Gtpase inhibitors and uses thereof

Abstract

Described herein, inter alia, are GTPase inhibitors and uses thereof.

Description

GTPase INHIBITORS AND USES THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 525,118, filed July 5, 2023, which is incorporated herein by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (048536- 768001WO_Sequence_Listing_ST26.xml; Size: 5,334 bytes; and Date of Creation: June 26, 2024) is hereby incorporated by reference in its entirety. BACKGROUND

[0003] Oncogenic mutations of Ras are one of the most common genetic alterations in human cancer, with an estimated disease burden of >3 million patients per year worldwide. In the KRAS gene, a GGT to GAT nucleotide transition at codon 12 (c.35 G>A) gives rise to KRAS G12D, the most frequent Ras mutation accounting for about 23% of Ras-driven cancers. Selective targeting of KRAS G12D while sparing wild type KRAS is a highly desirable therapeutic goal, as it would enable a large therapeutic window for cancer treatment. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY

[0004] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: (I).

[0005] R1is a Switch II Binding Pocket binding moiety.

[0006] L1is a bond or divalent linker.

[0007] .

[0008] R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, ^NHC(O)NR2CNR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -C(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -PR2AR2B, -P(O)R2AR2B, -OP(O)OR2AOR2B, ^SiR2AR2BR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0009] R2A, R2B, R2C, and R2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0010] X2is independently –F, -Cl, -Br, or –I. The symbol n2 is an integer from 0 to 4. The symbols m2 and v2 are independently 1 or 2.

[0011] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to Ras(G12D) with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0013] In an aspect is provided a method of treating a K-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to K-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0014] In an aspect is provided a method of treating an H-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to H-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0015] In an aspect is provided a method of treating an N-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to N-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0016] In an aspect is provided a method of modulating the level of activity of a K-Ras protein in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to K-Ras with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0017] In an aspect is provided a method of modulating the level of activity of an H-Ras protein in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to H-Ras with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0018] In an aspect is provided a method of modulating the level of activity of an N-Ras protein in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to N-Ras with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0019] In an aspect is provided a K-Ras protein covalently bound to a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is covalent bound to an aspartate residue of the K-Ras protein.

[0020] In an aspect is provided an H-Ras protein covalently bound to a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is covalent bound to an aspartate residue of the H-Ras protein.

[0021] In an aspect is provided an N-Ras protein covalently bound to a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is covalent bound to an aspartate residue of the N-Ras protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIGS.1A-1G. Compound 1 is a covalent inhibitor of KRAS G12D. FIG.1A: Chemical structure of Compound 1. FIG.1B: Intact protein mass spectrometry traces of KRAS G12D in the absence (black) or presence (grey) of Compound 1. FIG.1C: Covalent labeling kinetics of KRAS G12D with Compound 1. FIG.1D: Proposed mechanism of the denitrogenative alkylation of Asp12 by Compound 1. FIG.1E: Covalent labeling selectivity of Compound 1. FIG.1F: Compound 1 labeled endogenous KRAS G12D. FIG.1G: Compound 1 rapidly, covalently engaged endogenous KRAS G12D and inhibited downstream signaling pathways.

[0023] FIGS.2A-2B. Compound 1 inhibited KRAS G12D-driven cell growth. FIG.2A: On-target inhibition of KRAS G12D led to cell growth inhibition of Ba / F3 KRAS G12D by Compound 1. FIG.2B: Compound 1 selectively inhibited growth of KRAS G12D cancer cell lines (dotted curves) but not non-G12D cancer cell lines (crossed curves). DETAILED DESCRIPTION I. Definitions

[0024] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0025] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0026] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is anuncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0027] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0028] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3,-O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0029] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from aheteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0030] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0031] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0032] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenylring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0033] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

[0034] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0035] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0036] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0037] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system,heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0038] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0039] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0040] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: . [0stituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, substituted or unsubstituted C1-C5alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0042] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0043] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN,-NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0044] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present.

[0045] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as afloating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0046] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0047] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U areindependently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0048] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0049] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and(B) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH,-NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10aryl, C10aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0050] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0051] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0052] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0053] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0054] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0055] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted orunsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0056] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0057] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substitutedwith a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0058] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0059] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different.

[0060] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

[0061] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1may be substituted with one or more first substituent groups denoted by R1.1, R2may be substituted with one or more first substituent groups denoted by R2.1, R3may be substituted with one or more first substituent groupsdenoted by R3.1, R4may be substituted with one or more first substituent groups denoted by R4.1, R5may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1Amay be substituted with one or more first substituent groups denoted by R1A.1, R2Amay be substituted with one or more first substituent groups denoted by R2A.1, R3Amay be substituted with one or more first substituent groups denoted by R3A.1, R4Amay be substituted with one or more first substituent groups denoted by R4A.1, R5Amay be substituted with one or more first substituent groups denoted by R5A.1and the like up to or exceeding an R100Amay be substituted with one or more first substituent groups denoted by R100A.1. As a further example, L1may be substituted with oneor more first substituent groups denoted by RL1.1, L2may be substituted with one or more firstsubstituent groups denoted by RL2.1, L3may be substituted with one or more first substituent groups denoted by RL3.1, L4may be substituted with one or more first substituent groups denoted by RL4.1, L5may be substituted with one or more first substituent groups denoted by RL5.1and the like up to or exceeding an L100which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWWor LWWwherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW.1or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1, R5.1… R100.1; R1A.1, R2A.1, R3A.1, R4A.1, R5A.1… R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1… RL100.1) may be 4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2… R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2…e ented herein as RWW.1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW.2.

[0062] Finally, each second substituent group (e.g., R1.2, R2.2, R3.2, R4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2… R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2… RL100.2) may be further100.3; R1A.3, R2A.3, R3A.3, R4A.3, R5A.3… R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3… RL100.3;. , , e represented herein as RWW.2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW.3. Each of the firstsubstituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

[0063] Thus, as used herein, RWWrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, LWWis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted i h one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWWis phenyl, the said phenyl group is optionally substituted by one or more RWW.1groups as defined herein below, e.g., when RWW.1is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2is optionally substituted by one or more RWW.3. By way of example when the RWWgroup is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to:.

[0064] , , , , , -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1is independently –F, -Cl, -Br, or –I.

[0065] RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.2is independently –F, -Cl, -Br, or –I.

[0066] RWW.3is independently oxo, halogen, -CXWW.33, -CHXWW.32, -CH2XWW.3, -OCXWW.33, -OCH2XWW.3, -OCHXWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.3is independently –F, -Cl, -Br, or –I.

[0067] Where two different RWWsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group, RWW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWWsubstituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2and RWW.3refers to the designated number of one of the two different RWWsubstituents. For example, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100A.1, RWW.2is R100A.2, and RWW.3is R100A.3. Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100B.1, RWW.2is R100B.2, and RWW.3is R100B.3. RWW.1, RWW.2and RWW.3in this paragraph are as defined in the preceding paragraphs.

[0068] RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, W.2-substituted oror unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ONH2,NHC(O)NHNH2, NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.1is independently –F, -Cl, -Br, or –I.

[0069] RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.2is independently –F, -Cl, -Br, or –I.

[0070] RLWW.3is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.33, -OCH2XLWW.3, -OCHXLWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.3is independently –F, -Cl, -Br, or –I.

[0071] In the event that any R group recited in a claim or chemical formula description set forth herein (RWWsubstituent) is not specifically defined in this disclosure, then that R group (RWWgroup) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWWis independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3are as defined above.

[0072] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWWsubstituent) is not explicitly defined, then that L group (LWWgroup) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-substitutedor unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2and RLWW.3are as defined above.

[0073] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0074] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0075] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in isomeric forms, all such isomeric forms of the compounds being within the scope of the disclosure.

[0076] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0077] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0078] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0079] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0080] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0081] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0082] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g.,ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0083] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such thatsubsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex.

[0084] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0085] “Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0086] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20alkyl, or unsubstituted2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0087] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[0088] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0089] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of suchcompounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0090] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0091] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0092] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0093] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0094] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0095] “Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0096] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0097] The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0098] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0099] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

[0100] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0101] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule,protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0102] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0103] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0104] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0105] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by atleast 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0106] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0107] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0108] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0109] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0110] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellularcompartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is cancer (e.g., pancreatic ductal adenocarncinoma, colorectal adenocarcinoma, colorectal carcinoma, rectal carcinoma, rectal adenocarcinoma, colon adenocarcinoma, plasma cell myeloma, bile duct carcinoma, chronic myelomonocytic leukemia, acute myeloid leukemia, lung adenocarcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, rhabdomyosarcoma, endometrium carcinoma, thyroid carcinoma, bladder carcinoma, ovarian carcinoma, or myelodysplastic syndrome). In embodiments, the disease is Costello syndrome.

[0111] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0112] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia,acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0113] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0114] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with acompound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0115] The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0116] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0117] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example,metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0118] The terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0119] The term “visceral metastasis” refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0120] As used herein, the term “RASopathy” refers to a disease caused by germline mutations of genes encoding components of the RAS / MAPK signaling pathway. In embodiments, the RASopathy is a mosaic RASopathy. In embodiments, the RASopathy is a germline RASopathy. In embodiments, the RASopathy is a developmental syndrome. In embodiments, the RASopathy is Noonan syndrome. In embodiments, the RASopathy is epidermal nevus. In embodiments, the RASopathy is Schimmelpenning syndrome. In embodiments, the RASopathy is sebaceous nevus. In embodiments, the RASopathy is talipes equinovarus (e.g., congenital talipes equinovarus). In embodiments, the RASopathy is PIK3CA-related overgrowth syndrome (PROS). In embodiments, the RASopathy is PTEN- Hamartoma of the soft tissue (PHOST). In embodiments, the RASopathy is fibroadipose overgrowth, hemihyperplasia-multiple lipomatosis, congenital lipomatous overgrowth, vascular malformations, epidermal nevus, spinal and skeletal syndrome, macrodactyly syndrome, megalocephaly syndrome, or congenital diffuse infiltrative lipomatosis. In embodiments, the RASopathy is Klippel-Trenaunay syndrome (KTS), venous malformation, or lymphatic malformation. In embodiments, the RASopathy is capillary malformation-AV malformation syndrome. In embodiments, the RASopathy is autoimmune lymphoproliferative syndrome. In embodiments, the RASopathy is cardiofaciocutaneoussyndrome. In embodiments, the RASopathy is hereditary gingival fibromatosis type 1. In embodiments, the RASopathy is neurofibromatosis type 1. In embodiments, the RASopathy is Costello syndrome. In embodiments, the RASopathy is Legius syndrome.

[0121] As used herein, the term “Switch II GTPase protein-associated disease” refers to any disease or condition caused by aberrant activity or signaling of a Switch II GTPase protein. In embodiments, the Switch II GTPase protein-associated disease is cancer (e.g., pancreatic ductal adenocarncinoma, colorectal adenocarcinoma, colorectal carcinoma, rectal carcinoma, rectal adenocarcinoma, colon adenocarcinoma, plasma cell myeloma, bile duct carcinoma, chronic myelomonocytic leukemia, acute myeloid leukemia, lung adenocarcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, rhabdomyosarcoma, endometrium carcinoma, thyroid carcinoma, bladder carcinoma, ovarian carcinoma, or myelodysplastic syndrome).

[0122] As used herein, the term “K-Ras(G12D)-associated disease” refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G12D). In embodiments, the K- Ras(G12D)-associated disease is cancer. In embodiments, the K-Ras(G12D)-associated disease is a RASopathy.

[0123] As used herein, the term “H-Ras(G12D)-associated disease” refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G12D). In embodiments, the H- Ras(G12D)-associated disease is cancer. In embodiments, the H-Ras(G12D)-associated disease is a RASopathy.

[0124] As used herein, the term “N-Ras(G12D)-associated disease” refers to any disease or condition caused by aberrant activity or signaling of N-Ras(G12D). In embodiments, the N- Ras(G12D)-associated disease is cancer. In embodiments, the N-Ras(G12D)-associated disease is a RASopathy.

[0125] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug.

[0126] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, orother physical means. For example, detectable agents include18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra,225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu,32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT / US2015 / 022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0127] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra and225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomicnumbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0128] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0129] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0130] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0131] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be co-administered to the patient. Co- administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0132] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0133] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0134] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however,may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer or RASopathy) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0135] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer or RASopathy) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0136] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0137] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0138] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0139] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0140] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0141] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0142] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of acorresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0143] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0144] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0145] An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected protein corresponds to G12 of K-Ras when the selected residue occupies the same essential spatial or other structural relationship as G12 of K-Ras. In some embodiments, where a selected protein is aligned for maximum homology with K-Ras, the position in the aligned selected protein aligning with G12 is said to correspond to G12. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with K-Ras and the overall structures compared. In this case, an amino acid that occupies the same essential position as G12 in the structural model is said to correspond to the G12 residue.

[0146] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein,protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.

[0147] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes.

[0148] The term “Switch II” as used herein refers to a protein domain of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras) formed by residues corresponding to residues 60-76 of K-Ras, H-Ras, or N-Ras (e.g., K-Ras Switch II refers to residues 60-76 of K-Ras, H-Ras Switch II refers to residues 60-76 of H-Ras, N-Ras Switch II refers to residues 60-76 of N- Ras). A “Switch II Binding Pocket” is a cavity bound (the limits or boundaries of which are made), at least in part, by the amino acid residues that form Switch II. In some embodiments, a “Switch II Binding Pocket” is a cavity, in the GDP bound form of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras), bound (the limits or boundaries of which are made), at least in part, by the amino acid residues that form Switch II. A “Switch II Binding Pocket binding moiety” is a moiety of a compound (e.g., as described herein) that binds to the Switch II Binding Pocket.

[0149] The term “Switch II GTPase protein” as used herein refers to a GTPase protein including a Switch II. In embodiments, the Switch II GTPase protein includes a Switch II Binding Pocket. In embodiments, the Switch II GTPase protein is a Ras protein. In embodiments, the Switch II GTPase protein is K-Ras. In embodiments, the Switch II GTPase protein is H-Ras. In embodiments, the Switch II GTPase protein is N-Ras. In embodiments, the Switch II GTPase protein is ARF1 (e.g., UniProt P84077). In embodiments, the Switch IIGTPase protein is ARF3 (e.g., UniProt P61204). In embodiments, the Switch II GTPase protein is ARF4 (e.g., UniProt P18085). In embodiments, the Switch II GTPase protein is ARF5 (e.g., UniProt P84085). In embodiments, the Switch II GTPase protein is ARF6 (e.g., UniProt P62330). In embodiments, the Switch II GTPase protein is TRIM23 (e.g., UniProt P36406). In embodiments, the Switch II GTPase protein is ARL1 (e.g., UniProt P40616). In embodiments, the Switch II GTPase protein is ARL2 (e.g., UniProt P36404). In embodiments, the Switch II GTPase protein is ARL3 (e.g., UniProt P36405). In embodiments, the Switch II GTPase protein is ARL4A (e.g., UniProt P40617). In embodiments, the Switch II GTPase protein is ARL4B. In embodiments, the Switch II GTPase protein is ARL5. In embodiments, the Switch II GTPase protein is ARL6 (e.g., UniProt Q9H0F7). In embodiments, the Switch II GTPase protein is ARL7. In embodiments, the Switch II GTPase protein is ARL8. In embodiments, the Switch II GTPase protein is ARL9 (e.g., UniProt Q6T311). In embodiments, the Switch II GTPase protein is ARL12. In embodiments, the Switch II GTPase protein is ARL11 (e.g., UniProt Q969Q4). In embodiments, the Switch II GTPase protein is ARF7. In embodiments, the Switch II GTPase protein is 339231 (e.g., UniProt Q0P5N6). In embodiments, the Switch II GTPase protein is DKFZp761. In embodiments, the Switch II GTPase protein is ARFRP1 (e.g., UniProt Q13795). In embodiments, the Switch II GTPase protein is ARFRP2 (e.g., UniProt Q9NXU5). In embodiments, the Switch II GTPase protein is ARL10A (e.g., UniProt Q8N8L6). In embodiments, the Switch II GTPase protein is ARL10B (e.g., UniProt Q96BM9). In embodiments, the Switch II GTPase protein is ARL10C. In embodiments, the Switch II GTPase protein is 344988. In embodiments, the Switch II GTPase protein is SARA1 (e.g., UniProt Q6FID4). In embodiments, the Switch II GTPase protein is SARA2.

[0150] The term “Switch II GTPase protein aspartate residue” as used herein refers to an aspartate residue of a Switch II GTPase protein. In embodiments, the Switch II GTPase protein aspartate residue is an aspartate residue corresponding to the 12 position of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the Switch II GTPase protein aspartate residue is an aspartate residue corresponding to the 13 position of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the Switch II GTPase protein aspartate residue is a natural Switch II GTPase protein aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a mutant Switch II GTPase protein aspartate residue. In embodiments, the mutant Switch II GTPase protein aspartate residue is aspartate residue 12 of K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D).

[0151] The term “Ras” refers to one or more of the family of human Ras GTPase proteins (e.g. K-Ras, H-Ras, N-Ras), including homologs, isoforms, and functional fragments thereof.

[0152] The term “K-Ras” refers to the protein that in humans is encoded by the KRAS gene. The K-Ras protein is a GTPase, which converts guanosine triphosphate to guanosine diphosphate. A mutation in the K-Ras protein (e.g., an amino acid substitution) can result in various malignancies (e.g., lung adenocarcinoma, pancreatic cancer, or colorectal cancer). The term “K-Ras” may refer to the nucleotide sequence or protein sequence of human KRAS (e.g., Entrez 3845, UniProt P01116, RefSeq NM_004985.4, RefSeq NM_033360.3, RefSeq NP_004976.2, or RefSeq NP_203524.1). In embodiments, K-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILD TAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVL VGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKI SKEEKTPGCVKIKKCIIM (SEQ ID NO:1).

[0153] The term “H-Ras” refers to the enzyme that in humans is encoded by the HRAS gene. The H-Ras protein is a GTPase, which converts guanosine triphosphate to guanosine diphosphate. Mutations in the H-Ras protein (e.g., an amino acid substitution) can result in various malignancies (e.g., bladder cancer, thyroid cancer, salivary duct carcinoma, epithelial carcinoma, or kidney cancer). The term “H-Ras” may refer to the nucleotide sequence or protein sequence of human HRAS (e.g., Entrez 3265, UniProt P01112, RefSeq NM_001130442.2, RefSeq NM_001318054.1, RefSeq NM_005343.3, RefSeq NM_00176795.4, RefSeq NP_001123914.1, RefSeq NP_001304983.1, RefSeq NP_005334.1, or RefSeq NP_789765.1). In embodiments, H-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILD TAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVL VGNKCDLAARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRK LNPPDESGPGCMSCKCVLS (SEQ ID NO:2).

[0154] The term “N-Ras” refers to the enzyme that in humans is encoded by the NRAS gene. The N-Ras protein is a GTPase, which converts guanosine triphosphate to guanosine diphosphate. The term “N-Ras” may refer to the nucleotide sequence or protein sequence ofhuman NRAS (e.g., Entrez 4893, UniProt P01111, RefSeq NM_002524.4, or RefSeq NP_002515.1). In embodiments, N-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILD TAGQEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVL VGNKCDLPTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKK LNSSDDGTQGCMGLPCVVM (SEQ ID NO:3).

[0155] In embodiments, the Switch II Binding Pocket is bound at least in part by one or more of V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and / or I100 of K-Ras or equivalent residues in homologous, related (e.g., H-Ras or N-Ras), or mutant Ras proteins. A compound as described herein (including embodiments, examples, and figures), which binds to amino acids that form or contacts amino acids that form the Switch II Binding Pocket is a “Switch II Binding Pocket binding compound” and a moiety of a compound that binds to amino acids that form or contacts amino acids that form the Switch II Binding Pocket is a “Switch II Binding Pocket binding moiety”.

[0156] In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts one amino acid that forms the Switch II Binding Pocket. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts multiple amino acids that form the Switch II Binding Pocket. In embodiments, a Switch II Binding Pocket binding compound or Switch II- Binding Pocket binding moiety binds or contacts one amino acid selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N- Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts multiple K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts two K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99,and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts three K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts four K-Ras amino acids selected from amino acids in a mutant K- Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts five K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H- Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts six K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N- Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts seven K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K- Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts eight K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H- Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts nine K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N- Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch IIBinding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts ten K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K- Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts eleven K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H- Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts twelve K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N- Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts thirteen K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K- Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts fourteen K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts fifteen K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12D)), related Ras (e.g., H-Ras, H-Ras(G12D), N-Ras, or N-Ras(G12D)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.

[0157] The term “selective” or “selectivity” or the like in reference to a compound or agent refers to the compound’s or agent’s ability to cause an increase or decrease in activity of a particular molecular target (e.g., protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity toward mutant K-Ras(G12D) would preferentially inhibit K-Ras(G12D) over other K-Ras proteins (e.g., wild type K-Ras)).In embodiments, a “Ras(G12D)-selective compound” refers to a compound (e.g., compound described herein) having selectivity towards Ras(G12D). II. Compounds

[0158] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: (I). ty.X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, ^NHC(O)NR2CNR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -C(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -PR2AR2B, -P(O)R2AR2B, -OP(O)OR2AOR2B, ^SiR2AR2BR2C, substituted or unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0163] R2A, R2B, R2C, and R2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl(e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0164] X2is independently –F, -Cl, -Br, or –I.

[0165] The symbol n2 is an integer from 0 to 4.

[0166] The symbols m2 and v2 are independently 1 or 2.

[0167] In embodiments, the compound is not: O O N N N N , .

[0168] In embodiments, E is capable of forming a covalent bond with a Switch II GTPase protein aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a natural Switch II GTPase protein aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a mutant Switch II GTPase protein aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an aspartate residue corresponding to the 12 position of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the mutant Switch II GTPase protein aspartate residue is aspartate residue 12 of K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D).

[0169] In embodiments, the Switch II GTPase protein aspartate residue is a Ras protein aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a K-Ras aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an H- Ras aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an N-Ras aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARF1 (e.g., UniProt P84077) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARF3 (e.g., UniProt P61204) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARF4 (e.g., UniProt P18085) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARF5 (e.g., UniProt P84085) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARF6 (e.g., UniProt P62330) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a TRIM23 (e.g., UniProt P36406) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL1 (e.g., UniProt P40616) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL2 (e.g., UniProt P36404) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL3 (e.g., UniProt P36405) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL4A (e.g., UniProt P40617) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL4B aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL5 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL6 (e.g., UniProt Q9H0F7) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL7 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL8 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL9 (e.g., UniProt Q6T311) aspartate residue. In embodiments, the Switch II GTPase protein aspartateresidue is an ARL12 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL11 (e.g., UniProt Q969Q4) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARF7 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a 339231 (e.g., UniProt Q0P5N6) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a DKFZp761 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARFRP1 (e.g., UniProt Q13795) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARFRP2 (e.g., UniProt Q9NXU5) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL10A (e.g., UniProt Q8N8L6) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL10B (e.g., UniProt Q96BM9) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is an ARL10C aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a 344988 aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a SARA1 (e.g., UniProt Q6FID4) aspartate residue. In embodiments, the Switch II GTPase protein aspartate residue is a SARA2 aspartate residue.

[0170] In embodiments, E is capable of forming a covalent bond with a K-Ras aspartate residue. In embodiments, E is capable of forming a covalent bond with an H-Ras aspartate residue. In embodiments, E is capable of forming a covalent bond with an N-Ras aspartate residue.

[0171] In embodiments, R1-L1-H is capable of binding to a Switch II GTPase protein aspartate residue with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to K-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to H-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1- L1-H is capable of binding to N-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0172] In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kdof less than 5 nM, wherein R1and L1are asdescribed herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kd of less than 10 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) with a Kdof less than 20 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kdof less than 50 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) with a Kd of less than 100 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kd of less than 200 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) with a Kdof less than 300 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kdof less than 400 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) with a Kdof less than 500 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kdof less than 600 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) with a Kdof less than 700 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kdof less than 800 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) with a Kdof less than 900 nM, wherein R1and L1are as described herein, including in embodiments. In embodiments, R1-L1-H is capable of binding to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0173] In embodiments, E is a tautomeric form or an isomeric form , wherein R2is as described herein, including in embodiments. In embo, wherein R2is as described herein, including in embodiments. Inembodiments, E i , wherein R2is as described herein, including inembodiments. In embodiments , wherein R2is as described herein,including in embodiments. In embodiment , wherein R2is as describedherein, including in embodiments. In embodiment , wherein R2is as described herein, including in embodiments. A pernary skill in the art would understand that the compounds described herein can exist as any of the tautomeric or isomeric forms above.

[0174] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2is substituted, it is substituted with at least one substituent group. In embodiments, when R2is substituted, it is substituted with atleast one size-limited substituent group. In embodiments, when R2is substituted, it is substituted with at least one lower substituent group.

[0175] In embodiments, R2is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0176] In embodiments, R2is hydrogen. In embodiments, R2is halogen. In embodiments, R2is –F. In embodiments, R2is –Cl. In embodiments, R2is –Br. In embodiments, R2is –I. In embodiments, R2is –CCl3. In embodiments, R2is –CBr3. In embodiments, R2is –CF3. In embodiments, R2is –CI3. In embodiments, R2is -CH2Cl. In embodiments, R2is -CH2Br. In embodiments, R2is -CH2F. In embodiments, R2is -CH2I. In embodiments, R2is -CHCl2. In embodiments, R2is -CHBr2. In embodiments, R2is -CHF2. In embodiments, R2is -CHI2. In embodiments, R2is –CN. In embodiments, R2is –OH. In embodiments, R2is -NH2. In embodiments, R2is –COOH. In embodiments, R2is -CONH2. In embodiments, R2is -NO2. In embodiments, R2is –SH. In embodiments, R2is -SO2R2D. In embodiments, R2is -SO2CH3. In embodiments, R2is -SO2H. In embodiments, R2is -OSO2H. In embodiments, R2is -SO2NH2. In embodiments, R2is ^NHNH2. In embodiments, R2is ^ONH2. In embodiments, R2is ^NHC(O)NHNH2. In embodiments, R2is ^NHC(O)NH2. In embodiments, R2is -NHSO2H. In embodiments, R2is -NHC(O)H. In embodiments, R2is -NHC(O)OH. In embodiments, R2is –NHOH. In embodiments, R2is –OCCl3. In embodiments, R2is –OCBr3. In embodiments, R2is –OCF3. In embodiments, R2is –OCI3. In embodiments, R2is -OCH2Cl. In embodiments, R2is -OCH2Br. In embodiments, R2is -OCH2F. In embodiments, R2is -OCH2I. In embodiments, R2is -OCHCl2. In embodiments, R2is -OCHBr2. In embodiments, R2is -OCHF2. In embodiments, R2is -OCHI2. In embodiments, R2is -P(O)R2AR2B. In embodiments, R2is -P(O)(CH3)2. In embodiments, R2is ^SiR2AR2BR2C. In embodiments, R2is -Si(CH3)3. In embodiments, R2is unsubstituted C1-C4alkyl. In embodiments, R2is unsubstituted methyl. In embodiments, R2is unsubstituted ethyl. In embodiments, R2is unsubstituted propyl. In embodiments, R2isunsubstituted n-propyl. In embodiments, R2is unsubstituted isopropyl. In embodiments, R2is unsubstituted butyl. In embodiments, R2is unsubstituted n-butyl. In embodiments, R2is unsubstituted isobutyl. In embodiments, R2is unsubstituted tert-butyl. In embodiments, R2is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R2is substituted or unsubstituted phenyl.

[0177] In embodiments .

[0178] R20is independe-CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0179] The symbol z20 is an integer from 0 to 5.

[0180] In embodiments, a substituted R20(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R20is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R20is substituted, it is substituted with at least one substituent group. In embodiments, when R20is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20is substituted, it is substituted with at least one lower substituent group.

[0181] In embodiments, R20is independently halogen. In embodiments, R20is independently –F. In embodiments, R20is independently –Cl. In embodiments, R20is independently –Br. In embodiments, R20is independently –I. In embodiments, R20is independently –CCl3. In embodiments, R20is independently –CBr3. In embodiments, R20is independently –CF3. In embodiments, R20is independently –CI3. In embodiments, R20is independently -CH2Cl. In embodiments, R20is independently -CH2Br. In embodiments, R20is independently -CH2F. In embodiments, R20is independently -CH2I. In embodiments, R20is independently -CHCl2. In embodiments, R20is independently -CHBr2. In embodiments, R20is independently -CHF2. In embodiments, R20is independently -CHI2. In embodiments, R20is independently –CN. In embodiments, R20is independently –OH. In embodiments, R20is independently -NH2. In embodiments, R20is independently –COOH. In embodiments, R20is independently -CONH2. In embodiments, R20is independently -NO2. In embodiments, R20is independently –SH. In embodiments, R20is independently –SO3H. In embodiments, R20is independently –OSO3H. In embodiments, R20is independently -SO2NH2. In embodiments, R20is independently ^NHNH2. In embodiments, R20is independently ^ONH2. In embodiments, R20is independently ^NHC(O)NHNH2. In embodiments, R20is independently ^NHC(O)NH2. In embodiments, R20is independently -NHSO2H. In embodiments, R20is independently -NHC(O)H. In embodiments, R20is independently -NHC(O)OH. In embodiments, R20is independently –NHOH. In embodiments, R20is independently –OCCl3. In embodiments, R20is independently –OCBr3. In embodiments, R20is independently –OCF3. In embodiments, R20is independently –OCI3. In embodiments, R20is independently -OCH2Cl. In embodiments, R20is independently -OCH2Br. In embodiments, R20is independently -OCH2F. In embodiments, R20is independently -OCH2I. In embodiments, R20is independently -OCHCl2. In embodiments, R20is independently -OCHBr2. In embodiments, R20is independently -OCHF2. In embodiments, R20is independently -OCHI2. In embodiments, R20is independently –SF5. In embodiments, R20is independently unsubstituted C1-C4 alkyl. In embodiments, R20is independently unsubstituted methyl. In embodiments, R20is independently unsubstituted ethyl. In embodiments, R20is independently unsubstituted propyl. In embodiments, R20is independently unsubstituted n-propyl. In embodiments, R20is independently unsubstituted isopropyl. In embodiments, R20is independently unsubstituted butyl. In embodiments, R20is independently unsubstituted n-butyl. In embodiments, R20is independently unsubstituted isobutyl. In embodiments, R20isindependently unsubstituted tert-butyl. In embodiments, R20is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R20is independently unsubstituted methoxy. In embodiments, R20is independently unsubstituted ethoxy. In embodiments, R20is independently unsubstituted propoxy. In embodiments, R20is independently unsubstituted n- propoxy. In embodiments, R20is independently unsubstituted isopropoxy. In embodiments, R20is independently unsubstituted butoxy. In embodiments, R20is independently unsubstituted n-butoxy. In embodiments, R20is independently unsubstituted isobutoxy. In embodiments, R20is independently unsubstituted tert-butoxy.

[0182] In embodiments, z20 is 0. In embodiments, z20 is 1. In embodiments, z20 is 2. In embodiments, z20 is 3. In embodiments, z20 is 4. In embodiments, z20 is 5.

[0183] In embodiments, R2is hydrogen, -CX23, -SO2R2D, -P(O)R2AR2B, ^SiR2AR2BR2C, unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted phenyl. In embodiments, R2is hydrogen, -CH3, -CH2CH3, -CH2CH(CH3)2, -CF3, -Si(CH3)3, -P(O)(CH3)2, -S(O)2CH3, unsubstituted phenyl, , 2.In embodiments .

[0184] In embtuted R2A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Ais substituted, it is substituted with at least one substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one lower substituent group.

[0185] In embodiments, a substituted R2B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Bis substituted, it is substituted with at least one substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one lower substituent group.

[0186] In embodiments, a substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; eachsubstituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0187] In embodiments, a substituted R2C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Cis substituted, it is substituted with at least one substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one lower substituent group.

[0188] In embodiments, a substituted R2D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Dis substituted, it is substituted with at least one substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one lower substituent group.

[0189] In embodiments, R2Ais hydrogen. In embodiments, R2Ais unsubstituted C1-C4 alkyl. In embodiments, R2Ais unsubstituted methyl. In embodiments, R2Ais unsubstituted ethyl. In embodiments, R2Ais unsubstituted propyl. In embodiments, R2Ais unsubstituted n- propyl. In embodiments, R2Ais unsubstituted isopropyl. In embodiments, R2Aisunsubstituted butyl. In embodiments, R2Ais unsubstituted n-butyl. In embodiments, R2Ais unsubstituted isobutyl. In embodiments, R2Ais unsubstituted tert-butyl.

[0190] In embodiments, R2Bis hydrogen. In embodiments, R2Bis unsubstituted C1-C4 alkyl. In embodiments, R2Bis unsubstituted methyl. In embodiments, R2Bis unsubstituted ethyl. In embodiments, R2Bis unsubstituted propyl. In embodiments, R2Bis unsubstituted n- propyl. In embodiments, R2Bis unsubstituted isopropyl. In embodiments, R2Bis unsubstituted butyl. In embodiments, R2Bis unsubstituted n-butyl. In embodiments, R2Bis unsubstituted isobutyl. In embodiments, R2Bis unsubstituted tert-butyl.

[0191] In embodiments, R2Cis hydrogen. In embodiments, R2Cis unsubstituted C1-C4alkyl. In embodiments, R2Cis unsubstituted methyl. In embodiments, R2Cis unsubstituted ethyl. In embodiments, R2Cis unsubstituted propyl. In embodiments, R2Cis unsubstituted n- propyl. In embodiments, R2Cis unsubstituted isopropyl. In embodiments, R2Cis unsubstituted butyl. In embodiments, R2Cis unsubstituted n-butyl. In embodiments, R2Cis unsubstituted isobutyl. In embodiments, R2Cis unsubstituted tert-butyl.

[0192] In embodiments, R2Dis hydrogen. In embodiments, R2Dis unsubstituted C1-C4 alkyl. In embodiments, R2Dis unsubstituted methyl. In embodiments, R2Dis unsubstituted ethyl. In embodiments, R2Dis unsubstituted propyl. In embodiments, R2Dis unsubstituted n- propyl. In embodiments, R2Dis unsubstituted isopropyl. In embodiments, R2Dis unsubstituted butyl. In embodiments, R2Dis unsubstituted n-butyl. In embodiments, R2Dis unsubstituted isobutyl. In embodiments, R2Dis unsubstituted tert-butyl.

[0193] In embodiments, L1is –L101-L102-L103-.

[0194] L101is connected directly to E.

[0195] L101is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR101-, -C(O)NR101-, -NR101C(O)-, -NR101C(O)O-, -OC(O)NR101-, -NR101C(O)NR101-, -NR101C(NH)NR101-, -S(O)2-, -NR101S(O)2-, -S(O)2NR101-, substituted or unsubstituted alkylene (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 orphenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0196] L102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR102-, -C(O)NR102-, -NR102C(O)-, -NR102C(O)O-, -OC(O)NR102-, -NR102C(O)NR102-, -NR102C(NH)NR102-, -S(O)2-, -NR102S(O)2-, -S(O)2NR102-, substituted or unsubstituted alkylene (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0197] L103is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR103-, -C(O)NR103-, -NR103C(O)-, -NR103C(O)O-, -OC(O)NR103-, -NR103C(O)NR103-, -NR103C(NH)NR103-, -S(O)2-, -NR103S(O)2-, -S(O)2NR103-, substituted or unsubstituted alkylene (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0198] Each R101, R102, and R103is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0199] In embodiments, a substituted L101(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heterarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L101is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when L101is substituted, it is substituted with at least one substituent group. In embodiments, when L101is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L101is substituted, it is substituted with at least one lower substituent group.

[0200] In embodiments, L101is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O)2-, -NHS(O)2-, -S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0201] In embodiments, L101is a bond. In embodiments, L101is -C(O)-. In embodiments, L101is -C(O)O-. In embodiments, L101is -OC(O)-. In embodiments, L101is -O-. In embodiments, L101is -S-. In embodiments, L101is -NR101-. In embodiments, L101is -NH-. In embodiments, L101is -C(O)NR101-. In embodiments, L101is -C(O)NH-. In embodiments, L101is -NR101C(O)-. In embodiments, L101is –NHC(O)-. In embodiments, L101is -NR101C(O)O-. In embodiments, L101is -NHC(O)O-. In embodiments, L101is -OC(O)NR101-. In embodiments, L101is -OC(O)NH-. In embodiments, L101is -NR101C(O)NR101-. In embodiments, L101is -NHC(O)NH-. In embodiments, L101is -NR101C(NH)NR101-. In embodiments, L101is -NHC(NH)NH-. In embodiments, L101is -S(O)2-. In embodiments, L101is -NR101S(O)2-. In embodiments, L101is -NHS(O)2-. In embodiments, L101is -S(O)2NR101-. In embodiments, L101is -S(O)2NH-. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted C1-C6alkylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L101is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0202] In embodiments, a substituted R101(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R101is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R101is substituted, it is substituted with at least one substituent group. In embodiments, when R101is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R101is substituted, it is substituted with at least one lower substituent group.

[0203] In embodiments, R101is independently hydrogen or unsubstituted C1-C4alkyl. In embodiments, R101is independently hydrogen. In embodiments, R101is independently unsubstituted C1-C4alkyl. In embodiments, R101is independently unsubstituted methyl. In embodiments, R101is independently unsubstituted ethyl. In embodiments, R101is independently unsubstituted propyl. In embodiments, R101is independently unsubstituted n- propyl. In embodiments, R101is independently unsubstituted isopropyl. In embodiments, R101is independently unsubstituted butyl. In embodiments, R101is independentlyunsubstituted n-butyl. In embodiments, R101is independently unsubstituted isobutyl. In embodiments, R101is independently unsubstituted tert-butyl.

[0204] In embodiments, a substituted L102(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heterarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L102is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when L102is substituted, it is substituted with at least one substituent group. In embodiments, when L102is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L102is substituted, it is substituted with at least one lower substituent group.

[0205] In embodiments, L102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O)2-, -NHS(O)2-, -S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0206] In embodiments, L102is a bond. In embodiments, L102is -C(O)-. In embodiments, L102is -C(O)O-. In embodiments, L102is -OC(O)-. In embodiments, L102is -O-. In embodiments, L102is -S-. In embodiments, L102is -NR102-. In embodiments, L102is -NH-. In embodiments, L102is -C(O)NR102-. In embodiments, L102is -C(O)NH-. In embodiments, L102is -NR102C(O)-. In embodiments, L102is –NHC(O)-. In embodiments, L102is -NR102C(O)O-. In embodiments, L102is -NHC(O)O-. In embodiments, L102is -OC(O)NR102-. In embodiments, L102is -OC(O)NH-. In embodiments, L102is -NR102C(O)NR102-. In embodiments, L102is -NHC(O)NH-. In embodiments, L102is -NR102C(NH)NR102-. In embodiments, L102is -NHC(NH)NH-. In embodiments, L102is -S(O)2-. In embodiments, L102is -NR102S(O)2-. In embodiments, L102is -NHS(O)2-. In embodiments, L102is -S(O)2NR102-. In embodiments, L102is -S(O)2NH-. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted C1-C6alkylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L102is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0207] In embodiments, a substituted R102(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R102is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R102is substituted, it is substituted with at least one substituent group. In embodiments, when R102is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R102is substituted, it is substituted with at least one lower substituent group.

[0208] In embodiments, R102is independently hydrogen or unsubstituted C1-C4alkyl. In embodiments, R102is independently hydrogen. In embodiments, R102is independently unsubstituted C1-C4alkyl. In embodiments, R102is independently unsubstituted methyl. In embodiments, R102is independently unsubstituted ethyl. In embodiments, R102is independently unsubstituted propyl. In embodiments, R102is independently unsubstituted n- propyl. In embodiments, R102is independently unsubstituted isopropyl. In embodiments, R102is independently unsubstituted butyl. In embodiments, R102is independentlyunsubstituted n-butyl. In embodiments, R102is independently unsubstituted isobutyl. In embodiments, R102is independently unsubstituted tert-butyl.

[0209] In embodiments, a substituted L103(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heterarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L103is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when L103is substituted, it is substituted with at least one substituent group. In embodiments, when L103is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L103is substituted, it is substituted with at least one lower substituent group.

[0210] In embodiments, L103is a bond. In embodiments, L103is -C(O)-. In embodiments, L103is -C(O)O-. In embodiments, L103is -OC(O)-. In embodiments, L103is -O-. In embodiments, L103is -S-. In embodiments, L103is -NR103-. In embodiments, L103is -NH-. In embodiments, L103is -C(O)NR103-. In embodiments, L103is -C(O)NH-. In embodiments, L103is -NR103C(O)-. In embodiments, L103is –NHC(O)-. In embodiments, L103is -NR103C(O)O-. In embodiments, L103is -NHC(O)O-. In embodiments, L103is -OC(O)NR103-. In embodiments, L103is -OC(O)NH-. In embodiments, L103is -NR103C(O)NR103-. In embodiments, L103is -NHC(O)NH-. In embodiments, L103is -NR103C(NH)NR103-. In embodiments, L103is -NHC(NH)NH-. In embodiments, L103is -S(O)2-. In embodiments, L103is -NR103S(O)2-. In embodiments, L103is -NHS(O)2-. In embodiments, L103is -S(O)2NR103-. In embodiments, L103is -S(O)2NH-. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted C1-C6alkylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L103issubstituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L103is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0211] In embodiments, a substituted R103(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R103is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R103is substituted, it is substituted with at least one substituent group. In embodiments, when R103is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R103is substituted, it is substituted with at least one lower substituent group.

[0212] In embodiments, R103is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R103is independently hydrogen. In embodiments, R103is independently unsubstituted C1-C4 alkyl. In embodiments, R103is independently unsubstituted methyl. In embodiments, R103is independently unsubstituted ethyl. In embodiments, R103is independently unsubstituted propyl. In embodiments, R103is independently unsubstituted n- propyl. In embodiments, R103is independently unsubstituted isopropyl. In embodiments, R103is independently unsubstituted butyl. In embodiments, R103is independently unsubstituted n-butyl. In embodiments, R103is independently unsubstituted isobutyl. In embodiments, R103is independently unsubstituted tert-butyl.

[0213] In embodiments, L1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O)2-, -NHS(O)2-, -S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10orphenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0214] In embodiments, a substituted L1(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heterarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when L1is substituted, it is substituted with at least one substituent group. In embodiments, when L1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L1is substituted, it is substituted with at least one lower substituent group.

[0215] In embodiments, L1is a bond. In embodiments, L1is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L1is a substituted or unsubstituted pyrrolidinylene. In embodiments, L1is a substituted or unsubstituted piperidinylene. In embodiments, L1is a substituted or unsubstituted piperazinylene. In embodiments, L1is a spirocyclic substituted or unsubstituted 3 to 8 membered heterocycloalkylene.

[0216] In embodiments, L1is . Inembodiments, Lembodiments . 3

[0217] R is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl(e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0218] The symbol z3 is an integer from 0 to 9.

[0219] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0220] In embodiments, a substituted ring formed when two R3substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R3substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R3substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when thesubstituted ring formed when two R3substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R3substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0221] In embodiments, R3is independently oxo. In embodiments, R3is independently halogen. In embodiments, R3is independently –F. In embodiments, R3is independently –Cl. In embodiments, R3is independently –Br. In embodiments, R3is independently –I. In embodiments, R3is independently -CCl3. In embodiments, R3is independently -CBr3. In embodiments, R3is independently -CF3. In embodiments, R3is independently -CI3. In embodiments, R3is independently -CH2Cl. In embodiments, R3is independently -CH2Br. In embodiments, R3is independently -CH2F. In embodiments, R3is independently -CH2I. In embodiments, R3is independently -CHCl2. In embodiments, R3is independently -CHBr2. In embodiments, R3is independently -CHF2. In embodiments, R3is independently -CHI2. In embodiments, R3is independently –CN. In embodiments, R3is independently –OH. In embodiments, R3is independently -NH2. In embodiments, R3is independently –COOH. In embodiments, R3is independently -CONH2. In embodiments, R3is independently -NO2. In embodiments, R3is independently –SH. In embodiments, R3is independently -SO3H. In embodiments, R3is independently -OSO3H. In embodiments, R3is independently -SO2NH2. In embodiments, R3is independently ^NHNH2. In embodiments, R3is independently ^ONH2. In embodiments, R3is independently ^NHC(O)NHNH2. In embodiments, R3is independently ^NHC(O)NH2. In embodiments, R3is independently -NHSO2H. In embodiments, R3is independently -NHC(O)H. In embodiments, R3is independently -NHC(O)OH. In embodiments, R3is independently –NHOH. In embodiments, R3is independently -OCCl3. In embodiments, R3is independently -OCBr3. In embodiments, R3is independently -OCF3. In embodiments, R3is independently -OCI3. In embodiments, R3is independently -OCH2Cl. In embodiments, R3is independently -OCH2Br. In embodiments, R3is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCl2. In embodiments, R3is independently -OCHBr2. In embodiments, R3is independently -OCHF2. In embodiments, R3is independently -OCHI2. In embodiments, R3is independently unsubstituted C1-C4 alkyl. In embodiments, R3is independently unsubstituted methyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently unsubstituted propyl. In embodiments, R3is independently unsubstituted n-propyl. In embodiments, R3isindependently unsubstituted isopropyl. In embodiments, R3is independently unsubstituted butyl. In embodiments, R3is independently unsubstituted n-butyl. In embodiments, R3is independently unsubstituted isobutyl. In embodiments, R3is independently unsubstituted tert-butyl. In embodiments, R3is independently substituted C1-C4 alkyl. In embodiments, R3is independently substituted methyl. In embodiments, R3is independently substituted ethyl. In embodiments, R3is independently substituted propyl. In embodiments, R3is independently substituted n-propyl. In embodiments, R3is independently substituted isopropyl. In embodiments, R3is independently substituted butyl. In embodiments, R3is independently substituted n-butyl. In embodiments, R3is independently substituted isobutyl. In embodiments, R3is independently substituted tert-butyl. In embodiments, R3is independently . In embodiments, R3is independently unsubstituted 2 to 4 membered heIn embodiments, R3is independently unsubstituted methoxy. In embodiments, R3is independently unsubstituted ethoxy. In embodiments, R3is independently unsubstituted propoxy. In embodiments, R3is independently unsubstituted n- propoxy. In embodiments, R3is independently unsubstituted isopropoxy. In embodiments, R3is independently unsubstituted butoxy. In embodiments, R3is independently unsubstituted n-butoxy. In embodiments, R3is independently unsubstituted isobutoxy. In embodiments, R3is independently unsubstituted tert-butoxy.

[0222] In embodiments, two R3substituents are joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted C3-C8cycloalkyl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted pyrrolidinyl.

[0223] In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments, z3 is 8. In embodiments, z3 is 9.

[0224] In embodiments, L1i . In embodiments, L1. Inembodiments, L1i . In embodiments, L1. Innts,, embodiments, the compound contacts a residue of H-Ras Switch II. In embodiments, the compound contacts a residue of N-Ras Switch II. In embodiments, wherein the compound contacts K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)), R1contacts V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, or I100. In embodiments, R1contacts at least one of G60, E62, or E63 of K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)). In embodiments, the compound does not contact the residues of K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)) that contact GTP. In embodiments, the compound does not contact the residues of K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)) that contact the guanine of GTP or GDP. In embodiments, the compound does not contact the residues of K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)) that contact GDP. In embodiments, R1contacts residues that contact Switch II in the GTP bound form of K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)). In embodiments, R1contacts residues that contact Switch II in the GDP bound form of K-Ras (e.g., K-Ras(G12D) or human K-Ras(G12D)).

[0226] In embodiments, R1is –L10-R10.

[0227] L10is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR100-, -C(O)NR100-, -NR100C(O)-, -NR100C(O)O-, -OC(O)NR100-, -NR100C(O)NR100-, -NR100C(NH)NR100-, -S(O)2-, -NR100S(O)2-, -S(O)2NR100-, substituted or unsubstituted alkylene (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 orphenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0228] R100is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0229] R10is hydrogen, halogen, -CX103, -CHX102, -CH2X10, -OCX103, -OCH2X10, -OCHX102, -CN, -SOn10R10D, -SOv10NR10AR10B, ^NR10CNR10AR10B, ^ONR10AR10B, ^NHC(O)NR10CNR10AR10B, -NHC(O)NR10AR10B, -N(O)m10, -NR10AR10B, -C(O)R10C, -C(O)OR10C, -C(O)NR10AR10B, -OR10D, -SR10D, -NR10ASO2R10D, -NR10AC(O)R10C, -NR10AC(O)OR10C, -NR10AOR10C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0230] R10A, R10B, R10C, and R10Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl(e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0231] X10is independently –F, -Cl, -Br, or –I.

[0232] The symbol n10 is an integer from 0 to 4.

[0233] The symbols m10 and v10 are independently 1 or 2.

[0234] In embodiments, a substituted L10(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heterarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L10is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when L10is substituted, it is substituted with at least one substituent group. In embodiments, when L10is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L10is substituted, it is substituted with at least one lower substituent group.

[0235] In embodiments, L10is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O)2-, -NHS(O)2-, -S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10orphenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0236] In embodiments, L10is a bond. In embodiments, L10is -C(O)-. In embodiments, L10is -C(O)O-. In embodiments, L10is -OC(O)-. In embodiments, L10is -O-. In embodiments, L10is -S-. In embodiments, L10is -NR100-. In embodiments, L10is -NH-. In embodiments, L10is -C(O)NR100-. In embodiments, L10is -C(O)NH-. In embodiments, L10is -NR100C(O)-. In embodiments, L10is –NHC(O)-. In embodiments, L10is -NR100C(O)O-. In embodiments, L10is -NHC(O)O-. In embodiments, L10is -OC(O)NR100-. In embodiments, L10is -OC(O)NH-. In embodiments, L10is -NR100C(O)NR100-. In embodiments, L10is -NHC(O)NH-. In embodiments, L10is -NR100C(NH)NR100-. In embodiments, L10is -NHC(NH)NH-. In embodiments, L10is -S(O)2-. In embodiments, L10is -NR100S(O)2-. In embodiments, L10is -NHS(O)2-. In embodiments, L10is -S(O)2NR100-. In embodiments, L10is -S(O)2NH-. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted C1-C6alkylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L10is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0237] In embodiments, a substituted R100(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R100is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lowersubstituent group may optionally be different. In embodiments, when R100is substituted, it is substituted with at least one substituent group. In embodiments, when R100is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R100is substituted, it is substituted with at least one lower substituent group.

[0238] In embodiments, R100is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R100is independently hydrogen. In embodiments, R100is independently unsubstituted C1-C4 alkyl. In embodiments, R100is independently unsubstituted methyl. In embodiments, R100is independently unsubstituted ethyl. In embodiments, R100is independently unsubstituted propyl. In embodiments, R100is independently unsubstituted n- propyl. In embodiments, R100is independently unsubstituted isopropyl. In embodiments, R100is independently unsubstituted butyl. In embodiments, R100is independently unsubstituted n-butyl. In embodiments, R100is independently unsubstituted isobutyl. In embodiments, R100is independently unsubstituted tert-butyl.

[0239] In embodiments, a substituted R10(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10is substituted, it is substituted with at least one substituent group. In embodiments, when R10is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10is substituted, it is substituted with at least one lower substituent group.

[0240] In embodiments, R10is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R10is substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R10is substituted C3-C8 cycloalkyl. In embodiments, R10is substituted 3 to 8 membered heterocycloalkyl. In embodiments, R10is substituted C6-C10aryl. In embodiments, R10is substituted phenyl. In embodiments, R10is substituted 5 to 10 membered heteroaryl. In embodiments, R10is substituted pyrimidyl. In embodiments, R10issubstituted tetrahydropyridopyrimidyl. In embodiments, R10is substituted pyridopyrimidyl. In embodiments, R10is substituted quinazolinyl. In embodiments, R10is substituted pyrazolyl. In embodiments, R10is substituted piperazinyl.

[0241] In embodiments, a substituted R10A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one lower substituent group.

[0242] In embodiments, a substituted R10B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Bis substituted, it is substituted with at least one substituent group. In embodiments, when R10Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Bis substituted, it is substituted with at least one lower substituent group.

[0243] In embodiments, a substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined issubstituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0244] In embodiments, a substituted R10C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Cis substituted, it is substituted with at least one substituent group. In embodiments, when R10Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Cis substituted, it is substituted with at least one lower substituent group.

[0245] In embodiments, a substituted R10D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Dis substituted, it is substituted with at least one substituent group. In embodiments, when R10Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Dis substituted, it is substituted with at least one lower substituent group.

[0246] In embodiments, R10Ais hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R10Ais hydrogen. In embodiments, R10Ais unsubstituted C1-C4alkyl. In embodiments, R10Ais unsubstituted methyl. In embodiments, R10Ais unsubstituted ethyl. In embodiments, R10Ais unsubstituted propyl. In embodiments, R10Ais unsubstituted n-propyl. In embodiments, R10Ais unsubstituted isopropyl. In embodiments, R10Ais unsubstituted butyl. Inembodiments, R10Ais unsubstituted n-butyl. In embodiments, R10Ais unsubstituted isobutyl. In embodiments, R10Ais unsubstituted tert-butyl.

[0247] In embodiments, R10Bis hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R10Bis hydrogen. In embodiments, R10Bis unsubstituted C1-C4alkyl. In embodiments, R10Bis unsubstituted methyl. In embodiments, R10Bis unsubstituted ethyl. In embodiments, R10Bis unsubstituted propyl. In embodiments, R10Bis unsubstituted n-propyl. In embodiments, R10Bis unsubstituted isopropyl. In embodiments, R10Bis unsubstituted butyl. In embodiments, R10Bis unsubstituted n-butyl. In embodiments, R10Bis unsubstituted isobutyl. In embodiments, R10Bis unsubstituted tert-butyl.

[0248] In embodiments, R10Cis hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R10Cis hydrogen. In embodiments, R10Cis unsubstituted C1-C4alkyl. In embodiments, R10Cis unsubstituted methyl. In embodiments, R10Cis unsubstituted ethyl. In embodiments, R10Cis unsubstituted propyl. In embodiments, R10Cis unsubstituted n-propyl. In embodiments, R10Cis unsubstituted isopropyl. In embodiments, R10Cis unsubstituted butyl. In embodiments, R10Cis unsubstituted n-butyl. In embodiments, R10Cis unsubstituted isobutyl. In embodiments, R10Cis unsubstituted tert-butyl.

[0249] In embodiments, R10Dis hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R10Dis hydrogen. In embodiments, R10Dis unsubstituted C1-C4alkyl. In embodiments, R10Dis unsubstituted methyl. In embodiments, R10Dis unsubstituted ethyl. In embodiments, R10Dis unsubstituted propyl. In embodiments, R10Dis unsubstituted n-propyl. In embodiments, R10Dis unsubstituted isopropyl. In embodiments, R10Dis unsubstituted butyl. In embodiments, R10Dis unsubstituted n-butyl. In embodiments, R10Dis unsubstituted isobutyl. In embodiments, R10Dis unsubstituted tert-butyl.

[0250] In embodiments, R1is,N ,N ..

[0251] R is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl(e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0252] R5is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0253] R6is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0254] The symbol z4 is an integer from 0 to 11.

[0255] The symbol z5 is an integer from 0 to 9.

[0256] The symbol z6 is an integer from 0 to 9.

[0257] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4is substituted, it is substituted with at least one substituent group. In embodiments, when R4is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4is substituted, it is substituted with at least one lower substituent group.

[0258] In embodiments, R4is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0259] In embodiments, R4is independently oxo. In embodiments, R4is independently halogen. In embodiments, R4is independently –F. In embodiments, R4is independently –Cl. In embodiments, R4is independently –Br. In embodiments, R4is independently –I. In embodiments, R4is independently -CCl3. In embodiments, R4is independently -CBr3. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2Cl. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHCl2. In embodiments, R4is independently -CHBr2. Inembodiments, R4is independently -CHF2. In embodiments, R4is independently -CHI2. In embodiments, R4is independently –CN. In embodiments, R4is independently –OH. In embodiments, R4is independently -NH2. In embodiments, R4is independently –COOH. In embodiments, R4is independently -CONH2. In embodiments, R4is independently -NO2. In embodiments, R4is independently –SH. In embodiments, R4is independently -SO3H. In embodiments, R4is independently -OSO3H. In embodiments, R4is independently -SO2NH2. In embodiments, R4is independently ^NHNH2. In embodiments, R4is independently ^ONH2. In embodiments, R4is independently ^NHC(O)NHNH2. In embodiments, R4is independently ^NHC(O)NH2. In embodiments, R4is independently -NHSO2H. In embodiments, R4is independently -NHC(O)H. In embodiments, R4is independently -NHC(O)OH. In embodiments, R4is independently –NHOH. In embodiments, R4is independently -OCCl3. In embodiments, R4is independently -OCBr3. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2Cl. In embodiments, R4is independently -OCH2Br. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCl2. In embodiments, R4is independently -OCHBr2. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently unsubstituted C1-C4alkyl. In embodiments, R4is independently unsubstituted methyl. In embodiments, R4is independently unsubstituted ethyl. In embodiments, R4is independently unsubstituted propyl. In embodiments, R4is independently unsubstituted n-propyl. In embodiments, R4is independently unsubstituted isopropyl. In embodiments, R4is independently unsubstituted butyl. In embodiments, R4is independently unsubstituted n-butyl. In embodiments, R4is independently unsubstituted isobutyl. In embodiments, R4is independently unsubstituted tert-butyl. In embodiments, R4is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R4is independently unsubstituted methoxy. In embodiments, R4is independently unsubstituted ethoxy. In embodiments, R4is independently unsubstituted propoxy. In embodiments, R4is independently unsubstituted n-propoxy. In embodiments, R4is independently unsubstituted isopropoxy. In embodiments, R4is independently unsubstituted butoxy. In embodiments, R4is independently unsubstituted n-butoxy. In embodiments, R4is independently unsubstituted isobutoxy. In embodiments, R4is independently unsubstituted tert-butoxy. In embodiments, R4is independently substituted orunsubstituted phenyl. In embodiments, R4is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R4is independently a substituted pyridyl. In embodiments, R4is independently –O-alkyl-(substituted or unsubstituted heteterocycloalkyl). In embodiments, R4is independently –O-CH2-(substituted or unsubstituted heteterocycloalkyl). In embodiments, R4is independentl . In embodiments,. In embodiments, R4is independent .ntly s,R4

[0260] In embodiments, R is independently a halogen, -CF3, -OH, unsubstituted C1-C4alkyl, substituted 2 to 6 membered heteroalkyl, or substituted 5 to 6 membered heteroaryl. In embodiments, R4is independently a halogen, -OH, unsubstituted C1-C4alkyl, substituted 2 to 6 membered heteroalkyl, or substituted 5 to 6 membered heteroaryl. In embodiments, R4is independently –F, -Cl, -CF3, -OH, or unsubstituted methyl. In embodiments, R4is independently –F, -Cl, -OH, or unsubstituted methyl. In embodiments, R4is independently a2 to 6 membered heteroalkyl, substituted with substituted heterocycloalkyl or unsubstituted fused heterocycloalkyl.

[0261] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5. In embodiments, z4 is 6. In embodiments, z4 is 7. In embodiments, z4 is 8. In embodiments, z4 is 9. In embodiments, z4 is 10. In embodiments, z4 is 11.

[0262] In embodiments, a substituted R5(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5is substituted, it is substituted with at least one substituent group. In embodiments, when R5is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5is substituted, it is substituted with at least one lower substituent group.

[0263] In embodiments, R5is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0264] In embodiments, R5is independently oxo. In embodiments, R5is independently halogen. In embodiments, R5is independently –F. In embodiments, R5is independently –Cl. In embodiments, R5is independently –Br. In embodiments, R5is independently –I. In embodiments, R5is independently -CCl3. In embodiments, R5is independently -CBr3. Inembodiments, R5is independently -CF3. In embodiments, R5is independently -CI3. In embodiments, R5is independently -CH2Cl. In embodiments, R5is independently -CH2Br. In embodiments, R5is independently -CH2F. In embodiments, R5is independently -CH2I. In embodiments, R5is independently -CHCl2. In embodiments, R5is independently -CHBr2. In embodiments, R5is independently -CHF2. In embodiments, R5is independently -CHI2. In embodiments, R5is independently –CN. In embodiments, R5is independently –OH. In embodiments, R5is independently -NH2. In embodiments, R5is independently –COOH. In embodiments, R5is independently -CONH2. In embodiments, R5is independently -NO2. In embodiments, R5is independently –SH. In embodiments, R5is independently -SO3H. In embodiments, R5is independently -OSO3H. In embodiments, R5is independently -SO2NH2. In embodiments, R5is independently ^NHNH2. In embodiments, R5is independently ^ONH2. In embodiments, R5is independently ^NHC(O)NHNH2. In embodiments, R5is independently ^NHC(O)NH2. In embodiments, R5is independently -NHSO2H. In embodiments, R5is independently -NHC(O)H. In embodiments, R5is independently -NHC(O)OH. In embodiments, R5is independently –NHOH. In embodiments, R5is independently -OCCl3. In embodiments, R5is independently -OCBr3. In embodiments, R5is independently -OCF3. In embodiments, R5is independently -OCI3. In embodiments, R5is independently -OCH2Cl. In embodiments, R5is independently -OCH2Br. In embodiments, R5is independently -OCH2F. In embodiments, R5is independently -OCH2I. In embodiments, R5is independently -OCHCl2. In embodiments, R5is independently -OCHBr2. In embodiments, R5is independently -OCHF2. In embodiments, R5is independently -OCHI2. In embodiments, R5is independently unsubstituted C1-C4alkyl. In embodiments, R5is independently unsubstituted methyl. In embodiments, R5is independently unsubstituted ethyl. In embodiments, R5is independently unsubstituted propyl. In embodiments, R5is independently unsubstituted n-propyl. In embodiments, R5is independently unsubstituted isopropyl. In embodiments, R5is independently unsubstituted butyl. In embodiments, R5is independently unsubstituted n-butyl. In embodiments, R5is independently unsubstituted isobutyl. In embodiments, R5is independently unsubstituted tert-butyl. In embodiments, R5is independently unsubstituted C2-C4 alkynyl. In embodiments, R5is independently unsubstituted ethynyl. In embodiments, R5is independently unsubstituted propynyl. In embodiments, R5is independently unsubstituted butynyl. In embodiments, R5is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5is independently unsubstituted methoxy. In embodiments,R5is independently unsubstituted ethoxy. In embodiments, R5is independently unsubstituted propoxy. In embodiments, R5is independently unsubstituted n-propoxy. In embodiments, R5is independently unsubstituted isopropoxy. In embodiments, R5is independently unsubstituted butoxy. In embodiments, R5is independently unsubstituted n-butoxy. In embodiments, R5is independently unsubstituted isobutoxy. In embodiments, R5is independently unsubstituted tert-butoxy.

[0265] In embodiments, R5is independently a halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4alkyl, or unsubstituted C2-C4alkynyl. In embodiments, R5is independently –F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, or unsubstituted ethynyl.

[0266] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. In embodiments, z5 is 6. In embodiments, z5 is 7. In embodiments, z5 is 8. In embodiments, z5 is 9.

[0267] In embodiments, a substituted R6(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6is substituted, it is substituted with at least one substituent group. In embodiments, when R6is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6is substituted, it is substituted with at least one lower substituent group.

[0268] In embodiments, R6is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0269] In embodiments, R6is independently oxo. In embodiments, R6is independently halogen. In embodiments, R6is independently –F. In embodiments, R6is independently –Cl. In embodiments, R6is independently –Br. In embodiments, R6is independently –I. In embodiments, R6is independently -CCl3. In embodiments, R6is independently -CBr3. In embodiments, R6is independently -CF3. In embodiments, R6is independently -CI3. In embodiments, R6is independently -CH2Cl. In embodiments, R6is independently -CH2Br. In embodiments, R6is independently -CH2F. In embodiments, R6is independently -CH2I. In embodiments, R6is independently -CHCl2. In embodiments, R6is independently -CHBr2. In embodiments, R6is independently -CHF2. In embodiments, R6is independently -CHI2. In embodiments, R6is independently –CN. In embodiments, R6is independently –OH. In embodiments, R6is independently -NH2. In embodiments, R6is independently –COOH. In embodiments, R6is independently -CONH2. In embodiments, R6is independently -NO2. In embodiments, R6is independently –SH. In embodiments, R6is independently -SO3H. In embodiments, R6is independently -OSO3H. In embodiments, R6is independently -SO2NH2. In embodiments, R6is independently ^NHNH2. In embodiments, R6is independently ^ONH2. In embodiments, R6is independently ^NHC(O)NHNH2. In embodiments, R6is independently ^NHC(O)NH2. In embodiments, R6is independently -NHSO2H. In embodiments, R6is independently -NHC(O)H. In embodiments, R6is independently -NHC(O)OH. In embodiments, R6is independently –NHOH. In embodiments, R6is independently -OCCl3. In embodiments, R6is independently -OCBr3. In embodiments, R6is independently -OCF3. In embodiments, R6is independently -OCI3. In embodiments, R6is independently -OCH2Cl. In embodiments, R6is independently -OCH2Br. In embodiments, R6is independently -OCH2F. In embodiments, R6is independently -OCH2I. In embodiments, R6is independently -OCHCl2. In embodiments, R6is independently -OCHBr2. In embodiments, R6is independently -OCHF2. In embodiments, R6is independently -OCHI2. In embodiments, R6is independently unsubstituted C1-C4 alkyl. In embodiments, R6is independently unsubstituted methyl. In embodiments, R6is independently unsubstituted ethyl. In embodiments, R6is independently unsubstituted propyl. In embodiments, R6is independently unsubstituted n-propyl. In embodiments, R6is independently unsubstituted isopropyl. In embodiments, R6is independently unsubstituted butyl. In embodiments, R6is independently unsubstituted n-butyl. In embodiments, R6isindependently unsubstituted isobutyl. In embodiments, R6is independently unsubstituted tert-butyl. In embodiments, R6is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R6is independently unsubstituted methoxy. In embodiments, R6is independently unsubstituted ethoxy. In embodiments, R6is independently unsubstituted propoxy. In embodiments, R6is independently unsubstituted n-propoxy. In embodiments, R6is independently unsubstituted isopropoxy. In embodiments, R6is independently unsubstituted butoxy. In embodiments, R6is independently unsubstituted n-butoxy. In embodiments, R6is independently unsubstituted isobutoxy. In embodiments, R6is independently unsubstituted tert-butoxy.

[0270] In embodiments, R6is independently a halogen or unsubstituted C1-C4alkyl. In embodiments, R6is independently –Cl or unsubstituted methyl.

[0271] In embodiments, z6 is 0. In embodiments, z6 is 1. In embodiments, z6 is 2. In embodiments, z6 is 3. In embodiments, z6 is 4. In embodiments, z6 is 5. In embodiments, z6 is 6. In embodiments, z6 is 7. In embodiments, z6 is 8. In embodiments, z6 is 9.

[0272] In embodiments, R1is , , ,F N ,F F N ,F ,F F N , 1 iss s s s s s. InCl F N In

[0273] In embodiments, R1is a monovalent form of ARS-1620. In embodiments, R1is a 20,

[0274] In embodiments, R1is a monovalent form of AMG-510. In embodiments, R1is a monovalent form of a compound as described in Canon, J.et al. Nature 575, 217–223 (2019), which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1O G-compounds described in Canon, et al.

[0275] In embodiments, R1is a monovalent form of MRTX-849. In embodiments, R1is a monovalent form of a compound as described in Fell, J. B. et al. J. Med. Chem.63, 6679– 6693 (2020), which is herein incorporated by reference in its entirety for all purposes. InNOembodiments, R1is a monovalent form Inf aty or equivalent for compounds described in Fell, et al.

[0276] In embodiments, R1is a monovalent form of GDC-6036. In embodiments, R1is a monovalent form of a compound as described in WO2020097537, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalent. In embodiments, R1isf ay or equivalent for compounds described in WO2020097537.

[0277] In embodiments, R1is a monovalent form of MRTX1133. In embodiments, R1is a monovalent form of a compound as described in Wang, X. et al. J. Med. Chem.65, 3123– 3133 (2022), which is herein incorporated by reference in its entirety for all purposes. Inembodiments, R1is a monovalent form Inf a or

[0278] In embodiments, R1is a monovalent form of BBO-8520. In embodiments, R1is a monovalent form of putative BBO-8520. In embodiments, R1is a monovalent form of a compound as described in WO2023004102, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalent form of isf aportion of BBO-8520, wherein R1does not include th or equivalent for compounds described in WO2023004102.

[0279] In embodiments, R1is a monovalent form of JDQ-443. In embodiments, R1is a monovalent form of a compound as described in WO2021120890, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalentis form of a portion ofor equivalent for compounds described in WO2021120890.

[0280] In embodiments, R1is a monovalent form of BI-0474. In embodiments, R1is a monovalent form of a compound as described in Bröker, J. et al. J. Med. Chem.65, 14614– 14629 (2022), which is herein incorporated by reference in its entirety for all purposes. In In sNH2S CN In embodiments, R1is a monovalent form of a portion e the piperazinyl moiety or equivalent for compoundsdescribed in Bröker, et al.

[0281] In embodiments, R1is a monovalent form of a compound as described in WO2021118877, which is herein incorporated by reference in its entirety for all purposes. In embodiments In embodiments, R1is a monovalent form of a portion of a c 88177, wherein R does not include the acryloyl moiety or equivalent for compounds described in WO2021118877.

[0282] In embodiments, R1is a monovalent form of a compound as described in WO2021120045, which is herein incorporated by reference in its entirety for all purposes. In embodiments In embodiments, R1is a monovalent form of a portion o120045, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in WO2021120045.

[0283] In embodiments, R1is a monovalent form of sotorasib. In embodiments, R1is a monovalent form of a compound as described in US 10,519,146, US 11,236,091, and US11,426,404, which are herein incorporated by reference in their entirety for all purposes. In embodiments, R1is a monovalent form . In embodiments, R1. In embodiments, R1is a monovalent form of a portion ofot include the substituted piperazinyl moiety or equivalent for compounds described in US 10,519,146, US 11,236,091, and US 11,426,404.

[0284] In embodiments, R1is a monovalent form of adagrasib. In embodiments, R1is a monovalent form of a compound as described in WO 2021 / 037018, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalent isis is a monovalent form of a ted piperazinyl moiety orequivalent for compounds described in WO 2021 / 037018.

[0285] In embodiments, R1is a monovalent form of MRTX1257. In embodiments, R1is a monovalent form of a compound as described in US 2018 / 0072723, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalent is. In embodiments, R1is a monovalent form of a oes not include the substituted piperazinyl moiety orequivalent for compounds described in US 2018 / 0072723.

[0286] In embodiments, the compound has the formula: . R2, R5, and z5 are as described herein, including in ependently hydrogen or a4ny value of R as described herein, including in embodiments.

[0287] In embodiments, R4.1and R4.2are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0288] In embodiments, a substituted R4.1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substitutedheteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.1is substituted, it is substituted with at least one substituent group. In embodiments, when R4.1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.1is substituted, it is substituted with at least one lower substituent group.

[0289] In embodiments, a substituted R4.2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.2is substituted, it is substituted with at least one substituent group. In embodiments, when R4.2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.2is substituted, it is substituted with at least one lower substituent group.

[0290] In embodiments, the compound has the formula: , wherein R2is hydrogen, -CX23, -SO2R2D, -P(O)R2AR2B,, unsu st tute 1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted phenyl; R4.1is halogen; R4.2is –O-(C1-C4 alkyl), wherein the C1-C4alkyl is substituted with a 5 to 8 membered heterocycloalkyl optionally substituted with halogen or unsubstituted C1-C3 alkyl; R5is independently halogen, -OH, or unsubstituted C2-C4alkynyl (e.g., C2alkynyl); and z5 is 1, 2, or 3. In embodiments, R2ishydrogen, -CX23, -SO2R2D, -P(O)R2AR2B, ^SiR2AR2BR2C, unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted phenyl; R4.1is halogen; R4.2is –O-CH2-(5 to 8 membered heterocycloalkyl), wherein the 5 to 8 membered heterocycloalkyl is optionally substituted with halogen; R5is independently halogen, -OH, or unsubstituted C2alkynyl; and z5 is 1, 2, or 3. In embodiments, R2is hydrogen; R4.1is halogen; R4.2is –O-CH2-(5 to 8 membered heterocycloalkyl), wherein the 5 to 8 membered heterocycloalkyl is optionally substituted with halogen; R5is independently halogen, -OH, or unsubstituted C2 alkynyl; and z5 is 1, 2, or 3.

[0291] In embodiments, when R2is substituted, R2is substituted with one or more first substituent groups denoted by R2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1substituent group is substituted, the R2.1substituent group is substituted with one or more second substituent groups denoted by R2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2substituent group is substituted, the R2.2substituent group is substituted with one or more third substituent groups denoted by R2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

[0292] In embodiments, when R2Ais substituted, R2Ais substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2A, R2A.1, R2A.2, and R2A.3, respectively.

[0293] In embodiments, when R2Bis substituted, R2Bis substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2B, R2B.1, R2B.2, and R2B.3, respectively.

[0294] In embodiments, when R2Aand R2Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2A.1, R2A.2, and R2A.3, respectively.

[0295] In embodiments, when R2Aand R2Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted byR2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2B.1, R2B.2, and R2B.3, respectively.

[0296] In embodiments, when R2Cis substituted, R2Cis substituted with one or more first substituent groups denoted by R2C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.1substituent group is substituted, the R2C.1substituent group is substituted with one or more second substituent groups denoted by R2C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.2substituent group is substituted, the R2C.2substituent group is substituted with one or more third substituent groups denoted by R2C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2C, R2C.1, R2C.2, and R2C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2C, R2C.1, R2C.2, and R2C.3, respectively.

[0297] In embodiments, when R2Dis substituted, R2Dis substituted with one or more first substituent groups denoted by R2D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.1substituent group is substituted, the R2D.1substituent group is substituted with one or more second substituent groups denoted by R2D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.2substituent group is substituted, the R2D.2substituent group is substituted with one or more third substituent groups denoted by R2D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2D, R2D.1, R2D.2, and R2D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2D, R2D.1, R2D.2, and R2D.3, respectively.

[0298] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0299] In embodiments, when two R3substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0300] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituent groups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted,the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0301] In embodiments, when R4.1is substituted, R4.1is substituted with one or more first substituent groups denoted by R4.1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1.1substituent group is substituted, the R4.1.1substituent group is substituted with one or more second substituent groups denoted by R4.1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1.2substituent group is substituted, the R4.1.2substituent group is substituted with one or more third substituent groups denoted by R4.1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.1, R4.1.1, R4.1.2, and R4.1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in he description of “first substituent group(s)”, wherWW WW.1 WW.2ein R , R , R , and RWW.3correspond to R4.1, R4.1.1, R4.1.2, and R4.1.3, respectively.

[0302] In embodiments, when R4.2is substituted, R4.2is substituted with one or more first substituent groups denoted by R4.2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2.1substituent group is substituted, the R4.2.1substituent group is substituted with one or more second substituent groups denoted by R4.2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2.2substituent group is substituted, the R4.2.2substituent group is substituted with one or more third substituent groups denoted by R4.2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.2, R4.2.1, R4.2.2, and R4.2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.2, R4.2.1, R4.2.2, and R4.2.3, respectively.

[0303] In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

[0304] In embodiments, when R6is substituted, R6is substituted with one or more first substituent groups denoted by R6.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.1substituent group is substituted, the R6.1substituent group is substituted with one or more second substituent groups denoted by R6.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.2substituent group is substituted, the R6.2substituent group is substituted with one or more third substituent groups denoted by R6.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6, R6.1, R6.2, and R6.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6, R6.1, R6.2, and R6.3, respectively.

[0305] In embodiments, when R10is substituted, R10is substituted with one or more first substituent groups denoted by R10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1substituent group is substituted, the R10.1substituent group is substituted with one or more second substituent groups denoted by R10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2substituent group is substituted, the R10.2substituent group is substituted with one or more third substituent groups denoted by R10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10, R10.1, R10.2, and R10.3, respectively.

[0306] In embodiments, when R10Ais substituted, R10Ais substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituent groups denoted by R10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10A, R10A.1, R10A.2, and R10A.3, respectively.

[0307] In embodiments, when R10Bis substituted, R10Bis substituted with one or more first substituent groups denoted by R10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.1substituent group is substituted, the R10B.1substituent group is substituted with one or more second substituent groups denoted by R10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.2substituent group is substituted, the R10B.2substituent group is substituted with one or more third substituent groups denoted by R10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10B, R10B.1, R10B.2, and R10B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10B, R10B.1, R10B.2, and R10B.3, respectively.

[0308] In embodiments, when R10Aand R10Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituent groups denoted byR10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R10A.1, R10A.2, and R10A.3, respectively.

[0309] In embodiments, when R10Aand R10Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.1substituent group is substituted, the R10B.1substituent group is substituted with one or more second substituent groups denoted by R10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.2substituent group is substituted, the R10B.2substituent group is substituted with one or more third substituent groups denoted by R10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10B.1, R10B.2, and R10B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R10B.1, R10B.2, and R10B.3, respectively.

[0310] In embodiments, when R10Cis substituted, R10Cis substituted with one or more first substituent groups denoted by R10C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10C.1substituent group is substituted, the R10C.1substituent group is substituted with one or more second substituent groups denoted by R10C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10C.2substituent group is substituted, the R10C.2substituent group is substituted with one or more third substituent groups denoted by R10C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10C, R10C.1, R10C.2, and R10C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained inthe definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10C, R10C.1, R10C.2, and R10C.3, respectively.

[0311] In embodiments, when R10Dis substituted, R10Dis substituted with one or more first substituent groups denoted by R10D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10D.1substituent group is substituted, the R10D.1substituent group is substituted with one or more second substituent groups denoted by R10D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10D.2substituent group is substituted, the R10D.2substituent group is substituted with one or more third substituent groups denoted by R10D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10D, R10D.1, R10D.2, and R10D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10D, R10D.1, R10D.2, and R10D.3, respectively.

[0312] In embodiments, when R20is substituted, R20is substituted with one or more first substituent groups denoted by R20.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.1substituent group is substituted, the R20.1substituent group is substituted with one or more second substituent groups denoted by R20.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.2substituent group is substituted, the R20.2substituent group is substituted with one or more third substituent groups denoted by R20.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20, R20.1, R20.2, and R20.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20, R20.1, R20.2, and R20.3, respectively.

[0313] In embodiments, when R100is substituted, R100is substituted with one or more first substituent groups denoted by R100.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R100.1substituent group is substituted, the R100.1substituent group is substituted with one or more second substituent groups denoted by R100.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R100.2substituent group is substituted,the R100.2substituent group is substituted with one or more third substituent groups denoted by R100.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R100, R100.1, R100.2, and R100.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R100, R100.1, R100.2, and R100.3, respectively.

[0314] In embodiments, when R101is substituted, R101is substituted with one or more first substituent groups denoted by R101.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R101.1substituent group is substituted, the R101.1substituent group is substituted with one or more second substituent groups denoted by R101.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R101.2substituent group is substituted, the R101.2substituent group is substituted with one or more third substituent groups denoted by R101.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R101, R101.1, R101.2, and R101.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R101, R101.1, R101.2, and R101.3, respectively.

[0315] In embodiments, when R102is substituted, R102is substituted with one or more first substituent groups denoted by R102.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R102.1substituent group is substituted, the R102.1substituent group is substituted with one or more second substituent groups denoted by R102.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R102.2substituent group is substituted, the R102.2substituent group is substituted with one or more third substituent groups denoted by R102.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R102, R102.1, R102.2, and R102.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R102, R102.1, R102.2, and R102.3, respectively.

[0316] In embodiments, when R103is substituted, R103is substituted with one or more first substituent groups denoted by R103.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R103.1substituent group is substituted, the R103.1substituent group is substituted with one or more second substituent groups denoted by R103.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R103.2substituent group is substituted, the R103.2substituent group is substituted with one or more third substituent groups denoted by R103.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R103, R103.1, R103.2, and R103.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R103, R103.1, R103.2, and R103.3, respectively.

[0317] In embodiments, when L1is substituted, L1is substituted with one or more first substituent groups denoted by RL1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.1substituent group is substituted, the RL1.1substituent group is substituted with one or more second substituent groups denoted by RL1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.2substituent group is substituted, the RL1.2substituent group is substituted with one or more third substituent groups denoted by RL1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L1, RL1.1, RL1.2, and RL1.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L1, RL1.1, RL1.2, and RL1.3, respectively.

[0318] In embodiments, when L10is substituted, L10is substituted with one or more first substituent groups denoted by RL10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL10.1substituent group is substituted, the RL10.1substituent group is substituted with one or more second substituent groups denoted by RL10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL10.2substituent group is substituted, the RL10.2substituent group is substituted with one or more third substituent groups denoted by RL10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L10, RL10.1, RL10.2, and RL10.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explainedin the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L10, RL10.1, RL10.2, and RL10.3, respectively. 1 I b di h L101i b i d L101i b i d i h ne or more firstsubstituent groups denoted by RL101.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL101.1substituent group is substituted, the RL101.1substituent group is substituted with one or more second substituent groups denoted by RL101.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL101.2substituent group is substituted, the RL101.2substituent group is substituted with one or more third substituent groups denoted by RL101.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L101, RL101.1, RL101.2, and RL101.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L101, RL101.1, RL101.2, and RL101.3, respectively.r more first substituent groups denoted by RL102.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL102.1substituent group is substituted, the RL102.1substituent group is substituted with one or more second substituent groups denoted by RL102.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL102.2substituent group is substituted, the RL102.2substituent group is substituted with one or more third substituent groups denoted by RL102.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L102, RL102.1, RL102.2, and RL102.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L102, RL102.1, RL102.2, and RL102.3, respectively.

[0321] In embodiments, when L is substituted, L is substituted with one or more first substituent groups denoted by RL103.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL103.1substituent group is substituted, the RL103.1substituent group is substituted with one or more second substituent groups denoted by RL103.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL103.2substituent group is substituted,the RL103.2substituent group is substituted with one or more third substituent groups denoted by RL103.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L103, RL103.1, RL103.2, and RL103.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L103, RL103.1, RL103.2, and RL103.3, respectively.

[0322] In embodiments, the compound has the formula: ula: ula: ula:CH3O N ula: ula: ula:. In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula:CF3O N ula: ula: ula:ula: ula: ula:ula: ula: ula:ula: ula:ula: ula:ula: ula:ula: ula:ula: ula:ula: ula: ula:ula: ula: ula:la: la: la:O N N N ula: ula: ula: ula:ula: ula: ula: ula:ula: ula:la: ula: ula:ula:[ ] n em o ments, t e compoun n s as( ) (e.g., - as( ), - Ras(G12D), or N-Ras(G12D)) behind Switch II. In embodiments, the compound modulates the conformation of Switch II. In embodiments, the compound inhibits (e.g., by about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000 fold or more) Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) nucleotide exchange (e.g., GDP for GTP or GTP for GDP) relative to the absence of the compound. In embodiments, the compound inhibits release of GDP from Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound inhibits binding of GDP to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound inhibits binding of GTP to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound increases (e.g., by about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000,8000, 9000, 10000 fold or more) Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N- Ras(G12D)) nucleotide exchange (e.g., GDP for GTP or GTP for GDP) relative to the absence of the compound. In embodiments, the compound increases release of GDP from Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound increases release of GTP from Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound increases binding of GDP to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound inhibits binding of GTP to Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound inhibits binding of a GTP analog (e.g., mant-dGTP) to Ras(G12D) (e.g., K- Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) relative to the absence of the compound. In embodiments, the compound modulates the conformation of a Ras(G12D) (e.g., K- Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) amino acid that contacts GTP in the absence of the compound. In embodiments, the compound modulates the conformation of a Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) amino acid that contacts GDP in the absence of the compound. In embodiments, the compound modulates the conformation of a plurality of Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) amino acids that contact GTP in the absence of the compound. In embodiments, the compound modulates the conformation of a plurality of Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N- Ras(G12D)) amino acids that contact GDP in the absence of the compound. In embodiments, the compound modulates the binding of GTP and / or GDP to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) compared to binding in the absence of the compound. In embodiments, the compound modulates the release of GTP and / or GDP from Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) compared to release in the absence of the compound. In embodiments, the compound modulates the ratio of the binding of GTP and GDP to Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) compared to the ratio in the absence of the compound. In embodiments, the compound modulates the ratio of the rate of release of GTP and GDP from Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) compared to the ratio in the absence of the compound. In embodiments, the compound binds Ras(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) protein bound to GDP and, after release of the GDP, modulates the subsequent binding of GDP or GTP to the Ras bound to the compound. In embodiments, the compound bindsRas(G12D) (e.g., K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D)) protein bound to GDP and, after release of the GDP, modulates the subsequent binding of GDP to the Ras bound to the compound. In embodiments, the compound binds Ras(G12D) (e.g., K-Ras(G12D), H- Ras(G12D), or N-Ras(G12D)) protein bound to GDP and after release of the GDP, modulates the subsequent binding of GTP to the Ras bound to the compound.

[0324] In embodiments, the compound contacts the Switch II Binding Pocket of human K- Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to G60, Q61, D69, D92, H95, Y96, or Q99 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to G60 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q61 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to D69 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to D92 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to H95 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Y96 of human K-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q99 of human K-Ras protein.

[0325] In embodiments, the compound contacts the Switch II Binding Pocket of human H- Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to G60, Q61, D69, D92, Q95, Y96, or Q99 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to G60 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q61 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to D69 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to D92 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q95 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Y96 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q99 of human H-Ras protein.

[0326] In embodiments, the compound contacts the Switch II Binding Pocket of human N- Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to G60, Q61, D69, D92, L95, Y96, or Q99 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to G60 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q61 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to D69 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to D92 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to L95 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Y96 of human N-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q99 of human N-Ras protein.

[0327] In embodiments, the compound binds a human Ras(G12D) (e.g., human K- Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex more strongly than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 2-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 5-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 10-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 20-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, thecompound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 40-fold stronger than said compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 60-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 80-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 100-fold stronger than said compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions. In embodiments, the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 500-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions.

[0328] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0329] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). III. Pharmaceutical compositions

[0330] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0331] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. In embodiments, the compound is a compound of formula (I), including embodiments thereof. IV. Methods of use

[0332] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to Ras(G12D) with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0333] In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is leukemia. In embodiments, the cancer is thyroid cancer. In embodiments, the cancer is bladder cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic ductal adenocarncinoma. In embodiments, the cancer is colorectal adenocarcinoma. In embodiments, the cancer is colorectal carcinoma. In embodiments, the cancer is rectal carcinoma. In embodiments, the cancer is rectal adenocarcinoma. In embodiments, the cancer is colon adenocarcinoma. In embodiments, the cancer is plasma cell myeloma. In embodiments, the cancer is bile duct carcinoma. In embodiments, the cancer is chronic myelomonocytic leukemia. In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is lung adenocarcinoma. In embodiments, the cancer is non-small cell lung carcinoma. In embodiments, the cancer is squamous cell lung carcinoma. In embodiments, the cancer is rhabdomyosarcoma. In embodiments, the cancer is endometrium carcinoma. In embodiments, the cancer is thyroid carcinoma. In embodiments, the cancer is bladder carcinoma. In embodiments, the cancer is ovarian carcinoma. In embodiments, the cancer is myelodysplastic syndrome.

[0334] In an aspect is provided a method of treating a Switch II GTPase protein-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to the Switch II GTPase protein with a Kd of less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0335] In an aspect is provided a method of treating a K-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to K-Ras(G12D) with a Kdof less than 1 µM, wherein R1and L1are as described herein, including in embodiments.

[0336] In embodiments, the K-Ras(G12D)-associated disease is cancer (e.g., pancreatic ductal adenocarncinoma, colorectal adenocarcinoma, ...

Claims

WHAT IS CLAIMED IS: 1 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: (I); wherein ding Pocket binding moiety;L1is a bond or divalent linker; and wherein gen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, ^NHC(O)NR2CNR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -C(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -PR2AR2B, -P(O)R2AR2B, -OP(O)OR2AOR2B, ^SiR2AR2BR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2A, R2B, R2C, and R2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X2is independently –F, -Cl, -Br, or –I; n2 is an integer from 0 to 4; m2 and v2 are independently 1 or 2; and wherein the compound is not:O O N N N N N N 27 , 28 12. The compound of claim 1, wherein R is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

3. The compound of claim 1, wherein R2is hydrogen, -CX23, -SO2R2D, -P(O)R2AR2B, ^SiR2AR2BR2C, unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted phenyl.

4. The compound of claim 1, wherein R2is hydrogen, -CH3, -CH2CH3, -CH2CH(CH3)2, -CF3, -Si(CH3)3, -P(O)(CH3)2, -S(O)2CH3, unsubstituted phenyl,,. , .

6. The compound of claim 1, wherein L1is –L101-L102-L103-; L101is connected directly to E; L101is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR101-, -C(O)NR101-, -NR101C(O)-, -NR101C(O)O-, -OC(O)NR101-, -NR101C(O)NR101-, -NR101C(NH)NR101-, -S(O)2-, -NR101S(O)2-, -S(O)2NR101-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR102-, -C(O)NR102-, -NR102C(O)-, -NR102C(O)O-, -OC(O)NR102-, -NR102C(O)NR102-, -NR102C(NH)NR102-, -S(O)2-, -NR102S(O)2-, -S(O)2NR102-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L103is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR103-, -C(O)NR103-, -NR103C(O)-, -NR103C(O)O-, -OC(O)NR103-, -NR103C(O)NR103-, -NR103C(NH)NR103-, -S(O)2-, -NR103S(O)2-, -S(O)2NR103-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and each R101, R102, and R103is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, COOH CONH2 NO2 SH SO3H OSO3H SO2NH2 ^NHNH2 ^ONH2^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

7. The compound of claim 1, wherein L1is a bond.

8. The compound of claim 1, wherein L1is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene.

9. The compound of claim 1, wherein L1is a spirocyclic substituted or unsubstituted 3 to 8 membered heterocycloalkylene.

10. The compound of claim 6, wherein L1is orl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z3 is an integer from 0 to 9.

11. The compound of claim 10, wherein L1isN N .L10is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR100-, -C(O)NR100-, -NR100C(O)-, -NR100C(O)O-, -OC(O)NR100-, -NR100C(O)NR100-, -NR100C(NH)NR100-, -S(O)2-, -NR100S(O)2-, -S(O)2NR100-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R100is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10is hydrogen, halogen, -CX103, -CHX102, -CH2X10, -OCX103, -OCH2X10, -OCHX102, -CN, -SOn10R10D, -SOv10NR10AR10B, ^NR10CNR10AR10B, ^ONR10AR10B, ^NHC(O)NR10CNR10AR10B, -NHC(O)NR10AR10B, -N(O)m10, -NR10AR10B, -C(O)R10C, -C(O)OR10C, -C(O)NR10AR10B, -OR10D, -SR10D, -NR10ASO2R10D, -NR10AC(O)R10C, -NR10AC(O)OR10C, -NR10AOR10C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10A, R10B, R10C, and R10Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X10is independently –F, -Cl, -Br, or –I; n10 is an integer from 0 to 4; and m10 and v10 are independently 1 or 2.

13. The compound of claim 1, wherein R1is , ,or CI3, -CH2Cl, -CH2Br,-CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2,-NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11; z5 is an integer from 0 to 9; and z6 is an integer from 0 to 9.

14. The compound of claim 13, wherein R4is independently a halogen, -CF3, -OH, unsubstituted C1-C4 alkyl, substituted 2 to 6 membered heteroalkyl, or substituted 5 to 6 membered heteroaryl.

15. The compound of claim 13, wherein R4is independently –F, -Cl, -CF3, -OH, or unsubstituted methyl.

16. The compound of claim 13, wherein R4is independently a 2 to 6 membered heteroalkyl, substituted with substituted heterocycloalkyl or unsubstituted fused heterocycloalkyl.

17. The compound of claim 13, wherein R4is independently .

18. The compound of claim 13, wherein R4is independently a substituted pyridyl.

19. The compound of claim 13, wherein z4 is 1, 2, or 3.

20. The compound of claim 13, wherein R5is independently a halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4 alkyl, or unsubstituted C2-C4 alkynyl.

21. The compound of claim 13, wherein R5is independently –F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, or unsubstituted ethynyl.

22. The compound of claim 13, wherein z5 is 1, 2, or 3.

23. The compound of claim 13, wherein R6is independently a halogen or unsubstituted C1-C4 alkyl.

24. The compound of claim 13, wherein R6is independently –Cl or unsubstituted methyl.

25. The compound of claim 13, wherein z6 is 1 or 2.

26. The compound of claim 1, wherein R1is , , ,,F F N ,. e compoun o c a m , avng e ormu a: .

28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

29. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to Ras(G12D) with a Kdof less than 1 µM.

30. The method of claim 29, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, leukemia, thyroid cancer, bladder cancer, or ovarian cancer.

31. The method of claim 29, wherein the cancer is pancreatic ductal adenocarncinoma, colorectal adenocarcinoma, colorectal carcinoma, rectal carcinoma, rectal adenocarcinoma, colon adenocarcinoma, plasma cell myeloma, bile duct carcinoma, chronic myelomonocytic leukemia, acute myeloid leukemia, lung adenocarcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, rhabdomyosarcoma, endometrium carcinoma, thyroid carcinoma, bladder carcinoma, ovarian carcinoma, or myelodysplastic syndrome.

32. A method of treating a K-Ras(G12D)-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to K- Ras(G12D) with a Kdof less than 1 µM.

33. A method of treating an H-Ras(G12D)-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to H- Ras(G12D) with a Kdof less than 1 µM.

34. The method of claim 33, wherein said H-Ras(G12D)-associated disease is Costello syndrome.

35. A method of treating an N-Ras(G12D)-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to N- Ras(G12D) with a Kdof less than 1 µM.

36. A method of modulating the level of activity of a K-Ras protein in a cell, said method comprising contacting the cell with an effective amount of a compound ofone of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to K-Ras with a Kd of less than 1 µM.

37. The method of claim 36, wherein said modulating of said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, K-Ras subcellular localization, K-Ras post-translational processing, or K- Ras post-translational modifications.

38. The method of claim 36, wherein said modulating is increasing the activity of said K-Ras protein.

39. The method of claim 36, wherein said modulating is reducing the activity of said K-Ras protein.

40. The method of claim 36, wherein said K-Ras protein is a human K-Ras protein.

41. The method of claim 40, wherein said human K-Ras protein contains a G12D mutation.

42. A method of modulating the level of activity of an H-Ras protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to H-Ras with a Kdof less than 1 µM.

43. The method of claim 42, wherein said modulating of said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, H-Ras subcellular localization, H-Ras post-translational processing, or H- Ras post-translational modifications.

44. The method of claim 42, wherein said modulating is increasing the activity of said H-Ras protein.

45. The method of claim 42, wherein said modulating is reducing the activity of said H-Ras protein.

46. The method of claim 42, wherein said H-Ras protein is a human H-Ras protein.

47. The method of claim 46, wherein said human H-Ras protein contains a G12D mutation.

48. A method of modulating the level of activity of an N-Ras protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R1-L1-H is capable of binding to N-Ras with a Kd of less than 1 µM.

49. The method of claim 48, wherein said modulating of said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, N-Ras subcellular localization, N-Ras post-translational processing, or N- Ras post-translational modifications.

50. The method of claim 48, wherein said modulating is increasing the activity of said N-Ras protein.

51. The method of claim 48, wherein said modulating is reducing the activity of said N-Ras protein.

52. The method of claim 48, wherein said N-Ras protein is a human K-Ras protein.

53. The method of claim 52, wherein said human N-Ras protein contains a G12D mutation.

54. A K-Ras protein covalently bound to a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said K-Ras protein.

55. The covalently modified K-Ras protein of claim 54, wherein said compound is reversibly covalently bound to an aspartate residue of said K-Ras protein.

56. The covalently modified K-Ras protein of claim 54, wherein said compound is irreversibly covalently bound to an aspartate residue of said K-Ras protein.

57. The covalently modified K-Ras protein of claim 54, wherein said covalently modified K-Ras protein has a modulated activity relative to a control, wherein said activity is selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, K-Ras subcellular localization, K-Ras post-translational processing, and K-Ras post-translational modifications.

58. The covalently modified K-Ras protein of claim 54, wherein said K- Ras protein contains a G12D mutation.

59. The covalently modified K-Ras protein of claim 58, wherein said compound is covalently bonded to aspartate residue 12.

60. An H-Ras protein covalently bound to a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said H-Ras protein.

61. The covalently modified H-Ras protein of claim 60, wherein said compound is reversibly covalently bound to an aspartate residue of said H-Ras protein.

62. The covalently modified H-Ras protein of claim 60, wherein said compound is irreversibly covalently bound to an aspartate residue of said H-Ras protein.

63. The covalently modified H-Ras protein of claim 60, wherein said covalently modified H-Ras protein has a modulated activity relative to a control, wherein said activity is selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release,nucleotide binding, H-Ras subcellular localization, H-Ras post-translational processing, and H-Ras post-translational modifications.

64. The covalently modified H-Ras protein of claim 60, wherein said H- Ras protein contains a G12D mutation.

65. The covalently modified H-Ras protein of claim 64, wherein said compound is covalently bonded to aspartate residue 12.

66. An N-Ras protein covalently bound to a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said N-Ras protein.

67. The covalently modified N-Ras protein of claim 66, wherein said compound is reversibly covalently bound to an aspartate residue of said N-Ras protein.

68. The covalently modified N-Ras protein of claim 66, wherein said compound is irreversibly covalently bound to an aspartate residue of said N-Ras protein.

69. The covalently modified N-Ras protein of claim 66, wherein said covalently modified H-Ras protein has a modulated activity relative to a control, wherein said activity is selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, N-Ras subcellular localization, N-Ras post-translational processing, and N-Ras post-translational modifications.

70. The covalently modified N-Ras protein of claim 66, wherein said H- Ras protein contains a G12D mutation.

71. The covalently modified N-Ras protein of claim 70, wherein said compound is covalently bonded to aspartate residue 12.

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