 °C for 72 h. The crude product was purified by reversed-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product was combined and lyophilized to give 2-tert- butoxycarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (150 mg, 0.234 mmol, 34.48% yield) as a white oil. LCMS (ESI) m / z: [M+H]+641.5.

[0423] Step 5: A suspension of 2-tert-butoxycarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2- (3,4,5-trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carboxylate (150 mg, 0.234 mmol) in formic acid (2 mb) was stirred at 50 °C for 16 h. The crude product was purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give 2-[[(2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l-carbonyl]oxymethyl]prop-2-enoic acid (80 mg, 0.137 mmol, 58.45% yield) as a white solid. LCMS (ESI) m / z: [M+H]+585.4.

[0424] Step 6: To a solution of 2-[[(2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carbonyl]oxymethyl]prop-2-enoic acid (45 mg, 0.077 mmol) in DCM (3 mL) was added 1- chloro-N,N,2-trimethyl-prop-l-en-l -amine (21 mg, 0.154 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was used directly in the next step.

[0425] Step 7: To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l -naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahy dropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidine (80 mg, 0.124 mmol) and 2,6-lutidine (27 mg, 0.249 mmol) in DCM (5 mL) was added 2-chlorocarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (50 mg, 0.083 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: 1) to give the residue which was further purified by Prep-HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)- 3, 4, 5-trimethoxystyryl)phenoxy)carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (40 mg, 0.033 mmol, 39.83% yield) as a yellow solid . LCMS (ESI) m / z: [M+H]+1211.7.

[0426] Step 8 : A solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)- 3, 4, 5-trimethoxystyryl)phenoxy)carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (40 mg, 0.033 mmol) in formic acid (4 mL) was stirred at 25 °C for 3 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give a residue which was further purified by Prep-HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (17 mg, 0.015 mmol, 45.66% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 10.32 (s, OH), 9.06 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.19(d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (dd, J = 13.5, 7.4 Hz, 2H), 6.56 (d, J = 5.5 Hz, 2H), 6.53 - 6.40 (m, 2H), 5.70 - 5.44 (m, 2H), 5.39 - 5.18 (m, 1H), 4.86 - 4.31 (m, 6H), 4.18 - 3.99 (m, 3H), 3.93 (s, 1H), 3.73 (d, J = 2.8 Hz, 6H), 3.62 (dd, J = 7.4, 1.9 Hz, 10H), 3.15 - 3.04 (m, 3H), 3.01 (s, 3H), 2.89-2.82 (m, 3H), 2.14 (d, J = 4.6 Hz, 1H), 2.10 - 1.93 (m, 3H), 1.86-1.75 (m, 12H). LCMS (ESI) m / z: [M+H]+1167.7.Example 14: Preparation of Compound 14Compound 14

[0427] Step 1 To a solution of l-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2- yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-l-yl)-2-(hydroxymethyl)prop-2-en-l-one (50 mg, 0.077 mmol) in DCM (3 mL) was added PBn (20.76 mg, 0.077 mmol) in DCM (0.5mL) at 0 °C. The mixture was stirred at 25 °C for 10 minutes. The mixture was diluted with NaHCO? saturated aqueous solution and extracted with DCM, dried over Na2SC>4, and concentrated under vacuum to give crude l-((3S)-4-(7-(6- amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-l -yl)-2-(bromomethyl)prop-2-en-l -one (45 mg, 0.063 mmol, 82.08% yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+714.3.

[0428] Step 2'. To a solution of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (20 mg, 0.063 mmol) in ACN (3 mL) was added K2CO3 (26 mg, 0.189 mmol). The mixture was stirred at 25 °C for 10 minutes. Then l-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro- 8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-l-yl)-2- (brom omethyl)prop-2-en-l -one (45 mg, 0.063 mmol) in ACN (1 mL) was added to the mixture. The mixture was stirred at 60 °C for 3 h. The mixture was concentrated to provide a residue which was purified by Pre-TLC (DCM:MeOH=10: l) to give a crude product. The crude product was purified by Prep-HPLC to give l-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)- 6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin- l-yl)-2-((2-methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (8 mg, 0.009 mmol, 14.04% yield) as a white solid. *HNMR (400 MHz, DMSO-d6) 8 7.78 (s, 1H), 7.00 - 6.78 (m, 5H), 6.62 - 6.42 (m, 5H), 5.55 (s, 1H), 5.33 (s, 1H), 4.81 - 4.44 (m, 3H), 4.39 (ddd, J = 11.7, 7.6, 4.5 Hz, 1H), 4.28 (d, J = 13.5 Hz, 1H), 4.17 (dt, J = 10.8, 7.1 Hz, 1H), 4.01 (s, 1H), 3.74 (d, J = 3.2 Hz, 3H), 3.64 (s, 3H), 3.62 (s, 6H), 3.29 - 3.08 (m, 4H), 2.95 (t, J = 6.6 Hz, 1H), 2.61 (s, 1H), 2.37 (d, J = 10.4 Hz, 6H), 2.18 (q, J = 8.5 Hz, 1H), 1.94 (q, J = 9.0 Hz, 1H), 1.67 (dtd, J = 15.4, 11.7, 10.0, 4.9 Hz, 3H), 1.31 - 1.20 (m, 3H). LCMS (ESI) m / z: [M+H]+950.6.Example 15: Preparation of Compound 15

[0429] Step 1 To a solution of 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)- lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylic acid (100 mg, 0.194 mmol) in DCM (3 mb) was added a solution of l-chloro-N,N,2-trimethylprop-l-en-l -amine (78 mg, 0.582 mmol) in DCM (3mL) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min and quenched with MeOH. The reaction mixture used in the next step without further purification. LCMS (ESI) m / z: [M+H]+516.16.

[0430] Step 2: To a solution of 2-(chlorocarbonyl)allyl (4-(2-(2-(4-((2-cyanoethyl)amino)- l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (20 mg, 0.037 mmol) in DCM were added 2,6-lutidine (12 mg, 0.112 mmol) and 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (24 mg, 0.037mmol) at 0 °C. The reaction was stirred at 25 °C for 0.5 h. The residue was purified by silica gel column chromatography (2% MeOH in DCM) to give a residue. The residue was purified by prep- HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5- oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (10 mg, 0.008 mmol, 23.33% yield) as a white solid. LCMS (ESI) m / z: [M+H]+1141.42.

[0431] Step 3 To 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (4-(2-(2-(4-((2- cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate(120 mg, 0.052 mmol) was added formic acid (2 mb). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep-HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (4-(2-(2-(4-((2- cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (5 mg, 0.004 mmol, 8.67% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6)5 10.34 (s, 1H), 9.08 (s, 1H), 8.14 - 8.00 (m, 2H), 7.97 - 7.86 (m, 2H), 7.84 - 7.77 (m, 1H), 7.74 - 7.65 (m, 2H), 7.49 - 7.34 (m, 5H), 7.21 - 7.11 (m, 1H), 6.28 (s, 2H), 5.83 - 5.56 (m, 2H), 5.38 - 5.18 (m, 1H), 4.91 (s, 6H), 4.15 - 3.99 (m, 2H), 3.94 (s, 1H), 3.84 - 3.64 (m, 4H), 3.15 - 2.91 (m, 6H), 2.86 - 2.76 (m, 1H), 2.13 - 1.71 (m, 10H). LCMS (ESI) m / z: [M+H]+1098.6.Example 16: Preparation of Compound 16

[0432] Step 1 To a solution of 2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]aniline (300 mg, 0.841 mmol) in DCM (8 mL) was added triphosgene (149 mg, 0.505 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. Then TEA (255 mg, 2.531 mmol) was added. The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere.The mixture was concentrated to provide a residue directly used for next step. LCMS (ESI) m / z: [M+H]+383.2.

[0433] Step 2'. To a solution of 4-(3-isocyanato-4-methoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)isoxazole (300 mg, 0.784 mmol) in DCM (5 mL) were added tert-butyl 2- (hydroxymethyl)prop-2-enoate (186 mg, 1.180 mmol) and TEA (158 mg, 1.570 mmol). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE:EtOAc=3: l) to give tert-butyl 2-[[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2-enoate (80 mg, 0.148 mmol, 18.86% yield) as a colorless oil. LCMS (ESI) m / z: [M+H]+541.3.

[0434] Step 3'. To a solution of tert-butyl 2-[[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2-enoate (80 mg, 0.148 mmol) in DCM (2 mL) was added TFA (1.5 g, 13.071 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Cis reverse column chromatography (ACN: H O=3: 1) to give 2- [[2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2- enoic acid (50 mg, 0.103 mmol, 69.74% yield) as a white solid. LCMS (ESI) m / z: [M+H]+485.3.

[0435] Step 4: To a solution of 2-[[2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4- yl]phenyl]carbamoyloxymethyl]prop-2-enoic acid (10 mg, 0.021 mmol) in DCM (1 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en-l -amine (14 mg, 0.103 mmol). The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. Then the mixture was concentrated to provide a residue which was directly used for next step. LCMS (ESI) m / z: [M+H]+521.5.

[0436] Step 5 To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l -naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahy dropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidine (64 mg, 0.099 mmol) in DCM (2 mL) were added lutidine (32 mg, 0.298 mmol) and 2-chlorocarbonylallyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (50 mg, 0.099 mmol). The reaction mixture was stirred at 25 °C for 15 mins under air atmosphere. Then the mixture was purified by silica gel column chromatography (DCM: MeOH=10: l) to give 2-[3-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[2- methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (40 mg, 0.036 mmol, 36.21% yield) as a white solid. LCMS (ESI) m / z: [M+H]+1111.6.

[0437] Step 6: To 2-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (30 mg, 0.027 mmol) was added formic acid (2.4 g, 53.010 mmol, 2 ml). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep- HPLC to give 2-[3-[7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (20 mg, 0.018 mmol, 69.42% yield) as a white solid. ' H NMR (400 MHz, DMSO-d6) 8 9.05 (s, 1H), 8.79 (s, 2H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 6.88 (s, 2H), 5.66 (s, 1H), 5.54 (s, 1H), 5.38 - 5.18 (m, 1H), 4.83 - 4.37 (m, 6H), 4.12 (d, J = 10.3 Hz, 1H), 4.03 (d, J = 10.5 Hz, 1H), 3.91 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.67 (s, 6H), 3.51 (s, 3H), 3.11 - 3.06 (m, 2H), 3.01 (s, 1H), 2.83 (dd, J = 15.4, 8.1 Hz, 1H), 2.09 (dd, J = 32.7, 3.9 Hz, 2H), 2.01 (dd, J = 7.6, 4.2 Hz, 1H), 1.88 - 1.69 (m, 7H). LCMS (ESI) m / z: [M+H]+1067.6.Example 17: Preparation of Compound 17Compound 17

[0438] Step 1. To a solution of 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol (300 mg, 0.948 mmol) in DMF (6 mL) were added bis(4-nitrophenyl) carbonate (720 mg, 2.380 mmol) and DIEA (368 mg, 2.840 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. Then the mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL><3) and the combined organic layers were washed with brine, dried over Na2SO4, and the obtained crude product was subjected to silica gel column chromatography (PE / EtO Ac=3 : 1 ) to give [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl](4- nitrophenyl) carbonate (400 mg, 0.830 mmol, 87.61% yield) as a yellow oil. LCMS (ESI) m / z: [M+H]+482.3.

[0439] Step 2 To a solution of [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] (4-nitrophenyl) carbonate (530 mg, 1 .100 mmol) in DCM (3 mL) were added tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (269 mg, 1.430 mmol) and DIEA (426 mg, 3.300 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (PE: EtOAc=2:l) to give [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-[2-[tert- butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (500 mg, 0.942 mmol, 85.60% yield) as a yellow oil. LCMS (ESI) m / z: [M+H-100]+431.3.

[0440] Step 3: To a suspension of [2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenyl] N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl- carbamate (500 mg, 0.94 mmol) in DCM (3 mL) was added TFA (1.5 g, 13.070 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The crude product was purified by reversed-phase column (Mobile phase: A: water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give [2-methoxy-5-[(Z)-2-(3, 4,5- trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[2-(methylamino)ethyl]carbamate (265 mg, 0.616 mmol, 65.33% yield) as a white solid. LCMS (ESI) m / z: [M+H]1431.3.

[0441] Step 4'. To a solution of tert-butyl 2-(hydroxymethyl)prop-2-enoate (374 mg, 2.370 mmol) in DCM (10 mL) were added TEA (159 mg, 1.580 mmol) and triphosgene (351.55 mg, 1.18 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then [2- methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-met...

Claims

1. CLAIMSor 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 tubulin inhibitor payload moiety.

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

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

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

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

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

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

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

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

14. The compound of any one of claims 1-13, wherein the compound is a compound of Formula II:II or a pharmaceutically acceptable salt thereof, wherein:Y is CR2or N;R1is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C -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;R5is hydrogen, -OR6, v°\^ / Cy1, -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 heterocyclyl ene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.

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 R3is 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 20, 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 substituted30. 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 moietyis selected from:

33. The compound of any one of claims 14-27, wherein the compound is a compound of Formula Il-b or Il-d:or a pharmaceutically acceptable salt thereof, 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; and n 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:III or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Rais independently halogen, -OR33, -N(Raa)2, or optionally substituted Ci-6 aliphatic; each Rbis independently halogen, -ORaa, -N(Rail)2, or optionally substituted Ci-6 aliphatic;Rcand Rdare each independently hydrogen, halogen or optionally substituted Ci-6 aliphatic; each Raais independently hydrogen or optionally substituted Ci-6 aliphatic; a is 0, 1, 2, 3, 4, or 5; and b is 0, 1, 2, 3, 4, or 5.

38. The compound of claim 37, wherein at least one Rais -OR33.

39. The compound of claim 37 or 38, wherein at least one Rbis -ORaa.

40. The compound of any one of claims 37-39, wherein each Rbis -ORaa.

41. The compound of any one of claims 37-40, wherein Reis hydrogen.

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

43. The compound of any one of claims 37-42, wherein each R33is independently optionally substituted Ci-6 aliphatic.

44. The compound of any one of claims 37-43, wherein a is 1 or 2.

45. The compound of any one of claims 37-44, wherein b is 3.

46. The compound of any one of claims 37-45, wherein the compound is a compound of Formula Ill-b:or a pharmaceutically acceptable salt thereof.

47. The compound of any one of claims 1-36, wherein the compound is a compound ofFormula IV:IV or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Reis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic, or two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rfis independently halogen or optionally substituted Ci-6 aliphatic, each Rgis independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic;each Rbbis independently hydrogen or optionally substituted Ci-6 aliphatic; e is 0, 1, 2, 3, 4, or 5; f is 0, 1, 2, or 3; and g is 0, 1, 2, 3, 4, or 5.

48. The compound of claim 47, wherein Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

49. The compound of claim 48, wherein Ring Z is selected from:wherein each ring is substituted with / instances of Rf.

50. The compound of any one of claims 47-49, wherein at least one Reis -ORbb.

51. The compound of any one of claims 47-50, wherein two Reare taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

52. The compound of any one of claims 47-51, wherein at least one Rsis -ORbb.

53. The compound of any one of claims 47-52, wherein each Rgis -ORbb.

54. The compound of any one of claims 47-53, wherein each Rbbis independently optionally substituted Ci-6 aliphatic.

55. The compound of any one of claims 47-54, wherein e is 1, 2, or 3.

56. The compound of any one of claims 47-55, wherein f is 0.

57. The compound of any one of claims 47-56, wherein g is 3.

58. The compound of any one of claims 47-57, wherein the compound is a compound ofor a pharmaceutically acceptable salt thereof.

59. The compound of any one of claims 1-36, wherein the compound is a compound ofFormula V:V or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z’ is NH, O, or S; each Rhis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic;R' is hydrogen, halogen, optionally substituted Ci-6 aliphatic, or optionally substituted phenyl; each Rkis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Recis independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

60. The compound of claim 59, wherein Z1is NH.

61. The compound of claim 59 or 60, wherein at least one Rhis -ORCC.

62. The compound of any one of claims 59-61, wherein R' is optionally substituted Ci-6 aliphatic or optionally substituted phenyl.

63. The compound of any one of claims 59-62, wherein at least one Rkis -ORec.

64. The compound of any one of claims 59-63, wherein each Rkis -ORCC.

65. The compound of any one of claims 59-64, wherein each Rccis independently optionally substituted Ci-6 aliphatic.

66. The compound of any one of claims 59-65, wherein h is 1.

67. The compound of any one of claims 59-66, wherein k is 3.

68. The compound of any one of claims 59-67, wherein the compound is a compound ofFormula V-b:V-b or a pharmaceutically acceptable salt thereof.

69. The compound of any one of claims 1-36, wherein the compound is a compound of Formula V’:V’ or a pharmaceutically acceptable salt thereof, wherein: each Rhis independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rkis independently halogen, -ORce, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rceis independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.

70. The compound of claim 69, wherein Rhis methyl.

71. The compound of claim 69 or 70, wherein each Rkis -OR“.

72. The compound of any one of claims 69-71, wherein each Rccis independently optionally substituted Ci-6 aliphatic.

73. The compound of any one of claims 69-72, wherein h is 1.

74. The compound of any one of claims 69-73, wherein k is 3.

75. The compound of any one of claims 69-74, wherein the compound is a compound ofFormula V’-a:V’-a or a pharmaceutically acceptable salt thereof.

76. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Z2is CH or N;Ring Y is phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Q is -CH2- or -C(O)-;W is -CH2-, -CHOH-, -C(O)-, -NH-, or -O-;Rmis hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rnis independently halogen or optionally substituted Ci-6 aliphatic; each Rpis independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rddis independently hydrogen or optionally substituted Ci-6 aliphatic; n4 is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

77. The compound of claim 76, wherein Z2is CH.

78. The compound of claim 76, wherein Z2is N.

79. The compound of any one of claims 76-78, wherein Ring Y is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

80. The compound of any one of claims 76-78, wherein Ring Y is a 3- to 7-membered carbocyclic ring.

81. The compound of any one of claims 76-80, wherein Q is -C(O)-.

82. The compound of any one of claims 76-81, wherein W is -NH-.

83. The compound of any one of claims 76-82, wherein Rmis -N(H)(Rdd).

84. The compound of any one of claims 76-83, wherein at least one Rpis -ORdd.

85. The compound of any one of claims 76-84, wherein each Rddis optionally substituted Ci-6 aliphatic.

86. The compound of any one of claims 76-85, wherein n4 is 0.

87. The compound of any one of claims 76-86, wherein p is 1.

88. The compound of any one of claims 76-86, wherein the compound is a compound ofFormula Vl-b or Formula VI-c:or a pharmaceutically acceptable salt thereof.

89. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VII:VII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rqis independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci-6 aliphatic; each Rris independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci-6 aliphatic; each Rsis independently halogen or optionally substituted Ci-6 aliphatic;Rlis -N(RCC)(CI-4 alkylene)CN; each Reeis independently hydrogen or optionally substituted Ci-6 aliphatic; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, or 4; and s is 0, 1, or 2.

90. The compound of claim 89, wherein the Ring X is91. The compound of claim 89 or 90, wherein Rlis -N(H)(CI-4 alkylene)CN.

92. The compound of any one of claims 89-91, wherein q is 0.

93. The compound of any one of claims 89-92, wherein r is 0.

94. The compound of any one of claims 89-93, wherein s is 0.

95. The compound of any one of claims 89-94, wherein the compound is a compound of Formula Vll-b:VILb or a pharmaceutically acceptable salt thereof.

96. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VIII:VIII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;M is a covalent bond or C1-4 alkylene; each Ruis independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 aliphatic; each Rvis independently halogen, -ORft, -N(Rft)2, or optionally substituted Ci-6 aliphatic; each Rftis independently hydrogen or optionally substituted Ci-6 aliphatic;R88is hydrogen or optionally substituted Ci.6 aliphatic; u is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, 3, or 4.

97. The compound of claim 96, wherein M is a covalent bond.

98. The compound of claim 96 or 97, wherein at least one Ruis -ORff.

99. The compound of any one of claims 96-98, wherein each Rffis independently optionally substituted Ci-6 aliphatic.

100. The compound of any one of claims 96-99, wherein R8Sis hydrogen.

101. The compound of any one of claims 96-100, wherein u is 1 or 2.

102. The compound of any one of claims 96-101, wherein v is 0.

103. The compound of any one of claims 96-102, wherein the compound is a compound ofFormula Vlll-b or Formula VIII-c:or a pharmaceutically acceptable salt thereof.

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

105. A pharmaceutical composition, comprising the compound of any one of claims 1-104, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

106. A method of inhibiting tubulin, comprising contacting the compound of any one of claims 1-104 or the composition of claim 105 with a KRAS protein (e.g., KRASO12C).

107. A method of releasing a tubulin inhibitor payload (e.g., a tubulin inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-104 or the composition of claim 105 with a KRAS protein (e.g., KRASG12C).

108. A method of delivering a tubulin inhibitor payload (e.g., a tubulin inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-104 or the composition of claim 105 with a KRAS protein (e.g., KRASG12C).

109. The method of any one of claims 106-108, wherein the contacting occurs in a cell harboring a KRASG12Cmutant protein.

110. The method of any one of claims 106-108, wherein the contacting occurs in a subject (e.g., a human subject).

111. A method, comprising administering the compound of any one of claims 1-104 or the composition of claim 105 to a subject in need thereof.

112. 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 1-104 or the composition of claim 105 to a subject in need thereof.

113. The method of claim 112, wherein the disease, disorder, or condition associated with KRAS is a cancer.

114. A method of treating cancer, comprising administering the compound of any one of claims 1-95 or the composition of claim 105 to a subject in need thereof.

115. The method of claim 113 or 114, wherein the cancer is non-small cell lung cancer or colorectal cancer.

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