Gtpase inhibitors and uses thereof

Abstract

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

Description

GTPase INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 547,090 filed November 2, 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- 777001WO_Sequence_Listing_ST26.xml; Size 322,145 bytes; and Date of Creation: October 25, 2024) are hereby incorporated by reference in their entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under grant nos. F31 NS 122434, R01 CA244550, and K99 CA277358, awarded by The National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0004] The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) to comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Previous efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of GTP and lack of allosteric regulatory sites. Disclosed herein, inter alia, are solutions to these and other problems in the art.BRIEF SUMMARY

[0005] In an aspect is provided a Ras GTPase family protein including a cysteine residue at an ammo acid position equivalent to position 23 of RalA (SEQ ID NO: 2), position 12 of RaplA (SEQ ID NO: 3), or position 15 of Rheb (SEQ ID NO: 4); wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras.

[0006] In an aspect is provided a Rho GTPase family protein including a cysteine residue at an ammo acid position equivalent to position 12 of Rael (SEQ ID NO: 5) or position 14 of RhoA (SEQ ID NO: 6).

[0007] In an aspect is provided a Rab GTPase family protein including a cysteine residue at an amino acid position equivalent to position 20 of Rabi A (SEQ ID NO: 7) or position 30 of Rab5C (SEQ ID NO: 8).

[0008] In an aspect is provided a GTPase family protein covalently bound to a Switch II Binding Pocket inhibitor at an amino acid position equivalent to position 12 of K-Ras; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras.

[0009] In an aspect is provided a method of determining a phenotype of a cell, including: (i) contacting a cell expressing the Ras GTPase family protein as described herein with a Switch II Binding Pocket inhibitor; and (ii) determining a change in phenotype of the cell relative to the absence of the Switch II Binding Pocket inhibitor.

[0010] In an aspect is provided a method of determining a phenotype of a cell, including: (i) contacting a cell expressing the Rho GTPase family protein as described herein with a Switch II Binding Pocket inhibitor; and (ii) determining a change in phenotype of the cell relative to the absence of the Switch II Binding Pocket inhibitor.

[0011] In an aspect is provided a method of determining a phenotype of a cell, including: (i) contacting a cell expressing the Rab GTPase family protein as described herein with a Switch II Binding Pocket inhibitor; and (ii) determining a change in phenotype of the cell relative to the absence of the Switch II Binding Pocket inhibitor.

[0012] In an aspect is provided a method of inhibiting a GTPase family protein in a cell, including contacting the cell with a Switch II Binding Pocket inhibitor; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the GTPase family protein is not K-Ras, H-Ras, or N- Ras.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIGS.1A-1K. Covalent SII pocket inhibition of K-Ras(G12C), H-Ras(G12C), and N-Ras(G12C). FIG.1A: X-ray structure of K-Ras(G12C) bound to AMG510 (PDB 6OIM). FIG.1B: Chemical structures of optimized K-Ras(G12C) inhibitors tested in our screen. FIG.1C: Time-dependent covalent modification of K-Ras(G12C) by various compounds (5 ^M). FIG.1D: Time-dependent covalent modification of H-Ras(G12C) by various compounds (5 ^M). FIG.1E: Time-dependent covalent modification of N-Ras(G12C) by various compounds (5 ^M). FIG.1F: Crystal structure of H-Ras(G12C)^GDP^AMG510 adduct. FIG.1G: Comparison of the structures of K-Ras(G12C)^GDP^AMG510 (PDB 6OIM) and H-Ras(G12C)^GDP^AMG510. FIG.1H: Intrinsic, Sos-, or EDTA-mediated nucleotide exchange of BODIPY-GDP with N-Ras(G12C)^GDP and N- Ras(G12C)^GDP^AMG510 adduct. FIG.1I: Differential scanning fluorimetry of N- Ras(G12C)^GDP and N-Ras(G12C)^GDP^AMG510 adduct. FIGS.1J-1K: Relative growth of MOLM-14(QS)-NRAS-Q61K (J) and MOLM-14(QS)-NRAS-G12C (K) cells (+ 25 nM gilteritinib) after treatment with K-Ras(G12C) inhibitors for 72 h. Data are presented as mean ^s.d. (n = 3) and are representative of two independent experiments.

[0014] FIGS.2A-2K. Targeting Ras-Family GTPases. FIG.2A: Family tree of human superfamily of Ras-like GTPases (5). FIG.2B: Covalent modification of RalA(G23C) with compounds 1-10 (50 ^M, 12 h). FIG.2C: Intact protein mass spectra of RalA(G23C)^GDP and RalA(G23C)^GDP^MRTX1257 adduct. FIG.2D: Time-dependent covalent modification of RalA(G23C) with different compounds (50 ^M). FIG.2E: Differential scanning fluorimetry of RalA(G23C)^GDP and RalA(G23C)^GDP^GDC6036 adduct. FIG. 2F: Covalent modification of Rap1A(G12C) with compounds 1-10 (50 ^M, 12 h). FIG.2G: Intact protein mass spectra of Rap1A(G12C, L96F)^GDP and Rap1A(G12C,L96F)^GDP^GDC6036 adduct. FIG.2H: Time-dependent covalent modification of Rap1A(G12C) and Rap1A(G12C, L96F) with different compounds (50 ^M). FIG.2I: Differential scanning fluorimetry of Rap1A(G12C, L96F)^GDP and Rap1A(G12C, L96F)^GDP^GDC6036 adduct. FIG.2J: Covalent modification of RalA(G23C)^GDP, Rap1A(G12C, L96F)^GDD, RalA(G23C)^GppNHp, and Rap1A(G12C, L96F)^GppNHp with MRTX1257 and GDC6036 (50 ^M, 1 h).

[0015] FIGS.3A-3E. Cellular Targeting of Ras-Family GTPases. FIG.3A: Peptides showing significant differences in HDX at any time point (>0.35 Da and >4.5%) mapped onto a homology-model of RalA based on MRTX849 bound K-Ras(G12C) (PDB 6USZ). FIG.3B: Immunoblot of HeLa cells transiently overexpressing EGFP-RalA(WT) and EGFP- RalA(G23C). FIG.3C: RalA activity measured by RalA G-LISATM. HeLa cells were transiently transfected, treated with different concentration of MRTX1257 for 12h, and lysates were tested at 0.5 mg / mL. Data are presented as mean ^ SEM (n = 2) and are representative of three independent experiments. FIG.3D: Intrinsic, RAPGEF5-, or EDTA- mediated nucleotide exchange of BODIPY-GDP with Rap1A(G12C, L96F)^GDP and Rap1A(G12C, L96F)^GDP^GDC6036 adduct. FIG.3E: IP of active GTP-bound Rap1 using GST-RalGDS-RBS of HeLa cells transiently overexpressing EGFP-Rap1A(WT) and EGFP- Rap1A(G12C, L96F) and treated with different concentrations of GDC6036.

[0016] FIGS.4A-4H. Targeting Rho- and Rab-Family GTPases. FIG.4A: Covalent modification of Rac1(G12C) with compounds 1-10 (50 ^M, 12 h). FIG.4B: Covalent modification of RhoA(G14C) with compounds 1-10 (50 ^M, 12 h). FIG.4C: Time- dependent covalent modification of Rac1(G12C), RhoA(G14C), and Rac1(WT) with GDC6036 (50 ^M). FIG.4D: Time-dependent covalent modification of various Rac1 mutants with GDC6036 (50 ^M). FIG.4E: Covalent modification of Rab1A(S20C) with compounds 1-10 (50 ^M, 12 h). FIG.4F: Covalent modification of Rab5C(S63C) with compounds 1-10 (50 ^M, 12 h). FIG.4G: Time-dependent covalent modification of Rab1A(S20C), Rab5C(S63C), and RabL5(WT) with MRTX1257 (50 ^M). FIG.4H: Time- dependent covalent modification of various Rab1A mutants with MRTX1257 (50 ^M).

[0017] FIGS.5A-5K. Cellular Targeting and Development of Optimized Ligands for Rab and Rho GTPases. FIG.5A: Peptides showing significant differences in HDX at any time point (>0.35 Da and >4.5%) mapped onto a homology-model of Rab1A based on MRTX849 bound K-Ras(G12C) (PDB 6USZ). FIG.5B: Differential scanning fluorimetry of Rac1(G12C)^GDP and Rac1(G12C)^GDP^GDC6036 adduct. FIG.5C: Rac1 activity measured by Rac1 G-LISATM. HeLa cells were transiently transfected, treated with different concentration of GDC6036 for 12 h, and lysates were tested at 0.5 mg / mL. Data are presented as mean ^ SEM (n = 2) and are representative of three independent experiments. FIG.5D: Chemical structures of novel Switch II pocket inhibitors to improve targeting of Rac1(G12C). FIGS.5E-5F: Ligand Poses of MD simulation minimization of GDC6036, andligands 11-14. FIG.5G: Quantum mechanics (B3LYP / 6-31+G** IEF-PCM) calculations of relative transition state barriers and covalent adduct energies with the respective warhead motifs (normalized to 11). FIG.5H: Time-dependent covalent modification of Rac1(G12C) with GDC6036 and compounds 11-14 (50 ^M). FIG.5I: Time-dependent covalent modification of Rac1(G12C, K96H) with GDC6036 and compounds 11-14 (50 ^M). FIG. 5J: Differential scanning fluorimetry of Rac1(G12C)^GDP, Rac1(G12C)^GDP^GDC6036 adduct, and Rac1(G12C)^GDP^11 adduct. FIG.5K: Differential scanning fluorimetry of Rac1(G12C,K96H)^GDP, Rac1(G12C,K96H)^GDP^GDC6036 adduct, and Rac1(G12C,K96H)^GDP^11 adduct.

[0018] FIGS.6A-6C. H-Ras(G12C) DSF and Nucleotide Exchange. FIG.6A: Differential scanning fluorimetry of H-Ras(G12C)^GDP and H-Ras(G12C)^GDP^AMG510 adduct. FIG. 6B: Intrinsic, Sos-, or EDTA-mediated nucleotide exchange of BODIPY-GDP with N- Ras(G12C)^GDP. FIG.6C: Intrinsic, Sos-, or EDTA-mediated nucleotide exchange of BODIPY-GDP with N-Ras(G12C)^GDP^AMG510 adduct.

[0019] FIGS.7A-7B. All HDX-MS peptide changes #D for experiments examining changes in dynamics caused by binding of MRTX1257. FIG.7A: The sum of the number of deuteron difference for all peptides analyzed over the entire deuterium exchange time course for RalA(G23C)^GDP and RalA(G23C)^GDP^MRTX1257. FIG.7B: The sum of the number of deuteron difference for all peptides analyzed over the entire deuterium exchange time course for Rab1A(S20C,E108Q)^GDP and Rab1A(S20C,E108Q)^GDP^MRTX1257. Peptides colored in red are those that had a significant change (>0.35 Da and 4.5% difference at any timepoint, with a two-tailed t-test p < 0.01). Each point represents a single peptide, and error bars are shown as the sum of S.D. across all time points (n = 3 for each time point).

[0020] FIGS.8A-8B. GDC6036 (8) analogs with MRTX1257 (11), MRTX1133(- acrylamide) (12), and JDQ443 (13) warheads exhibit different level of stability and warhead positioning in non-covalent MD simulations. FIG.8A: 13 exhibits significant larger root mean square deviation on ligand heavy atoms, than 8, 11 and 12, suggesting compromised stability of the Rac1-13 complex. FIG.8B: Sub-optimal warhead placement thus potential impaired covalent modification is suggested by comparing of G12C S^^ (yellow beads) positioning from Rac1-13 covalent MD simulations to the warhead reacting C atom (greenbeads) positioning from Rac1-13 non-covalent MD simulations, projecting onto the initial covalent model of 13 (sticks) bound Rac1(G12C) (grey cartoon).

[0021] FIGS.9A-9C. Sequence alignment of select GTPase family proteins depicting the amino acid positions equivalent to positions 12, 95, 96, and 99 of K-Ras, denoted as “K- Ras(G12)-equivalent)”, “K-Ras(H95 / Y96)-equivalent”, and “K-Ras(Q99)-equivalent”, respectively. Amino acids omitted for optimum alignment are indicated with the “^” symbol. Large C-terminal sequence extensions for RHOBTB and RHOT proteins have been removed (indicated by the “#” symbol). A listing of the sequences is provided in Example 3.

[0022] FIGS.10A-10E. Cellular targeting of Ras-family GTPases with RMC-6291. FIG. 10A: X-ray structure of tricomplex of RMC-4998, K-Ras(G12C), and CypA (PDB: 8G9P). K-Ras residues involved in binding RMC-4998 are G13, P34, I36, A59, and Y64. Negatively charged K-Ras residues involved in binding CypA are E31, D33, and E37. FIG.10B: Immunoblot of HeLa cells transiently overexpressing K-Ras or K-Ras(G12C). HeLa cells were transiently transfected, treated with different concentration of RMC-6291 for 3 h, and blotted for Ras. FIG.10C: Immunoblot of HeLa cells transiently overexpressing M-Ras or M-Ras(G22C). HeLa cells were transiently transfected, treated with different concentration of RMC-6291 for 3 h, and blotted for M-Ras. FIG.10D: Immunoblot of HeLa cells transiently overexpressing R-Ras1 or R-Ras1(G38C). HeLa cells were transiently transfected, treated with different concentration of RMC-6291 for 3 h, and blotted for R-Ras. FIG.10E: Immunoblot of HeLa cells transiently overexpressing Rheb or Rheb(R15C). HeLa cells were transiently transfected, treated with different concentration of RMC-6291 for 3 h, and blotted for Rheb. Data are representative of three independent experiments. DETAILED DESCRIPTION I. Definitions

[0023] 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.

[0024] 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-.

[0025] 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-C10 means 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 an uncyclized 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.

[0026] 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.

[0027] 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 mayoptionally 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.

[0028] 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 a heteroalkene. 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.

[0029] 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.

[0030] 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 whereinat 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.

[0031] 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 cycloalkenyl ring 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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” refersto 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 6 members, 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.

[0036] 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 thesame 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.

[0037] The symbol “ ” denotes the point of attachment of a chemical moiety to theremainder of a molecule or chemical formula.

[0038] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0039] 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: . [stituted (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-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0041] 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.

[0042] 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., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0043] 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 unsubstitutedheteroaryl. 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.

[0044] 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 a floating 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.

[0045] 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-formingsubstituents 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.

[0046] 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 are independently -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.

[0047] In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0048] 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, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), 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-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8membered 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-C10 aryl, 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: (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, -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-C6 cycloalkyl, 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 (ii) 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- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered 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, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), 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 (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, -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, orC5-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-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10aryl, 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-C20alkylene, 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-C8 cycloalkylene, 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-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0053] In some embodiments, 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-C7cycloalkyl, 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-C10aryl, 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-C10 arylene, 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.

[0054] 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 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).

[0055] 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.

[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 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 substituted with a plurality of size-limited substituent groups, each size-limited 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 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.

[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 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.

[0059] 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.

[0060] 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 groups denoted 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 one or more first substituent groups denoted by RL1.1, L2may be substituted with one or more first substituent 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 further substituted with one or more second substituent groups (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, respectively). Thus, each first substituent group, which may alternatively be represented 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.

[0061] 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 further substituted with one or more third substituent groups (e.g., R1.3, R2.3, R3.3, R4.3, R5.3… R100.3;R1A.3, R2A.3, R3A.3, R4A.3, R5A.3… R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3… RL100.3; respectively). Thus, each second substituent group, which may alternatively be 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 first substituent 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.

[0062] 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 with 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:.

[0063] 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, -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)NHNH2, ^NHC(O)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 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1is independently –F, -Cl, -Br, or –I.

[0064] 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, -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, -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.

[0065] 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, -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.

[0066] 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.

[0067] 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, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.2-substituted or unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), RLWW.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), 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 6 membered). 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, -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.

[0068] 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, -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, -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.

[0069] 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, -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.

[0070] 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, -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 ofthe subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3 areas defined above.

[0071] 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-, -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-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), 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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).

[0082] 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 that subsequent 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 todisulfides, 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.

[0083] 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.

[0084] “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.

[0085] 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 unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0086] 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 substitutedwith 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.

[0087] 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.

[0088] 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 such compounds 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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 otherheterologous location, e.g., in a genome of a recombinant organism, such that it is notassociated 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.

[0094] “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).

[0095] 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.

[0096] 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 ofdegeneration 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.

[0097] 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 used herein, 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 theamount 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).

[0098] “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).

[0099] “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.

[0100] 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.

[0101] 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 derivativefrom 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.

[0102] 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.

[0103] 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.

[0104] 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 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 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.

[0105] 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.

[0106] 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.).

[0107] 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.

[0108] “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.

[0109] “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, cellular compartment, 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 celllung carcinoma, squamous cell lung carcinoma, rhabdomyosarcoma, endometrium carcinoma, thyroid carcinoma, bladder carcinoma, ovarian carcinoma, or myelodysplastic syndrome). In embodiments, the disease is Costello syndrome. In embodiments, the disease is a disease as described in Yin, G. et al. Signal Transduct Target Ther.8(1): 212 (2023), which is herein incorporated by reference in its entirety for all purposes.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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 a compound 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.

[0114] 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, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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 cardiofaciocutaneous syndrome. 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.

[0120] 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).

[0121] 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.

[0122] 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, or other 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, radiolabeledammonia, 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.

[0123] 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 atomic numbers 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.

[0124] “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.

[0125] 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.

[0126] 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.

[0127] 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 and transmucosal (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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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 orRASopathy) 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.

[0132] 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.

[0133] 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.

[0134] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0135] 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.

[0136] 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 havethe 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.

[0137] 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.

[0138] 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 a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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 ty pically 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.

[0143] 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.

[0144] The term “Switch II” as used herein refers to a protein domain of a GTPase protein (e.g., Ras, Rho, or Rab) formed by residues corresponding to residues 60-76 of K-Ras (e.g., K-Ras Switch II refers to residues 60-76 of K-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, Rho, or Rab), 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.

[0145] 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 a Rho protein. In embodiments, the Switch II GTPase protein is a Rab protein. In embodiments, the Switch II GTPase protein is DIRAS 1 (e.g., UniProt 095057). In embodiments, the Switch II GTPase protein is DIRAS2 (e.g., UniProt L8ECH1). In embodiments, the Switch II GTPase protein is DIRAS3 (e.g., UniProt 095661). In embodiments, the Switch II GTPase protein is ERAS (e.g., UniProt Q7Z444). In embodiments, the Switch II GTPase protein is HRAS (e.g., UniProt P01112). In embodiments, the Switch II GTPase protein is KRAS (e.g., UniProt P01116). In embodiments, the Switch II GTPase protein is MRAS (e.g., UniProt 014807). In embodiments, the Switch II GTPase protein is NKIRAS1 (e.g., UniProt G5E9P3). In embodiments, the Switch II GTPase protein is NKIRAS2 (e.g., UniProt Q9NYR9). In embodiments, the Switch II GTPase protein is NRAS (e.g., UniProt P01111). In embodiments, the Switch II GTPase protein is RALA (e.g., UniProt Pl 1233). In embodiments, the Switch II GTPase protein is RALB (e.g., UniProt Pl 1234). In embodiments, the Switch II GTPase protein is RAP1A (e.g., UniProt P62834). In embodiments, the Switch II GTPase protein is RAP1B (e.g., UniProt P61224). In embodiments, the Switch II GTPase protein is RAP2A (e.g., UniProt P10114). In embodiments, the Switch II GTPase protein is RAP2B (e.g., UniProt P61225). In embodiments, the Switch II GTPase protein is RAP2C (e.g., UniProt Q9Y3L5). In embodiments, the Switch II GTPase protein is RASD1 (e.g., UniProt Q9Y272). In embodiments, the Switch II GTPase protein is RASD2 (e.g., UniProt Q96D21). In embodiments, the Switch II GTPase protein is RASL10A (e.g., UniProt Q92737). Inembodiments, the Switch II GTPase protein is RASL10B (e.g., UniProt Q96S79). In embodiments, the Switch II GTPase protein is RASL11A (e.g., UniProt Q6T310). In embodiments, the Switch II GTPase protein is RASL11B (e.g., UniProt Q9BPW5). In embodiments, the Switch II GTPase protein is RASL12 (e g., UniProt Q9NYN1). In embodiments, the Switch II GTPase protein is RERG (e.g., UniProt Q96A58). In embodiments, the Switch II GTPase protein is RERGL (e.g., UniProt Q9H628). In embodiments, the Switch II GTPase protein is RRAD (e.g., UniProt P55042). In embodiments, the Switch II GTPase protein is RRAS (e.g., UniProt Pl 0301 ). In embodiments, the Switch II GTPase protein is RRAS2 (e.g., UniProt P62070). In embodiments, the Switch II GTPase protein is RHEB (e.g., UniProt QI 5382). In embodiments, the Switch II GTPase protein is RHEBL1 (e.g., UniProt Q8TAI7). In embodiments, the Switch II GTPase protein is GEM (e.g., UniProt P55040). In embodiments, the Switch II GTPase protein is REMI (e.g., UniProt 035929). In embodiments, the Switch II GTPase protein is REM2 (e.g., UniProt Q8IYK8). In embodiments, the Switch II GTPase protein is RIT1 (e.g., UniProt Q92963). In embodiments, the Switch II GTPase protein is RIT2 (e.g., UniProt Q99578). In embodiments, the Switch II GTPase protein is RHOA (e.g., UniProt P61586). In embodiments, the Switch II GTPase protein is RHOB (e.g., UniProt P62745). In embodiments, the Switch II GTPase protein is RHOBTB1 (e.g., UniProt 094844). In embodiments, the Switch II GTPase protein is RHOBTB2 (e.g., UniProt Q9BYZ6). In embodiments, the Switch II GTPase protein is RHOBTB3 (e.g., UniProt 094955). In embodiments, the Switch II GTPase protein is RHOC (e.g., UniProt P08134). In embodiments, the Switch II GTPase protein is RHOD (e.g., UniProt 000212). In embodiments, the Switch II GTPase protein is RHOF (e.g., UniProt Q9HBH0). In embodiments, the Switch II GTPase protein is RHOG (e g., UniProt P84095). In embodiments, the Switch II GTPase protein is RHOH (e.g., UniProt Q15669). In embodiments, the Switch II GTPase protein is RHOJ (e.g., UniProt Q9H4E5). In embodiments, the Switch II GTPase protein is RHOQ (e.g., UniProt Pl 7081 ). In embodiments, the Switch II GTPase protein is RHOU (e.g., UniProt Q7L0Q8). In embodiments, the Switch II GTPase protein is RHOV (e.g., UniProt Q96L33). In embodiments, the Switch II GTPase protein is RND1 (e.g., UniProt Q92730). In embodiments, the Switch II GTPase protein is RND2 (e.g., UniProt P52198). In embodiments, the Switch II GTPase protein is RND3 (e.g., UniProt P61587). Inembodiments, the Switch II GTPase protein is RAC1 (e.g., UniProt P63000). In embodiments, the Switch II GTPase protein is RAC2 (e.g., UniProt P 15153). In embodiments, the Switch II GTPase protein is RAC3 (e.g., UniProt P60763). In embodiments, the Switch II GTPase protein is CDC42 (e.g., UniProt P60953). In embodiments, the Switch II GTPase protein is RABI A (e.g., UniProt P62820). In embodiments, the Switch II GTPase protein is RAB1B (e.g., UniProt Q9H0U4). In embodiments, the Switch II GTPase protein is RAB2 (e.g., UniProt P61019). In embodiments, the Switch II GTPase protein is RAB3A (e.g., UniProt P20336). In embodiments, the Switch II GTPase protein is RAB3B (e.g., UniProt P20337). In embodiments, the Switch II GTPase protein is RAB3C (e.g., UniProt Q96E17). In embodiments, the Switch II GTPase protein is RAB3D (e.g., UniProt 095716). In embodiments, the Switch II GTPase protein is RAB4A (e.g., UniProt P20338). In embodiments, the Switch II GTPase protein is RAB4B (e.g., UniProt P61018). In embodiments, the Switch II GTPase protein is RAB5A (e.g., UniProt P20339). In embodiments, the Switch II GTPase protein is RAB5B (e.g., UniProt P61020). In embodiments, the Switch II GTPase protein is RAB5C (e.g., UniProt P51148). In embodiments, the Switch II GTPase protein is RAB6A (e.g., UniProt P20340). In embodiments, the Switch II GTPase protein is RAB6B (e.g., UniProt Q9NRW1). In embodiments, the Switch II GTPase protein is RAB6C (e.g., UniProt Q9H0N0). In embodiments, the Switch II GTPase protein is RAB7A (e.g., UniProt P51149). In embodiments, the Switch II GTPase protein is RAB7B (e.g., UniProt Q96AH8). In embodiments, the Switch II GTPase protein is RAB7U1 (e.g., UniProt 014966). In embodiments, the Switch II GTPase protein is RAB8A (e.g., UniProt P61006). In embodiments, the Switch II GTPase protein is RAB8B (e.g., UniProt Q92930). In embodiments, the Switch II GTPase protein is RAB9 (e.g., UniProt P51151). In embodiments, the Switch II GTPase protein is RAB9B (e.g., UniProt Q8BHH2). In embodiments, the Switch II GTPase protein is RABL2A (e.g., UniProt Q9UBK7). In embodiments, the Switch II GTPase protein is RABL2B (e.g., UniProt Q9UNT1). In embodiments, the Switch II GTPase protein is RABL4 (e.g., UniProt Q9BW83). In embodiments, the Switch II GTPase protein is RAB10 (e.g., UniProt P61026). In embodiments, the Switch II GTPase protein is RABI 1A (e.g., UniProt P62491). In embodiments, the Switch II GTPase protein is RABI IB (e.g., UniProt Q15907). In embodiments, the Switch II GTPase protein is RAB12 (e.g., UniProt Q6IQ22). Inembodiments, the Switch II GTPase protein is RABIS (e.g., UniProt P51153). In embodiments, the Switch II GTPase protein is RAB14 (e.g., UniProt P61106). In embodiments, the Switch II GTPase protein is RAB15 (e.g., UniProt P59190). In embodiments, the Switch II GTPase protein is RAB17 (e.g., UniProt Q9H0T7). In embodiments, the Switch II GTPase protein is RABI 8 (e.g., UniProt Q9NP72). In embodiments, the Switch II GTPase protein is RAB19 (e.g., UniProt A4D1S5). In embodiments, the Switch II GTPase protein is RAB20 (e.g., UniProt Q9NX57). In embodiments, the Switch II GTPase protein is RAB21 (e.g., UniProt Q9UL25). In embodiments, the Switch II GTPase protein is RAB22A (e.g., UniProt Q9UL26). In embodiments, the Switch II GTPase protein is RAB23 (e.g., UniProt Q9ULC3). In embodiments, the Switch II GTPase protein is RAB24 (e.g., UniProt Q969Q5). In embodiments, the Switch II GTPase protein is RAB25 (e.g., UniProt P57735). In embodiments, the Switch II GTPase protein is RAB26 (e.g., UniProt Q9ULW5). In embodiments, the Switch II GTPase protein is RAB27A (e.g., UniProt P51159). In embodiments, the Switch II GTPase protein is RAB27B (e.g., UniProt 000194). In embodiments, the Switch II GTPase protein is RAB28 (e.g., UniProt P51157). In embodiments, the Switch II GTPase protein is RAB29 (e.g., UniProt 014966). In embodiments, the Switch II GTPase protein is RAB30 (e.g., UniProt Q15771). In embodiments, the Switch II GTPase protein is RAB31 (e.g., UniProt Q13636). In embodiments, the Switch II GTPase protein is RAB32 (e.g., UniProt Q13637). In embodiments, the Switch II GTPase protein is RAB33A (e.g., UniProt Q14088). In embodiments, the Switch II GTPase protein is RAB33B (e.g., UniProt Q9H082). In embodiments, the Switch II GTPase protein is RAB34 (e.g., UniProt Q9BZG1). In embodiments, the Switch II GTPase protein is RAB35 (e.g., UniProt Q15286). In embodiments, the Switch II GTPase protein is RAB36 (e.g., UniProt 095755). In embodiments, the Switch II GTPase protein is RAB37 (e.g., UniProt O96AX2). In embodiments, the Switch II GTPase protein is RAB38 (e.g., UniProt P57729). In embodiments, the Switch II GTPase protein is RAB39 (e.g., UniProt Q14964). In embodiments, the Switch II GTPase protein is RAB39B (e.g., UniProt Q96DA2). In embodiments, the Switch II GTPase protein is RAB40A (e.g., UniProt Q8WXH6). In embodiments, the Switch II GTPase protein is RAB40AL (e.g., UniProt P0C0E4). In embodiments, the Switch II GTPase protein is RAB40B (e.g., UniProt Q12829). In embodiments, the Switch II GTPase protein is RAB40C (e.g., UniProt Q96S21). Inembodiments, the Switch II GTPase protein is RAB41 (e.g., UniProt Q5JT25). In embodiments, the Switch II GTPase protein is RAB42 (e.g., UniProt Q8N4Z0).

[0146] The term “Ras” refers to one or more of the family of human Ras GTPase proteins (e g., K-Ras, H-Ras, N-Ras, DIRAS1, DIRAS2, ERAS, MRAS, NKIRAS1, NKIRAS2, RALA, RALB, RAP1A, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11 A, RASL1 IB, RASL12, REMI, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHEB, RHEBL1, RRAD, GEM, REM2, RIT1, or RIT2), including homologs, isoforms, and functional fragments thereof.

[0147] 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).

[0148] The term “RalA” refers to the GTPase family protein that in humans is encoded by the RALA gene. The term “RalA” may refer to the nucleotide sequence or protein sequence of human RalA (e.g., Entrez 5898, UniProt Pl 1233, RefSeq NP_005393.2, or RefSeq NM_005402.3). In embodiments, RalA has the following amino acid sequence:MAANKPKGQNSLALHKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKV VLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLCVFSITEMESFAATADFREQILR VKEDENVPFLLVGNKSDLEDKRQVSVEEAKNRAEQWNVNYVETSAKTRANVDKVF FDLMREIRARKMEDSKEKNGKKKRKSLAKRIRERCCIL (SEQ ID NO: 2).

[0149] The term “RaplA” refers to the GTPase family protein that in humans is encoded by the RAP1A gene. The term “RaplA” may refer to the nucleotide sequence or protein sequence of human RaplA (e.g., Entrez 5906, UniProt P62834, RefSeq NP 001010935.1,RefSeq NP 001278825.1, RefSeq NP_002875.1, RefSeq NM_001010935.2, RefSeq NM_001291896. 1, or RefSeq NM_002884.3). In embodiments. RaplA has the following amino acid sequence:MREYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDCQQCMLEIL DTAGTEQFTAMRDLYMKNGQGFALVYSITAQSTFNDLQDLREQILRVKDTEDVPMI LVGNKCDLEDERVVGKEQGQNLARQWCNCAFLESSAKSKINVNEIFYDLVRQINRK TPVEKKKPKKKSCLLL (SEQ ID NO: 3).

[0150] The term “Rheb” refers to the GTPase family protein that in humans is encoded by the RHEB gene. The term “Rheb” may refer to the nucleotide sequence or protein sequence of human Rheb (e.g., Entrez 6009, UniProt Q15382, RefSeq NP_005605.1, or RefSeq NM_005614.3). In embodiments, Rheb has the following amino acid sequence:MPQSKSRKIAILGYRSVGKSSLTIQFVEGQFVDSYDPTIENTFTKLITVNGQEYHLQLV DTAGQDEYSIFPQTYSIDINGYILVYSVTSIKSFEVIKVIHGKLLDMVGKVQIPIMLVG NKKDLHMERVISYEEGKALAESWNAAFLESSAKENQTAVDVFRRIILEAEKMDGAA SQGKSSCSVM (SEQ ID NO: 4).

[0151] The term “Rho” refers to one or more of the family of human Ras GTPase proteins (e g., RHOA, RHOB, RHOBTB1, RHOTB2, RHOTB3, RHOC, RHOD, RHOG, RHOH, RHO J, RHOQ, RHOU, RHOV, RND1, RND2, RND3, RAC1, RAC2, RAC3, or CDC42), including homologs, isoforms, and functional fragments thereof.

[0152] The term “Rael” refers to the GTPase family protein that in humans is encoded by the RAC1 gene. The term “Rael” may refer to the nucleotide sequence or protein sequence of human Rael (e.g., Entrez 5879, UniProt P63000, RefSeq NP_008839.2, RefSeq NP_061485.1, RefSeq NM_006908.4, or RefSeq NM_0f 8890.3). In embodiments, Rael has the following amino acid sequence:MQAIKCVVVGDGAVGKTCLLISYTTNAFPGEYIPTVFDNYSANVMVDGKPVNLGLW DTAGQEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRAKWYPEVRHHCPNTPIILVG TKLDLRDDKDTIEKLKEKKLTPITYPQGLAMAKEIGAVKYLECSALTQRGLKTVFDE AIRAVLCPPPVKKRKRKCLLL (SEQ ID NO: 5).

[0153] The term “RhoA” refers to the GTPase family protein that in humans is encoded by the RHOA gene. The term “RhoA” may refer to the nucleotide sequence or protein sequence of human RhoA (e.g., Entrez 387, UniProt P61586, RefSeq NP_001300870.1, RefSeqNP-001655.1, RefSeq NM 001313941.1, or RefSeq NM_001664.3). In embodiments, RhoA has the following amino acid sequence:MAAIRKKLVIVGDGACGKTCLLIVFSKDQFPEVYVPTVFENYVADIEVDGKQVELAL WDTAGQEDYDRLRPLSYPDTDVILMCFSIDSPDSLENIPEKWTPEVKHFCPNVPIILVG NKKDLRNDEHTRRELAKMKQEPVKPEEGRDMANRIGAFGYMECSAKTKDGVREVF EMATRAALQARRGKKKSGCLVL (SEQ ID NO: 6).

[0154] The term “Rab” refers to one or more of the family of human Ras GTPase proteins (e.g., RABI A, RAB IB, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB4A, RAB4B, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RAB2B, RABL4, RAB10, RABI 1 A, RAB11B, RAB12, RAB 13. RAB14, RAB15, RAB17, RAB18, RAB19, RAB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB29, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, or RAB43), including homologs, isoforms, and functional fragments thereof.

[0155] The term "Rabi A” refers to the GTPase family protein that in humans is encoded by the RAB1A gene. The term “Rabi A” may refer to the nucleotide sequence or protein sequence of human Rabi A (e.g., Entrez 5861, UniProt P62820, RefSeq NP_004152.1, RefSeq NP_056358.1, RefSeq NM_004161.4, or RefSeq NM_015543.1). In embodiments, RablA has the following amino acid sequence:MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKT IKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASEN VNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEI KKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 7).

[0156] The term “Rab5C” refers to the GTPase family protein that in humans is encoded by the RAB5C gene. The term “Rab5C” may refer to the nucleotide sequence or protein sequence of human Rab5C (e.g., Entrez 5878, UniProt P51148, RefSeq NP_001238968.1, RefSeq NP_004574.2, RefSeq NP_958842.1, RefSeq NM_001252039.1, RefSeq NM_004583.3, or RefSeq NM_201434.2). In embodiments, Rab5C has the following amino acid sequence:MAGRGGAARPNGPAAGNKICQFKLVLLGESAVGKSSLVLRFVKGQFHEYQESTIGA AFLTQTVCLDDTTVKFEIWDTAGQERYHSLAPMYYRGAQAAIVVYDITNTDTFARA KNWVKELQRQASPNIVIALAGNKADLASKRAVEFQEAQAYADDNSLLFMETSAKTA MNVNEIFMAIAKKLPKNEPQNATGAPGRNRGVDLQENNPASRSQCCSN (SEQ ID NO: 8).

[0157] In embodiments, the Switch II Binding Pocket is bound at least in part by one or more ofV7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and / or 1100 of K-Ras or equivalent residues in homologous, related (e.g., Ras GTPase family protein, Rho GTPase family protein, or Rab GTPase family protein), or mutant Ras, Rho, or Rab 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 inhibitor” 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”.

[0158] In embodiments, a Switch II Binding Pocket inhibitor 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 inhibitor 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 inhibitor or Switch II Binding Pocket binding moiety binds or contacts one amino acid selected from ammo acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts multiple Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts two Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts three Ras, Rho, or Rab GTPase family protein amino acids selected from ammo acids in a Ras, Rho, or Rab GTPase familyprotein corresponding to K-Ras residues V7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts four Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts five Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts six Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts seven Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts eight Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts nine Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts ten Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts eleven Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68,Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts twelve Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts thirteen Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, GIO, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts fourteen Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100. In embodiments, a Switch II Binding Pocket inhibitor or Switch II Binding Pocket binding moiety binds or contacts fifteen Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and 1100.

[0159] The term “tricomplex inhibitor” as used herein refers to a compound that binds to a GTPase family protein at the amino acid position equivalent to position 12 of K-Ras and cyclophilin A (CypA). In embodiments, the tricomplex inhibitor has the formula:embodiments, the tricomplex inhibitor has the formula:embodiments, the tri complex inhibitor is a compound as described in Schulze, C. J. et al. Science 381, 794-799 (2023), which is herein incorporated by reference in its entirety for all purposes. In embodiments, the tricomplex inhibitor is a compound as described in US 2021 / 0130303, which is herein incorporated by reference in its entirety for all purposes.

[0160] In embodiments, a tricomplex inhibitor binds or contacts one Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tricomplex inhibitor binds or contacts two Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tricomplex inhibitor binds or contacts three Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tricomplex inhibitor binds or contacts four Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tricomplex inhibitor binds or contacts five Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tricomplex inhibitor binds or contacts six Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tricomplex inhibitor binds or contacts seven Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59,and Y64. In embodiments, a tri complex inhibitor binds or contacts eight Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, a tri complex inhibitor binds or contacts nine Ras, Rho, or Rab GTPase family protein amino acids selected from amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues C12, G13, E31, D33, P34, 136, E37, A59, and Y64. In embodiments, amino acids in a Ras, Rho, or Rab GTPase family protein corresponding to K-Ras residues E31, D33, and / or E37 form noncovalent interactions with residues on CypA.II. Protein compositions

[0161] In an aspect is provided a Ras GTPase family protein including a cysteine residue at an ammo acid position equivalent to position 23 of RalA (SEQ ID NO: 2), position 12 of RaplA (SEQ ID NO: 3), or position 15 of Rheb (SEQ ID NO: 4); wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras.

[0162] A person having ordinary skill in the art would understand that the amino acid position equivalent to position 23 of RalA (SEQ ID NO: 2), position 12 of RaplA (SEQ ID NO: 3), or position 15 of Rheb (SEQ ID NO: 4) are all the same amino acid position.

[0163] In embodiments, the Ras GTPase family has at least 95% sequence identity to RalA (SEQ ID NO: 2). In embodiments, the cysteine residue is position 23 of RalA (SEQ ID NO: 2). In embodiments, the Ras GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 2.

[0164] In embodiments, the Ras GTPase family protein has at least 95% sequence identity to RaplA (SEQ ID NO: 3). In embodiments, the cysteine residue is at position 12 of RaplA (SEQ ID NO: 3). In embodiments, the Ras GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 3. In embodiments, the Ras GTPase family protein includes a phenylalanine at position 96 of SEQ ID NO: 3.

[0165] In embodiments, the Ras GTPase family protein has at least 95% sequence identity to Rheb (SEQ ID NO: 4). In embodiments, the cysteine residue is at position 12 of Rheb (SEQ ID NO: 4). In embodiments, the Ras GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 4.

[0166] In embodiments, the Ras GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

[0167] In embodiments, the Ras GTPase family protein is bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is covalently bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is reversibly covalently bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is irreversibly covalently bound to a Switch II Binding Pocket inhibitor (e g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is bound to a fragment of a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments).

[0168] In embodiments, the Ras GTPase family protein is bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is covalently bound to atncomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is reversibly covalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is irreversibly covalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Ras GTPase family protein is bound to a fragment of a tricomplex inhibitor (e.g., as described herein, including in embodiments).

[0169] In an aspect is provided a Rho GTPase family protein including a cysteine residue at an ammo acid position equivalent to position 12 of Rael (SEQ ID NO: 5) or position 14 of RhoA (SEQ ID NO: 6).

[0170] A person having ordinary skill in the art would understand that the amino acid position equivalent to position 12 of Rael (SEQ ID NO: 5) or position 14 of RhoA (SEQ ID NO: 6) are the same amino acid position.

[0171] In embodiments, the Rho GTPase family has at least 95% sequence identity to Rael (SEQ ID NO: 5). In embodiments, the cysteine residue is position 12 of Rael (SEQ ID NO: 5). In embodiments, the Rho GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 5. In embodiments, the Rho GTPase family proteinincludes a tyrosine at position 96 of SEQ ID NO: 5. In embodiments, the Rho GTPase family protein includes a tryptophan at position 96 of SEQ ID NO: 5. In embodiments, the Rho GTPase family protein includes a glutamine at position 100 of SEQ ID NO: 5. In embodiments, the Rho GTPase family protein includes a histidine at position 96 of SEQ ID NO: 5. In embodiments, the Rho GTPase family protein includes a serine at position 29 of SEQ ID NO: 5.

[0172] In embodiments, the Rho GTPase family protein has at least 95% sequence identity to RhoA (SEQ ID NO: 6). In embodiments, the cysteine residue is at position 14 of RhoA (SEQ ID NO: 6). In embodiments, the Rho GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 6.

[0173] In embodiments, the Rho GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 5 or SEQ ID NO: 6.

[0174] In embodiments, the Rho GTPase family protein is bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is covalently bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is reversibly covalently bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is irreversibly covalently bound to a Switch II Binding Pocket inhibitor (e g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is bound to a fragment of a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments).

[0175] In embodiments, the Rho GTPase family protein is bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is covalently bound to atncomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is reversibly covalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is irreversibly covalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rho GTPase family protein is bound to a fragment of atncomplex inhibitor (e.g., as described herein, including in embodiments).

[0176] In an aspect is provided a Rab GTPase family protein including a cysteine residue at an ammo acid position equivalent to position 20 of Rabi A (SEQ ID NO: 7) or position 30 of Rab5C (SEQ ID NO: 8).

[0177] A person having ordinary skill in the art would understand that the amino acid position equivalent to position 20 of RablA (SEQ ID NO: 7) or position 30 of Rab5C (SEQ ID NO: 8) are the same amino acid position.

[0178] In embodiments, the Rab GTPase family has at least 95% sequence identity to RablA (SEQ ID NO: 7). In embodiments, the cysteine residue is position 20 of RablA (SEQ ID NO: 7). In embodiments, the Rab GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 7. In embodiments, the Rab GTPase family protein includes a glutamine at position 108 of SEQ ID NO: 7.

[0179] In embodiments, the Rab GTPase family protein has at least 95% sequence identity to Rab5C (SEQ ID NO: 8). In embodiments, the cysteine residue is at position 30 of Rab5C (SEQ ID NO: 8). In embodiments, the Rab GTPase family protein includes at least one further amino acid mutation relative to SEQ ID NO: 8.

[0180] In embodiments, the Rab GTPase family protein includes at least one further amino acid mutation relative to RablA (SEQ ID NO: 7) or Rab5C (SEQ ID NO: 8).

[0181] In embodiments, the Rab GTPase family protein is bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is covalently bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is reversibly covalently bound to a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is irreversibly covalently bound to a Switch II Binding Pocket inhibitor (e g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is bound to a fragment of a Switch II Binding Pocket inhibitor (e.g., as described herein, including in embodiments).

[0182] In embodiments, the Rab GTPase family protein is bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is covalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is reversiblycovalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is irreversibly covalently bound to a tricomplex inhibitor (e.g., as described herein, including in embodiments). In embodiments, the Rab GTPase family protein is bound to a fragment of a tricomplex inhibitor (e.g., as described herein, including in embodiments).

[0183] In embodiments, the Switch II Binding Pocket inhibitor has the formula: RklJ-lAlAE1(I), or a pharmaceutically acceptable salt thereof.

[0184] R1is a Switch II Binding Pocket binding moiety.

[0185] L1is a bond or a divalent linker.

[0186] L2is a bond or a divalent linker.

[0187] L3is a bond or a divalent linker.

[0188] Prior to covalently bonding to the cysteine residue, E1is an electrophilic moiety capable of forming a covalent bond with the cysteine residue.

[0189] In embodiments, the GTPase family protein (e.g., the Ras GTPase family protein, the Rho GTPase family protein, or the Rab GTPase family protein) covalently bonded to a Switch II Binding Pocket inhibitor described herein is the product of a reaction between the GTPase family protein and a Switch II Binding Pocket inhibitor described herein. It will be understood that the covalently bonded GTPase family protein and the Switch II Binding Pocket inhibitor described herein are the remnants of the reactant GTPase family protein and Switch II Binding Pocket inhibitor, wherein each reactant now participates in the covalent bond between the GTPase family protein and Switch II Binding Pocket inhibitor. In embodiments of the covalently bonded GTPase family protein and Switch II Binding Pocket inhibitor described herein, the remnant of the E1or E2substituent is a linker including a covalent bond between the GTPase family protein and the remainder of the Switch II Binding Pocket inhibitor described herein. It will be understood by a person of ordinary skill in the art that when a GTPase family protein is covalently bonded to a Switch II Binding Pocket inhibitor described herein, the Switch II Binding Pocket inhibitor described herein forms a remnant of the pre-reacted Switch II Binding Pocket inhibitor wherein a bond connects the remnant of the Switch II Binding Pocket inhibitor to the remnant of the GTPase family protein (e.g., cysteine sulfur, sulfur of amino acid corresponding to G23C of human RalA(G23C)). In embodiments, the remnant of the E1or E2substituent is a linker selectedfrom a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -CH2NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) 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 (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) 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 (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C10or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). As a non-limiting example, the RalA(G23C) protein covalently bonded to a Switch II Binding Pocket inhibitor of formula (I) may have the formula: , wherein the monovalent S is the sulfur of a RalA(G23C) proteining to cysteine residue 23 of human RalA(G23C)), which is bonded to the remainder of the RalA(G23C) protein and wherein R1, L1, L2, and L3are as described herein, including in embodiments.

[0190] In an aspect is provided a GTPase family protein covalently bound to a Switch II Binding Pocket inhibitor at an amino acid position equivalent to position 12 of K-Ras; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras. The term “amino acid position equivalent to position 12 of K-Ras” as used herein refers to the position denoted “K-Ras(G12)-equivalent” in FIGS.9A-9C. In embodiments, the “amino acid position equivalent to position 12 of K-Ras” is as indicated in Table 1. In embodiments, the “amino acid position equivalent to position 12 of K-Ras” is the position denoted “G1” in Colicelli, J. Sci STKE., 2004(250): RE13, which is herein incorporated by reference in its entirety and for all purposes.

[0191] In an aspect is provided a GTPase family protein covalently bound to a tricomplex inhibitor at an ammo acid position equivalent to position 12 of K-Ras; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras. The term “amino acid position equivalent to position 12 of K-Ras” as used herein refers to the position denoted “K-Ras(G12)-equivalenf ’ in FIGS. 9A-9C. In embodiments, the “amino acid position equivalent to position 12 of K-Ras” is as indicated in Table 1. In embodiments, the “amino acid position equivalent to position 12 of K-Ras” is the position denoted “Gl” in Colicelli, J. Sci STKE., 2004(250): RE13, which is herein incorporated by reference in its entirety and for all purposes.

[0192] Table 1

[0193] In embodiments, the GTPase family protein is ERAS, RASD1, RASD2, RASL10B, RASL11B, RASL12, RHEB, RHEBL1, GEM, REM2, RHOBTB1, RHOBTB2, RHOBTB3, RHOH, RND3, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB8A, RAB8B, RABL2A, RABL2B, RAB10, RAB11A, RAB11B, RAB12, RAB I 3. RAB14, RAB15, RAB18, RAB19, RAB20, RAB22A, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB31, RAB33A, RAB33B, RAB35, RAB37, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, or RAB41.

[0194] In embodiments, the GTPase family protein is RASD2, RASL10B, RASL12, RHEB, RHEBL1, GEM, RHOBTB1, RHOBTB2, RHOBTB3, RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB8A, RAB8B, RABL2A, RABL2B, RAB10, RAB11A, RABI IB, RAB12, RAB I 3. RAB14, RAB15, RAB18, RAB19, RAB20, RAB22A, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB31, RAB33A, RAB33B, RAB35, RAB37, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, or RAB41.

[0195] In embodiments, the covalently bound GTPase family protein has a cysteine residue, a serine residue, a threonine residue, an arginine residue, a glutamine residue, an asparagine residue, a methionine residue, a glutamic acid residue, or an aspartic acid residue at the amino acid position equivalent to position 12 of K-Ras. In embodiments, the covalently bound GTPase family protein has an amino acid as indicated in Table 1 at the amino acid position equivalent to position 12 of K-Ras.

[0196] In embodiments, the GTPase family protein is Rael, and the amino acid at the position equivalent to position 12 of K-Ras is glycine. In embodiments, the GTPase family protein is Rael, and the amino acid at the position equivalent to position 12 of K-Ras is glycine 12. In embodiments, the GTPase family protein is Rael, and the amino acid at theposition equivalent to position 95 of K-Ras is lysine. In embodiments, the GTPase family protein is Rael, and the ammo acid at the position equivalent to position 95 of K-Ras is lysine 96. In embodiments, the GTPase family protein is Rael, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan. In embodiments, the GTPase family protein is Rael, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan 97. In embodiments, the GTPase family protein is Rael, and the amino acid at the position equivalent to position 99 of K-Ras is glutamic acid. In embodiments, the GTPase family protein is Rael, and the amino acid at the position equivalent to position 99 of K-Ras is glutamic acid 100.

[0197] In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 12 of K-Ras is glycine. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 12 of K-Ras is glycine 14. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 95 of K-Ras is lysine. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 95 of K-Ras is lysine 98. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan 99. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 99 of K-Ras is glutamic acid. In embodiments, the GTPase family protein is RhoA, and the amino acid at the position equivalent to position 99 of K-Ras is glutamic acid 102.

[0198] In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 12 of K-Ras is serine. In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 12 of K-Ras is serine 17. In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 95 of K-Ras is asparagine. In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 95 of K-Ras is asparagine 101. In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan. In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan 102. In embodiments, the GTPase family protein is Rab8, and the amino acidat the position equivalent to position 99 of K-Ras is asparagine. In embodiments, the GTPase family protein is Rab8, and the amino acid at the position equivalent to position 99 of K-Ras is asparagine 105.

[0199] In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 12 of K-Ras is serine. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 12 of K-Ras is serine 18. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 95 of K-Ras is lysine. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 95 of K-Ras is lysine 102. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 96 of K-Ras is tryptophan 103. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 99 of K-Ras is asparagine. In embodiments, the GTPase family protein is RablO, and the amino acid at the position equivalent to position 99 of K-Ras is asparagine 106.

[0200] In an aspect is provided a GTPase family protein covalently bound to a Switch II Binding Pocket inhibitor at an amino acid position equivalent to position 95 of K-Ras; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras. The term “amino acid position equivalent to position 95 of K-Ras” as used herein refers to the position denoted “K-Ras(H95)-equivalent” in FIGS. 9A-9C.

[0201] In an aspect is provided a GTPase family protein covalently bound to a Switch II Binding Pocket inhibitor at an amino acid position equivalent to position 96 of K-Ras; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras. The term “amino acid position equivalent to position 96 of K-Ras” as used herein refers to the position denoted “K-Ras(Y96)-equivalent” in FIGS. 9A-9C.

[0202] In an aspect is provided a GTPase family protein covalently bound to a Switch II Binding Pocket inhibitor at an amino acid position equivalent to position 99 of K-Ras; wherein the GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein the Ras GTPase family protein is notK-Ras, H-Ras, or N-Ras. The term “amino acid position equivalent to position 99 of K-Ras” as used herein refers to the position denoted “K-Ras(Y96)-equivalent” in FIGS. 9A-9C.

[0203] In embodiments, the Switch II Binding Pocket inhibitor has the formula: R1-L1-L2-L3-E2(II), or a pharmaceutically acceptable salt thereof.

[0204] R1is a Switch II Binding Pocket binding moiety.

[0205] L1is a bond or a divalent linker.

[0206] L2is a bond or a divalent linker.

[0207] L3is a bond or a divalent linker.

[0208] Prior to covalently bonding, E2is an electrophilic moiety capable of forming a covalent bond with the cysteine residue, the serine residue, the threonine residue, the arginine residue, the glutamine residue, the asparagine residue, the methionine residue, or the glutamic acid residue.

[0209] In embodiments, R1is hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci- Ce, 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0210] In embodiments, a substituted R1(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 R1is 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 R1is substituted, it is substituted with at least one substituent group. In embodiments, when R1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0211] In embodiments, R1is substituted or unsubstituted fused ring aryl or substituted or unsubstituted fused ring heteroaryl.

[0212] In embodiments, R1is hydrogen, R3-substituted substituted or unsubstituted alkyl, R3-substituted substituted or unsubstituted heteroalkyl, R3-substituted substituted or unsubstituted cy cloalkyl, R3-substituted substituted or unsubstituted heterocycloalkyl, R3- substituted substituted or unsubstituted aryl, or R3-substituted substituted or unsubstituted heteroaryl. In embodiments, R1is R3-substituted or unsubstituted aiyl or R3-substituted or unsubstituted heteroaryl. In embodiments, R1is R3-substituted substituted or unsubstituted fused ring aryl or R3-substituted substituted or unsubstituted fused ring heteroaryl.

[0213] R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B, -NR3DC(O)NR3CNR3AR3B, -NR3CC(O)NR3AR3B, -N(0)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, 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-Cs, C3-C6, C4-C6, or Cs-Cs), 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., Ce-Cio or 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0214] R3A, R3B, R3C, and R3Dare independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCb, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 orunsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3Aand R3Bsubstituents 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).

[0215] Each X3is independently -F, -Cl, -Br, or -I.

[0216] The symbol n3 is an integer from 0 to 4.

[0217] The symbols m3 and v3 are independently 1 or 2.

[0218] In embodiments, R1is R3-substituted pyridinyl, R3-substituted pyrimidinyl, R3-substituted thiophenyl, R3-substituted furanyl, R3-substituted indolyl, R3-substituted benzoxadiazolyl, R3-substituted benzodioxolyl, R3-substituted benzodioxanyl, R3-substituted thianaphthanyl, R3-substituted pyrrolopyridinyl, R3-substituted indazolyl, R3-substituted quinolinyl, R3-substituted quinoxahnyl, R3-substituted pyridopyrazinyl, R3-substituted quinazolinonyl, R3-substituted benzoisoxazolyl, R3-substituted imidazopyridinyl, R3-substituted benzofuranyl, R3-substituted benzothiophenyl, R3-substituted phenyl, R3-substituted naphthyl, R3-substituted biphenyl, R3-substituted pyrrolyl, R3-substituted pyrazolyl, R3-substituted imidazolyl, R3-substituted pyrazinyl, R3-substituted oxazolyl, R3-substituted isoxazolyl, R3-substituted thiazolyl, R3-substituted furylthienyl, R3-substituted pyridyl, R3-substituted pyrimidyl, R3-substituted benzothiazolyl, R3-substituted purinyl, R3-substituted benzimidazolyl, R3-substituted isoquinolyl, R3-substituted thiadiazolyl, R3-substituted oxadiazolyl, R3-substituted pyrrolyl, R3-substituted diazolyl, R3-substituted triazolyl, R3-substituted tetrazolyl, R3-substituted benzothiadiazolyl, R3-substituted isothiazolyl, R3-substituted pyrazolopyrimidinyl, R3-substituted pyrrolopyrimidinyl, R3-substituted benzotriazolyl, or R3-substituted quinolyl.

[0219] In embodiments, R1is unsubstituted pyridinyl, unsubstituted pyrimidinyl, unsubstituted thiophenyl, unsubstituted furanyl, unsubstituted indolyl, unsubstituted benzoxadiazolyl, unsubstituted benzodioxolyl, unsubstituted benzodioxanyl, unsubstituted thianaphthanyl, unsubstituted pyrrolopyridinyl, unsubstituted indazolyl, unsubstitutedquinolinyl, unsubstituted quinoxalinyl, unsubstituted pyridopyrazinyl, unsubstituted quinazolinonyl, unsubstituted benzoisoxazolyl, unsubstituted imidazopyridinyl, unsubstituted benzofuranyl, unsubstituted benzothiophenyl, unsubstituted phenyl, unsubstituted naphthyl, unsubstituted biphenyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, unsubstituted pyrazinyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted thiazolyl, unsubstituted furylthienyl, unsubstituted pyridyl, unsubstituted pyrimidyl, unsubstituted benzothiazolyl, unsubstituted purinyl, unsubstituted benzimidazolyl, unsubstituted isoquinolyl, unsubstituted thiadiazolyl, unsubstituted oxadiazolyl, unsubstituted pyrrolyl, unsubstituted diazolyl, unsubstituted triazolyl, unsubstituted tetrazolyl, unsubstituted benzothiadiazolyl, unsubstituted isothiazolyl, unsubstituted pyrazolopyrimidinyl, unsubstituted pyrrolopyrimidinyl, unsubstituted benzotriazolyl, or unsubstituted quinolyl.

[0220] In embodiments, R1is:described herein, including in embodiments.The symbol z3 is an integer from 0 to 7.

[0221] 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.

[0222] 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. Inembodiments, when the substituted ring formed when two R3substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted 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.

[0223] In embodiments, R3is independently oxo, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or 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 Cs- Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0224] 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 -CCI3. In embodiments, R3is independently -CBrs. In embodiments, R3is independently -CF3. In embodiments, R3is independently -CI3. In embodiments, R3is independently -CH2CI. In embodiments, R3is independently -CH2Br. In embodiments, R3is independently -CH2F. In embodiments, R3is independently -CH2I. In embodiments, R3is independently -CHC12. In embodiments, R3is independently -CHBr2. In embodiments, R3is independently -CHF2. In embodiments, R3is independently -CHI2. Inembodiments, 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 -OCCh. In embodiments, R3is independently -OCBr,. In embodiments, R3is independently -OCF3. In embodiments, R3is independently -OCI3. In embodiments, R3is independently -OCH2CI. In embodiments, R3is independently -OCH2Br. In embodiments, R3is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCh. In embodiments, R3is independently -OCHBn 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, R3is independently 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 unsubstituted 2 to 4 membered heteroalkyl. In 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.

[0225] In embodiments, a substituted R3A(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, orlower substituent group; wherein if the substituted R3Ais 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 R3Ais substituted, it is substituted with at least one substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one lower substituent group.

[0226] In embodiments, a substituted R3B(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 R3Bis 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 R3Bis substituted, it is substituted with at least one substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one lower substituent group.

[0227] In embodiments, a substituted ring formed when R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0228] In embodiments, a substituted R3C(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 R3Cis 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 R3Cis substituted, it is substituted with at least one substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one lower substituent group.

[0229] In embodiments, a substituted R3D(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 R3Dis 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 R3Dis substituted, it is substituted with at least one substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one lower substituent group.

[0230] In embodiments, R3Ais independently hydrogen. In embodiments, R3Ais independently unsubstituted C1-C4 alkyl. In embodiments, R3Ais independently unsubstituted methyl. In embodiments, R3Ais independently unsubstituted ethyl. In embodiments, R3Ais independently unsubstituted propyl. In embodiments, R3Ais independently unsubstituted n-propyl. In embodiments, R3Ais independently unsubstituted isopropyl. In embodiments, R3Ais independently unsubstituted butyl. In embodiments, R3Ais independently unsubstituted n-butyl. In embodiments, R3Ais independently unsubstituted isobutyl. In embodiments, R3Ais independently unsubstituted tert-butyl.

[0231] In embodiments, R3Bis independently hydrogen. In embodiments, R3Bis independently unsubstituted C1-C4 alkyl. In embodiments, R3Bis independently unsubstituted methyl. In embodiments, R3Bis independently unsubstituted ethyl. In embodiments, R3Bis independently unsubstituted propyl. In embodiments, R3Bisindependently unsubstituted n-propyl. In embodiments, R3Bis independently unsubstituted isopropyl. In embodiments, R3Bis independently unsubstituted butyl. In embodiments, R3Bis independently unsubstituted n-butyl. In embodiments, R3Bis independently unsubstituted isobutyl. In embodiments, R3Bis independently unsubstituted tert-butyl.

[0232] In embodiments, R3Cis independently hydrogen. In embodiments, R3Cis independently unsubstituted C1-C4 alkyl. In embodiments, R3Cis independently unsubstituted methyl. In embodiments, R3Cis independently unsubstituted ethyl. In embodiments, R3Cis independently unsubstituted propyl. In embodiments, R3Cis independently unsubstituted n-propyl. In embodiments, R3Cis independently unsubstituted isopropyl. In embodiments, R3Cis independently unsubstituted butyl. In embodiments, R3Cis independently unsubstituted n-butyl. In embodiments, R3Cis independently unsubstituted isobutyl. In embodiments, R3Cis independently unsubstituted tert-butyl.

[0233] In embodiments, R3Dis independently hydrogen. In embodiments, R3Dis independently unsubstituted C1-C4 alkyl. In embodiments, R3Dis independently unsubstituted methy l. In embodiments, R3Dis independently unsubstituted ethyl. In embodiments, R3Dis independently unsubstituted propyl. In embodiments, R3Dis independently unsubstituted n-propyl. In embodiments, R3Dis independently unsubstituted isopropyl. In embodiments, R3Dis independently unsubstituted butyl. In embodiments, R3Dis independently unsubstituted n-butyl. In embodiments, R3Dis independently unsubstituted isobutyl. In embodiments, R3Dis independently unsubstituted tert-butyl.

[0234] 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.

[0235] In embodiments, R1is

[0236] R40, R41, and R42are independently oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCb, -CHBr2, -CHF2, -CHb, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0237] The symbol z40 is an integer from 0 to 11.

[0238] The symbol z41 is an integer from 0 to 9.

[0239] The symbol z42 is an integer from 0 to 9.

[0240] In embodiments, a substituted R40(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 R40is 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 R40is substituted, it is substituted with at least one substituent group. In embodiments, when R40is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R40is substituted, it is substituted with at least one lower substituent group.

[0241] In embodiments, R40is independently halogen, -CC13, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCb, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted orunsubstituted 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., Cs-Cs, Cs-Ce, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0242] In embodiments, R40is independently oxo. In embodiments, R40is independently halogen. In embodiments, R40is independently -F. In embodiments, R40is independently -Cl. In embodiments, R40is independently -Br. In embodiments, R40is independently -I. In embodiments, R40is independently -CCI3. In embodiments, R40is independently -CBr,. In embodiments, R40is independently -CF3. In embodiments, R40is independently -CI3. In embodiments, R40is independently -CH2CI. In embodiments, R40is independently -CFhBr. In embodiments, R40is independently -CH2F. In embodiments, R40is independently -CH2I. In embodiments, R40is independently -CHCb. In embodiments, R40is independently -CHBr2. In embodiments, R40is independently -CHF2. In embodiments, R40is independently -CHI2. In embodiments, R40is independently -CN. In embodiments, R40is independently -OH. In embodiments, R40is independently -NH2. In embodiments, R40is independently -COOH. In embodiments, R40is independently -CONH2. In embodiments, R40is independently -NO2. In embodiments, R40is independently -SH. In embodiments, R40is independently -SO3H. In embodiments, R40is independently -OSO3H. In embodiments, R40is independently -SO2NH2. In embodiments, R40is independently -NHNH2. In embodiments, R40is independently -ONH2. In embodiments, R40is independently -NHC(O)NHNH2. In embodiments, R40is independently -NHC(O)NH2. In embodiments, R40is independently -NHSO2H. In embodiments, R40is independently -NHC(O)H. In embodiments, R40is independently -NHC(O)OH. In embodiments, R40is independently -NHOH. In embodiments, R40is independently -OCCI3. In embodiments, R40is independently -OCBr,. In embodiments, R40is independently -OCF3. In embodiments, R40is independently -OCI3. In embodiments, R40is independently -OCH2CI. In embodiments, R40is independently -OCH2Br. In embodiments, R40is independently -OCH2F. In embodiments, R40is independently -OCH2I. In embodiments, R40is independently -OCHCI2. In embodiments, R40is independently -OCHBr2. In embodiments, R40is independently -OCHF2. In embodiments, R40is independently -OCHI2. In embodiments, R40is independently unsubstituted C1-C4 alkyl. In embodiments, R40is independentlyunsubstituted methyl. In embodiments, R40is independently unsubstituted ethyl. In embodiments, R40is independently unsubstituted propyl. In embodiments, R40is independently unsubstituted n-propyl. In embodiments, R40is independently unsubstituted isopropyl. In embodiments, R40is independently unsubstituted butyl. In embodiments, R40is independently unsubstituted n-butyl. In embodiments, R40is independently unsubstituted isobutyl. In embodiments, R40is independently unsubstituted tert-butyl. In embodiments, R40is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R40is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R40is independently unsubstituted methoxy. In embodiments, R40is independently unsubstituted ethoxy. In embodiments, R40is independently unsubstituted propoxy. In embodiments, R40is independently unsubstituted n-propoxy. In embodiments, R40is independently unsubstituted isopropoxy. In embodiments, R40is independently unsubstituted butoxy. In embodiments, R40is independently unsubstituted n-butoxy. In embodiments, R40is independently unsubstituted isobutoxy. In embodiments, R40is independently unsubstituted tert-butoxy. In embodiments, R40is independently substituted or unsubstituted phenyl. In embodiments, R40is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R40is independently a substituted pyridyl. In embodiments, R40is independently -O-alkyl-(substituted or unsubstituted heteterocycloalkyl). In embodiments, R40is independently -O-CH2-(substituted or unsubstituted heteterocycloalkyl). In embodiments, R40is independentlyIn embodiments, R40is independentlyIn embodiments, R40is independentlyIn embodiments, R40is independentlyembodiments, R40is independentlyIn embodiments, R40is independently. In embodiments, R40is independentlyembodiments, R40is independently. In embodiments, R40is independentlyIn embodiments, R40is independently

[0243] In embodiments, z40 is 0. In embodiments, z40 is 1. In embodiments, z40 is 2. In embodiments, z40 is 3. In embodiments, z40 is 4. In embodiments, z40 is 5. In embodiments, z40 is 6. In embodiments, z40 is 7. In embodiments, z40 is 8. In embodiments, z40 is 9. In embodiments, z40 is 10. In embodiments, z40 is 11.

[0244] In embodiments, a substituted R41(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 R41is 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 R41is substituted, it is substituted with at least one substituent group. In embodiments, when R41is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R41is substituted, it is substituted with at least one lower substituent group.

[0245] In embodiments, R41is independently halogen, -CCh, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCb, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 3membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0246] In embodiments, R41is independently oxo. In embodiments, R41is independently halogen. In embodiments, R41is independently -F. In embodiments, R41is independently -Cl. In embodiments, R41is independently -Br. In embodiments, R41is independently -I. In embodiments, R41is independently -CCI3. In embodiments, R41is independently -CBn. In embodiments, R41is independently -CF3. In embodiments, R41is independently -CI3. In embodiments, R41is independently -CH2CI. In embodiments, R41is independently -CFhBr. In embodiments, R41is independently -CH2F. In embodiments, R41is independently -CH2I. In embodiments, R41is independently -CHCb. In embodiments, R41is independently -CHBr2. In embodiments, R41is independently -CHF2. In embodiments, R41is independently -CHI2. In embodiments, R41is independently -CN. In embodiments, R41is independently -OH. In embodiments, R41is independently -NH2. In embodiments, R41is independently -COOH. In embodiments, R41is independently -CONH2. In embodiments, R41is independently -NO2. In embodiments, R41is independently -SH. In embodiments, R41is independently -SO3H. In embodiments, R41is independently -OSO3H. In embodiments, R41is independently -SO2NH2. In embodiments, R41is independently -NHNH2. In embodiments, R41is independently -ONH2. In embodiments, R41is independently -NHC(O)NHNH2. In embodiments, R41is independently -NHC(O)NH2. In embodiments, R41is independently -NHSO2H. In embodiments, R41is independently -NHC(O)H. In embodiments, R41is independently -NHC(O)OH. In embodiments, R41is independently -NHOH. In embodiments, R41is independently -OCCI3. In embodiments, R41is independently -OCBr,. In embodiments, R41is independently -OCF3. In embodiments, R41is independently -OCI3. In embodiments, R41is independently -OCH2CI. In embodiments, R41is independently -OCH2Br. In embodiments, R41is independently -OCH2F. In embodiments, R41is independently -OCH2I. In embodiments, R41is independently -OCHCI2. In embodiments, R41is independently -OCHBr2. In embodiments, R41is independently -OCHF2. In embodiments, R41is independently -OCHI2. In embodiments, R41is independently unsubstituted C1-C4 alkyl. In embodiments, R41is independently unsubstituted methyl. In embodiments, R41is independently unsubstituted ethyl. In embodiments, R41isindependently unsubstituted propyl. In embodiments, R41is independently unsubstituted n- propyl. In embodiments, R41is independently unsubstituted isopropyl. In embodiments, R41is independently unsubstituted butyl. In embodiments, R41is independently unsubstituted n- butyl. In embodiments, R41is independently unsubstituted isobutyl. In embodiments, R41is independently unsubstituted tert-butyl. In embodiments, R41is independently unsubstituted C2-C4 alkynyl. In embodiments, R41is independently unsubstituted ethynyl. In embodiments, R41is independently unsubstituted propynyl. In embodiments, R41is independently unsubstituted butynyl. In embodiments, R41is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R41is independently unsubstituted methoxy. In embodiments, R41is independently unsubstituted ethoxy. In embodiments, R41is independently unsubstituted propoxy. In embodiments, R41is independently unsubstituted n-propoxy. In embodiments, R41is independently unsubstituted isopropoxy. In embodiments, R41is independently unsubstituted butoxy. In embodiments, R41is independently unsubstituted n-butoxy. In embodiments, R41is independently unsubstituted isobutoxy. In embodiments, R41is independently unsubstituted tert-butoxy.

[0247] In embodiments, z41 is 0. In embodiments, z41 is 1. In embodiments, z41 is 2. In embodiments, z41 is 3. In embodiments, z41 is 4. In embodiments, z41 is 5. In embodiments, z41 is 6. In embodiments, z41 is 7. In embodiments, z41 is 8. In embodiments, z41 is 9.

[0248] In embodiments, a substituted R42(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 R42is 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 R42is substituted, it is substituted with at least one substituent group. In embodiments, when R42is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R42is substituted, it is substituted with at least one lower substituent group.

[0249] In embodiments, R42is independently halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -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, -OCCh, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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-Ce, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0250] In embodiments, R42is independently oxo. In embodiments, R42is independently halogen. In embodiments, R42is independently -F. In embodiments, R42is independently -Cl. In embodiments, R42is independently -Br. In embodiments, R42is independently -I. In embodiments, R42is independently -CCI3. In embodiments, R42is independently -CBr3. In embodiments, R42is independently -CF3. In embodiments, R42is independently -CI3. In embodiments, R42is independently -CH2CI. In embodiments, R42is independently -QbBr. In embodiments, R42is independently -CH2F. In embodiments, R42is independently -CH2I. In embodiments, R42is independently -CHC12. In embodiments, R42is independently -CHBr2. In embodiments, R42is independently -CHF2. In embodiments, R42is independently -CHI2. In embodiments, R42is independently -CN. In embodiments, R42is independently -OH. In embodiments, R42is independently -NH2. In embodiments, R42is independently -COOH. In embodiments, R42is independently -CONH2. In embodiments, R42is independently -NO2. In embodiments, R42is independently -SH. In embodiments, R42is independently -SO3H. In embodiments, R42is independently -OSO3H. In embodiments, R42is independently -SO2NH2. In embodiments, R42is independently -NHNH2. In embodiments, R42is independently -ONH2. In embodiments, R42is independently -NHC(O)NHNH2. In embodiments, R42is independently -NHC(O)NH2. In embodiments, R42is independently -NHSO2H. In embodiments, R42is independently -NHC(O)H. In embodiments, R42is independently -NHC(O)OH. In embodiments, R42is independently -NHOH. In embodiments, R42is independently -OCCI3. In embodiments, R42is independently -OCBn. In embodiments, R42is independently -OCF3. In embodiments, R42is independently -OCI3. In embodiments, R42is independently -OCH2CI. In embodiments, R42is independently -OCH2Br. In embodiments, R42is independently -OCH2F. In embodiments, R42is independently -OCH2I. In embodiments, R42is independently -OCHCI2.In embodiments, R42is independently -OCHBn. In embodiments, R42is independently -OCHF2. In embodiments, R42is independently -OCHI2. In embodiments, R42is independently unsubstituted C1-C4 alkyl. In embodiments, R42is independently unsubstituted methyl. In embodiments, R42is independently unsubstituted ethyl. In embodiments, R42is independently unsubstituted propyl. In embodiments, R42is independently unsubstituted n- propyl. In embodiments, R42is independently unsubstituted isopropyl. In embodiments, R42is independently unsubstituted butyl. In embodiments, R42is independently unsubstituted n- butyl. In embodiments, R42is independently unsubstituted isobutyl. In embodiments, R42is independently unsubstituted tert-butyl. In embodiments, R42is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R42is independently unsubstituted methoxy. In embodiments, R42is independently unsubstituted ethoxy. In embodiments, R42is independently unsubstituted propoxy. In embodiments, R42is independently unsubstituted n-propoxy. In embodiments, R42is independently unsubstituted isopropoxy. In embodiments, R42is independently unsubstituted butoxy. In embodiments, R42is independently unsubstituted n-butoxy. In embodiments, R42is independently unsubstituted isobutoxy. In embodiments, R42is independently unsubstituted tert-butoxy.

[0251] In embodiments, z42 is 0. In embodiments, z42 is 1. In embodiments, z42 is 2. In embodiments, z42 is 3. In embodiments, z42 is 4. In embodiments, z42 is 5. In embodiments, z42 is 42. In embodiments, z42 is 7. In embodiments, z42 is 8. In embodiments, z42 is 9.

[0252] In embodiments, R1isembodiments,5

[0253] In embodiments, R1is a monovalent form of ARS-1620. In embodiments, R1is a monovalent formembodiments, R1is. In embodiments, R1is a monovalent form of a portion of ARS-1620, wherein R1does not include the substituted piperazinyl moiety .

[0254] 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, R1510, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in Canon, et al.

[0255] 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. Inportion of MRTX-849, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in Fell, et al.

[0256] In embodiments, R1is a monovalent form of GDC-6036. In embodiments, R1is a monovalent form of a compound as described in W02020097537, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalentportion of GDC-6036, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in W02020097537.

[0257] 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. In embodiments, R1is a monovalent formIn embodiments, R1is a monovalent form of a portion of MRTX1133, wherein R1does not include the diazabicyclooctanyl moiety or equivalent for compounds described in Wang, et al.

[0258] 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 W02023004102, which is herein incorporated by reference in its entirety for all purposes. In embodiments, R1is a monovalent form ofportion of BBO-8520, wherein R1does not include ther equivalent for compounds described in W02023004102.

[0259] 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 monovalent, orm of a portion of JDQ-443, wherein R1does not include the azaspiroheptanyl moiety or equivalent for compounds described in WO2021120890.

[0260] In embodiments, R1is a monovalent form of BI-0474. In embodiments, R1is a monovalent form of a compound as described in Broker, J. et al. J. Med. Chem. 65, 14614—14629 (2022), which is herein incorporated by reference in its entirety for all purposes. Inof BI-0474, wherein R1does not include the piperazinyl moiety or equivalent for compounds described in Broker, et al.

[0261] 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. Inembodiments,embodiments, R1is a monovalent form of a portion of a compound described in WO2021118877, wherein R1does not include the acryloyl moiety or equivalent for compounds described in WO2021118877.

[0262] 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. InIn embodiments, R1is a monovalent form of a portion of a compound descnbed in WO2021120045, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in WO2021120045.

[0263] 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. Inembodiments, R1is a monovalent formembodiments, R1embodiments, R1is a monovalent form of a portion of sotorasib, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in US 10,519,146, US 11,236,091, and US 11,426,404.

[0264] 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, a monovalent form of a portion of adagrasib, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in WO 2021 / 037018.

[0265] 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. In embodiments, R1is a monovalent form of a portion of MRTX1257, wherein R1does not include the substituted piperazinyl moiety or equivalent for compounds described in US 2018 / 0072723.

[0266] In embodiments, L1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10A-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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).

[0267] In embodiments, L2is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20A-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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).

[0268] In embodiments, L3is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, -NR30C(O)O-, -OC(O)NR30-, -NR30C(O)NR30A-, -S(O)2-, -NR30S(O)2-, -S(O)2NR30-, 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 unsubstitutedheterocycloalkylene (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).

[0269] R10, R10A, R20, R20A, R30, and R30Aare independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -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).

[0270] In embodiments, a substituted L1(e.g., 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 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.

[0271] 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-, -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., 3to 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).

[0272] In embodiments, L1is a bond. In embodiments, L1is -C(O)-. In embodiments, L1is -C(O)O-. In embodiments, L1is -OC(O)-. In embodiments, L1is -O-. In embodiments, L1is -S-. In embodiments, L1is -NR10-. In embodiments, L1is -NH-. In embodiments, L1is -C(O)NR10-. In embodiments, L1is -C(O)NH-. In embodiments, L1is -NR10C(O)-. In embodiments, L1is –NHC(O)-. In embodiments, L1is -NR10C(O)O-. In embodiments, L1is -NHC(O)O-. In embodiments, L1is -OC(O)NR10-. In embodiments, L1is -OC(O)NH-. In embodiments, L1is -NR10C(O)NR10A-. In embodiments, L1is -NHC(O)NH-. In embodiments, L1is -S(O)2-. In embodiments, L1is -NR10S(O)2-. In embodiments, L1is -NHS(O)2-. In embodiments, L1is -S(O)2NR10-. In embodiments, L1is -S(O)2NH-. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted C1-C6 alkylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L1is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0273] In embodiments, L1is substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, L1is substituted or unsubstituted spirocyclic cycloalkylene or substituted or unsubstituted spirocyclic heterocycloalkylene.

[0274] In embodiments, a substituted R10(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 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.

[0275] In embodiments, R10is hydrogen. In embodiments, R10is unsubstituted C1-C4 alkyl. In embodiments, R10is unsubstituted methyl. In embodiments, R10is unsubstituted ethyl. In embodiments, R10is unsubstituted propyl. In embodiments, R10is unsubstituted n- propyl. In embodiments, R10is independently unsubstituted isopropyl. In embodiments, R10is unsubstituted butyl. In embodiments, R10is unsubstituted n-butyl. In embodiments, R10is unsubstituted isobutyl. In embodiments, R10is unsubstituted tert-butyl.

[0276] 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.

[0277] In embodiments, R10Ais hydrogen. In embodiments, R10Ais unsubstituted C1-C4 alkyl. In embodiments, R10Ais unsubstituted methyl. In embodiments, R10Ais unsubstituted ethyl. In embodiments, R10Ais unsubstituted propyl. In embodiments, R10Ais unsubstituted n-propyl. In embodiments, R10Ais independently unsubstituted isopropyl. In embodiments, R10Ais unsubstituted butyl. In embodiments, R10Ais unsubstituted n-butyl. In embodiments, R10Ais unsubstituted isobutyl. In embodiments, R10Ais unsubstituted tert-butyl.

[0278] In embodiments, a substituted L2(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substitutedarylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L2is 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 L2is substituted, it is substituted with at least one substituent group. In embodiments, when L2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L2is substituted, it is substituted with at least one lower substituent group.

[0279] In embodiments, L2is 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-, -S(O)2-, -NHS(O)2-, -S(O)2NH-, substituted or unsubstituted alkylene (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cjo or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0280] In embodiments, L2is a bond. In embodiments, L2is -C(O)-. In embodiments, L2is -C(O)O-. In embodiments, L2is -OC(O)-. In embodiments, L2is -O-. In embodiments, L2is -S-. In embodiments, L2is -NR20-. In embodiments, L2is -NH-. In embodiments, L2is -C(O)NR20-. In embodiments, L2is -C(O)NH-. In embodiments, L2is -NR2C(O)-. In embodiments, L2is -NHC(O)-. In embodiments, L2is -NR20C(O)O-. In embodiments, L2is -NHC(O)O-. In embodiments, L2is -OC(O)NR20-. In embodiments, L2is -OC(O)NH-. In embodiments, L2is -NR20C(O)NR20A-. In embodiments, L2is -NHC(O)NH-. In embodiments, L2is -S(O)2- In embodiments, L2is -NR20S(O)2-. In embodiments, L2is -NHS(O)2-. In embodiments, L2is -S(O)2NR2-. In embodiments, L2is -S(O)2NH-. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted Ci-Ce alkylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. Inembodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L2is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0281] In embodiments, L2is substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene. In embodiments, L2is substituted or unsubstituted spirocyclic cycloalkylene or substituted or unsubstituted spirocyclic heterocycloalkylene.

[0282] 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.

[0283] In embodiments, R20is hydrogen. In embodiments, R20is unsubstituted C1-C4 alkyl. In embodiments, R20is unsubstituted methyl. In embodiments, R20is unsubstituted ethyl. In embodiments, R20is unsubstituted propyl. In embodiments, R20is unsubstituted n- propyl. In embodiments, R20is unsubstituted isopropyl. In embodiments, R20is unsubstituted buty l. In embodiments, R20is unsubstituted n-butyl. In embodiments, R20is unsubstituted isobutyl. In embodiments, R20is unsubstituted tert-butyl.

[0284] In embodiments, a substituted R20A(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, orlower substituent group; wherein if the substituted R20Ais 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 R20Ais substituted, it is substituted with at least one substituent group. In embodiments, when R20Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20Ais substituted, it is substituted with at least one lower substituent group.

[0285] In embodiments, R20Ais hydrogen. In embodiments, R20Ais unsubstituted C1-C4alkyl. In embodiments, R20Ais unsubstituted methyl. In embodiments, R20Ais unsubstituted ethyl. In embodiments, R20Ais unsubstituted propyl. In embodiments, R20Ais unsubstituted n-propyl. In embodiments, R20Ais unsubstituted isopropyl. In embodiments, R20Ais unsubstituted butyl. In embodiments, R20Ais unsubstituted n-butyl. In embodiments, R20Ais unsubstituted isobutyl. In embodiments, R20Ais unsubstituted tert-butyl.

[0286] In embodiments, a substituted L3(e.g., 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 L3is 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 L3is substituted, it is substituted with at least one substituent group. In embodiments, when L3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L3is substituted, it is substituted with at least one lower substituent group.

[0287] In embodiments, L3is 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-, -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).

[0288] In embodiments, L3is a bond. In embodiments, L3is -C(O)-. In embodiments, L3is -C(O)O-. In embodiments, L3is -OC(O)-. In embodiments, L3is -O-. In embodiments, L3is -S-. In embodiments, L3is -NR30-. In embodiments, L3is -NH-. In embodiments, L3is -C(O)NR3-. In embodiments, L3is -C(O)NH-. In embodiments, L3is -NR30C(O)-. In embodiments, L3is –NHC(O)-. In embodiments, L3is -NR30C(O)O-. In embodiments, L3is -NHC(O)O-. In embodiments, L3is -OC(O)NR30-. In embodiments, L3is -OC(O)NH-. In embodiments, L3is -NR30C(O)NR30A-. In embodiments, L3is -NHC(O)NH-. In embodiments, L3is -S(O)2-. In embodiments, L3is -NR30S(O)2-. In embodiments, L3is -NHS(O)2-. In embodiments, L3is -S(O)2NR30-. In embodiments, L3is -S(O)2NH-. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted C1-C6alkylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted methylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted n-butylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted pentylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted hexylene. In embodiments, L3is substituted (e.g., oxo-substituted) or unsubstituted 2 to 6 membered heteroalkylene.

[0289] In embodiments, L3is substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, L3is substituted or unsubstituted spirocyclic cycloalkylene or substituted or unsubstituted spirocyclic heterocycloalkylene.

[0290] In embodiments, a substituted R30(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, orlower substituent group; wherein if the substituted R30is 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 R30is substituted, it is substituted with at least one substituent group. In embodiments, when R30is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R30is substituted, it is substituted with at least one lower substituent group.

[0291] In embodiments, R30is hydrogen. In embodiments, R30is unsubstituted C1-C4 alkyl. In embodiments, R30is unsubstituted methyl. In embodiments, R30is unsubstituted ethyl. In embodiments, R30is unsubstituted propyl. In embodiments, R30is unsubstituted n- propyl. In embodiments, R30is unsubstituted isopropyl. In embodiments, R30is unsubstituted buty l. In embodiments, R30is unsubstituted n-butyl. In embodiments, R30is unsubstituted isobutyl. In embodiments, R30is unsubstituted tert-butyl.

[0292] In embodiments, a substituted R30A(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 R30Ais 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 R30Ais substituted, it is substituted with at least one substituent group. In embodiments, when R30Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R30Ais substituted, it is substituted with at least one lower substituent group.

[0293] In embodiments, R30Ais hydrogen. In embodiments, R30Ais unsubstituted C1-C4 alkyl. In embodiments, R30Ais unsubstituted methyl. In embodiments, R30Ais unsubstituted ethyl. In embodiments, R30Ais unsubstituted propyl. In embodiments, R30Ais unsubstituted n-propyl. In embodiments, R30Ais unsubstituted isopropyl. In embodiments, R30Ais unsubstituted buty l. In embodiments, R30Ais unsubstituted n-butyl. In embodiments, R30Ais unsubstituted isobutyl. In embodiments, R30Ais unsubstituted tert-butyl.

[0294] In embodiments, L1, L2, or L3is independentlyor

[0295] R60is 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).

[0296] The symbol z60 is an integer from 0 to 14.

[0297] In embodiments, a substituted R60(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 R60is 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 R60is substituted, it is substituted with at least one substituent group. In embodiments, when R60is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R60is substituted, it is substituted with at least one lower substituent group.

[0298] In embodiments, R60is independently halogen, -CCI3, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCb, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0299] In embodiments, R60is independently oxo. In embodiments, R60is independently halogen. In embodiments, R60is independently -F. In embodiments, R60is independently -Cl. In embodiments, R60is independently -Br. In embodiments, R60is independently -I. In embodiments, R60is independently -CCI3. In embodiments, R60is independently -CBr,. In embodiments, R60is independently -CF3. In embodiments, R60is independently -CI3. In embodiments, R60is independently -CH2CI. In embodiments, R60is independently -CH2Br. In embodiments, R60is independently -CH2F. In embodiments, R60is independently -CH2I. In embodiments, R60is independently -CHC12. In embodiments, R60is independently -CHBr2. In embodiments, R60is independently -CHF2. In embodiments, R60is independently -CHI2. In embodiments, R60is independently -CN. In embodiments, R60is independently -OH. In embodiments, R60is independently -NH2. In embodiments, R60is independently -COOH. In embodiments, R60is independently -CONH2. In embodiments, R60is independently -NO2. In embodiments, R60is independently -SH. In embodiments, R60is independently -SO3H. In embodiments, R60is independently -OSO3H. In embodiments, R60is independently -SO2NH2. In embodiments, R60is independently -NHNH2. In embodiments, R60is independently -ONH2. In embodiments, R60is independently -NHC(O)NHNH2. In embodiments, R60is independently -NHC(O)NH2. In embodiments, R60is independently -NHSO2H. In embodiments, R60is independently -NHC(O)H. In embodiments, R60is independently -NHC(O)OH. In embodiments, R60is independently -NHOH. In embodiments, R60is independently -OCCI3. In embodiments, R60is independently -OCBr,. In embodiments, R60is independently -OCF3. In embodiments, R60is independently -OCI3. In embodiments, R60is independently -OCH2CI. In embodiments, R60is independently -OCFFBr. In embodiments, R60is independently -OCH2F. In embodiments, R60is independently -OCH2I. In embodiments, R60is independently -OCHCb. In embodiments, R60is independently -OCHBr2. In embodiments, R60is independently -OCHF2. In embodiments, R60is independently -OCHI2. In embodiments, R60is independently unsubstituted C1-C4 alkyl. In embodiments, R60is independently unsubstituted methyl. In embodiments, R60is independently unsubstituted ethyl. In embodiments, R60is independently unsubstituted propyl. In embodiments, R60is independently unsubstituted n- propyl. In embodiments, R60is independently unsubstituted isopropyl. In embodiments, R60is independently unsubstituted butyl. In embodiments, R60is independently unsubstituted n- butyl. In embodiments, R60is independently unsubstituted isobutyl. In embodiments, R60is independently unsubstituted tert-butyl. In embodiments, R60is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R60is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R60is independently unsubstituted methoxy. In embodiments, R60is independently unsubstituted ethoxy. In embodiments, R60is independently unsubstituted propoxy. In embodiments, R60is independently unsubstituted n- propoxy. In embodiments, R60is independently unsubstituted isopropoxy. In embodiments, R60is independently unsubstituted butoxy. In embodiments, R60is independently unsubstituted n-butoxy. In embodiments, R60is independently unsubstituted isobutoxy. In embodiments, R60is independently unsubstituted tert-butoxy.

[0300] In embodiments, z60 is 0. In embodiments, z60 is 1. In embodiments, z60 is 2. In embodiments, z60 is 3. In embodiments, z60 is 4. In embodiments, z60 is 5. In embodiments, z60 is 6. In embodiments, z60 is 7. In embodiments, z60 is 8. In embodiments, z60 is 9. In embodiments, z60 is 10. In embodiments, z60 is 11. In embodiments, z60 is 12. In embodiments, z60 is 13. In embodiments, z60 is 14.

[0301] In embodiments, -L1-L2-L3- isinembodiments.

[0302] In embodiments, In embodiments, -L1-L2-L3- isIn- is mbodiments.

[0303] In embodiments, -L1-L2-L3- is . In embodiments, -L1-L2-L3- isN N Inembodiments, In embodiments, -L1-L2-L3- .- is

[0305] R11, R12, R13, and R14are 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, -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-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0306] X11and X12are independently –F, -Cl, -Br, or –I.

[0307] In embodiments In embodiment .In embodiments In embodiment Inembodiments,embodiments,embodiments,embodiments,embodiments, E1isIn embodiments, E1isIn embodiments,, embodiments, E1is, In embodiments, E1isIn embodiments, E1isIn embodiments, E1is

[0308] In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the cysteine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the serine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the threonine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the arginine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the glutamine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the asparagine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the methionine residue. In embodiments, E2is an electrophilic moiety capable of forming a covalent bond with the glutamic acid residue.

[0309] In embodiments, E2is:including in embodiments.

[0310] In embodiments,embodiments,In embodiments,embodiments,embodiments,embodiments,embodiments,embodiments,embodiments, E2isIn embodiments, E2isIn embodiments,, embodiments, E2is, In embodiments, E2isIn embodiments, E2isIn embodiments, E2is

[0311] In embodiments, a substituted R11(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 R11is 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 R11is substituted, it is substituted with at least one substituent group. In embodiments, when R11is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11is substituted, it is substituted with at least one lower substituent group.

[0312] In embodiments, R11is hydrogen. In embodiments, R11is halogen. In embodiments, R11is -F. In embodiments, R11is -Cl. In embodiments, R11is -Br. In embodiments, R11is -I. In embodiments, R11is -CCh. In embodiments, R11is -CBrs. In embodiments, R11is -CF3. In embodiments, R11is -CI3. In embodiments, R11is -CH2CI. In embodiments, R11is -CEEBr. In embodiments, R11is -CH2F. In embodiments, R11is -CH2I. In embodiments, R11is -CHCI2. In embodiments, R11is -CHBr2. In embodiments, R11is -CHF2. In embodiments, R11is -CHI2. In embodiments, R11is -CN. In embodiments, R11is -OH. In embodiments, R11is -NH2. In embodiments, R11is -COOH. In embodiments, R11is -CONH2. In embodiments, R11is -NO2. In embodiments, R11is -SH. In embodiments, R11is -SO3H. In embodiments, R11is -OSO3H. In embodiments, R11is -SO2NH2. In embodiments, R11is -NHNH2. In embodiments, R11is -ONH2. In embodiments, R11is -NHC(O)NHNH2. In embodiments, R11is -NHC(O)NH2. In embodiments, R11is -NHSO2H. In embodiments, R11is -NHC(O)H. In embodiments, R11is -NHC(O)OH. In embodiments, R11is -NHOH. In embodiments, R11is -OCCI3. In embodiments, R11is -OCBr,. In embodiments, R11is -OCF3. In embodiments, R11is -OCI3. In embodiments, R11is -OCH2CI. In embodiments, R11is -OCH2BE In embodiments, R11is -OCH2F. In embodiments, R11is -OCH2I. In embodiments, R11is -OCHCb. In embodiments, R11is -OCHBn. In embodiments, R11is -OCHF2. In embodiments, R11is -OCHI2. In embodiments, R11is unsubstituted C1-C4 alkyl. In embodiments, R11is unsubstituted methyl. In embodiments, R11is unsubstituted ethyl. In embodiments, R11is unsubstituted propyl. In embodiments, R11is unsubstituted n-propyl. In embodiments, R11is unsubstituted isopropyl. In embodiments, R11is unsubstituted butyl. In embodiments, R11is unsubstituted n-butyl. In embodiments, R11is unsubstituted isobutyl. In embodiments, R11is unsubstituted tert-butyl.

[0313] In embodiments, a substituted R12(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 R12is 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 R12is substituted, it is substituted with at least one substituent group. In embodiments, when R12is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R12is substituted, it is substituted with at least one lower substituent group.

[0314] In embodiments, R12is hydrogen. In embodiments, R12is halogen. In embodiments, R12is -F. In embodiments, R12is -Cl. In embodiments, R12is -Br. In embodiments, R12is -I. In embodiments, R12is -CCh. In embodiments, R12is -CBrs. In embodiments, R12is -CF3. In embodiments, R12is -CI3. In embodiments, R12is -CH2CI. In embodiments, R12is -CFBBr. In embodiments, R12is -CH2F. In embodiments, R12is -CH2I. In embodiments, R12is -CHCb. In embodiments, R12is -CHBr2. In embodiments, R12is -CHF2. In embodiments, R12is -CHI2. In embodiments, R12is -CN. In embodiments, R12is -OH. In embodiments, R12is -NH2. In embodiments, R12is -COOH. In embodiments, R12is -CONH2. In embodiments, R12is -NO2. In embodiments, R12is -SH. In embodiments, R12is -SO3H. In embodiments, R12is -OSO3H. In embodiments, R12is -SO2NH2. In embodiments, R12is -NHNH2. In embodiments, R12is -ONH2. In embodiments, R12is -NHC(O)NHNH2. In embodiments, R12is -NHC(O)NH2. In embodiments, R12is -NHSO2H. In embodiments, R12is -NHC(O)H. In embodiments, R12is -NHC(O)OH. In embodiments, R12is -NHOH. In embodiments, R12is -OCCI3. Inembodiments, R12is -OCBn. In embodiments, R12is -OCF3. In embodiments, R12is -OCI3. In embodiments, R12is -OCH2CI. In embodiments, R12is -OCIfcBr. In embodiments, R12is -OCH2F. In embodiments, R12is -OCH2I. In embodiments, R12is -OCHCI2. In embodiments, R12is -OCHBr2. In embodiments, R12is -OCHF2. In embodiments, R12is -OCHI2. In embodiments, R12is unsubstituted C1-C4 alkyl. In embodiments, R12is unsubstituted methyl. In embodiments, R12is unsubstituted ethyl. In embodiments, R12is unsubstituted propyl. In embodiments, R12is unsubstituted n-propyl. In embodiments, R12is unsubstituted isopropyl. In embodiments, R12is unsubstituted butyl. In embodiments, R12is unsubstituted n-butyl. In embodiments, R12is unsubstituted isobutyl. In embodiments, R12is unsubstituted tert-butyl.

[0315] In embodiments, a substituted R13(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 R13is 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 R13is substituted, it is substituted with at least one substituent group. In embodiments, when R13is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R13is substituted, it is substituted with at least one lower substituent group.

[0316] In embodiments, R13is hydrogen. In embodiments, R13is halogen. In embodiments, R13is -F. In embodiments, R13is -Cl. In embodiments, R13is -Br. In embodiments, R13is -I. In embodiments, R13is -CCI3. In embodiments, R13is -CBE. In embodiments, R13is -CF3. In embodiments, R13is -CI3. In embodiments, R13is -CH2CI. In embodiments, R13is -CFhBr. In embodiments, R13is -CH2F. In embodiments, R13is -CH2I. In embodiments, R13is -CHCI2. In embodiments, R13is -CHBr2. In embodiments, R13is -CHF2. In embodiments, R13is -CHI2. In embodiments, R13is -CN. In embodiments, R13is -OH. In embodiments, R13is -NH2. In embodiments, R13is -COOH. In embodiments, R13is -CONH2. In embodiments, R13is -NO2. In embodiments, R13is -SH. In embodiments, R13is -SO3H. In embodiments, R13is -OSO3H. In embodiments, R13is -SO2NH2. In embodiments, R13is -NHNH2. In embodiments, R13is -ONH2. In embodiments, R13is -NHC(O)NHNH2. In embodiments, R13is -NHC(O)NH2. Inembodiments, R13is -NHSO2H. In embodiments, R13is -NHC(O)H. In embodiments, R13is -NHC(O)OH. In embodiments, R13is -NHOH. In embodiments, R13is -OCCh. In embodiments, R13is -OCBn. In embodiments, R13is -OCF3. In embodiments, R13is -OCI3. In embodiments, R13is -OCH2CI. In embodiments, R13is -OCH2BE In embodiments, R13is -OCH2F. In embodiments, R13is -OCH2I. In embodiments, R13is -OCHCI2. In embodiments, R13is -OCHBr2. In embodiments, R1’ is -OCHF2. In embodiments, R13is -OCHI2. In embodiments, R13is unsubstituted C1-C4 alkyl. In embodiments, R13is unsubstituted methyl. In embodiments, R13is unsubstituted ethyl. In embodiments, R13is unsubstituted propyl. In embodiments, R13is unsubstituted n-propyl. In embodiments, R13is unsubstituted isopropyl. In embodiments, R13is unsubstituted butyl. In embodiments, R13is unsubstituted n-butyl. In embodiments, R13is unsubstituted isobutyl. In embodiments, R13is unsubstituted tert-butyl.

[0317] In embodiments, a substituted R14(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 R14is 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 R14is substituted, it is substituted with at least one substituent group. In embodiments, when R14is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14is substituted, it is substituted with at least one lower substituent group.

[0318] In embodiments, R14is hydrogen. In embodiments, R14is halogen. In embodiments, R14is -F. In embodiments, R14is -Cl. In embodiments, R14is -Br. In embodiments, R14is -I. In embodiments, R14is -CCI3. In embodiments, R14is -CBE. In embodiments, R14is -CF3. In embodiments, R14is -CI3. In embodiments, R14is -CH2CI. In embodiments, R14is -CFFBr. In embodiments, R14is -CH2F. In embodiments, R14is -CH2I. In embodiments, R14is -CHCI2. In embodiments, R14is -CHBr2. In embodiments, R14is -CHF2. In embodiments, R14is -CHI2. In embodiments, R14is -CN. In embodiments, R14is -OH. In embodiments, R14is -NH2. In embodiments, R14is -COOH. In embodiments, R14is -CONH2. In embodiments, R14is -NO2. In embodiments, R14is -SH. In embodiments, R14is -SO3H. In embodiments, R14is -OSO3H. In embodiments, R14is -SO2NH2. In embodiments, R14is -NHNH2. In embodiments, R14is -ONH2. In embodiments, R14is -NHC(O)NHNH2. In embodiments, R14is -NHC(O)NE12. In embodiments, R14is -NHSO2H. In embodiments, R14is -NHC(O)H. In embodiments, R14is -NHC(O)OH. In embodiments, R14is -NHOH. In embodiments, R14is -OCCI3. In embodiments, R14is -OCBn. In embodiments, R14is -OCF3. In embodiments, R14is -OCI3. In embodiments, R14is -OCH2CI. In embodiments, R14is -OCFEBr. In embodiments, R14is -OCH2F. In embodiments, R14is -OCH2I. In embodiments, R14is -OCHCI2. In embodiments, R14is -OCHBr2. In embodiments, R14is -OCHF2. In embodiments, R14is -OCHI2. In embodiments, R14is unsubstituted C1-C4 alkyl. In embodiments, R14is unsubstituted methyl. In embodiments, R14is unsubstituted ethyl. In embodiments, R14is unsubstituted propyl. In embodiments, R14is unsubstituted n-propyl. In embodiments, R14is unsubstituted isopropyl. In embodiments, R14is unsubstituted butyl. In embodiments, R14is unsubstituted n-butyl. In embodiments, R14is unsubstituted isobutyl. In embodiments, R14is unsubstituted tert-butyl.

[0319] In embodiments, E2includes a 0-lactone. In embodiments, E2includes a 0-lactone.In embodiments, E2is:

[0320] Ring A is a cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) or heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).

[0321] L4is a bond or substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).

[0322] X is O or S.

[0323] Y is O, S, or NR9.

[0324] R4is 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); two R4substituents 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).

[0325] The symbol z4 is an integer from 0 to 10.

[0326] R5, R6, and R7are 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 orunsubstituted 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).

[0327] R8and R9are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -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).

[0328] In embodiments In embodiment InInInembodiments .

[0329] In embodiments, Ring A is a C3-C8cycloalkyl. In embodiments, Ring A is a cycloalkyl. In embodiments, Ring A is a cyclobutyl. In embodiments, Ring A is a cyclopentyl. In embodiments, Ring A is a cyclohexyl. In embodiments, Ring A is a cycloheptyl. In embodiments, Ring A is a cyclooctyl. In embodiments, Ring A is a 3 to 8 membered heterocycloalkyl. In embodiments, Ring A is a 5 to 6 membered heterocycloalkyl. In embodiments, Ring A is a piperidinyl, pyrrolidinyl, or piperazinyl. In embodiments, Ring A is a piperidinyl. In embodiments, Ring A is a pyrrolidinyl. In embodiments, Ring A is a piperazinyl.

[0330] In embodiments, E2is:are as described herein, including in embodiments. In embodiments,In embodiments,embodiments,embodiments,, . In embodiments,, In embodiments, E2is

[0331] In embodiments, a substituted L4(e.g., substituted alkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L4is 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 L4is substituted, it is substituted with at least one substituent group. In embodiments, when L4is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L4is substituted, it is substituted with at least one lower substituent group.

[0332] In embodiments, L4is a bond. In embodiments, L4is substituted or unsubstituted C1-C4 alkylene. In embodiments, L4is unsubstituted C1-C4 alkylene. In embodiments, L4is unsubstituted methylene. In embodiments, L4is unsubstituted ethylene. In embodiments, L4is unsubstituted propylene. In embodiments, L4is unsubstituted n-propylene. In embodiments, L4is unsubstituted isopropylene. In embodiments, L4is unsubstituted butylene. In embodiments, L4is unsubstituted n-butylene. In embodiments, L4is unsubstituted isobutylene. In embodiments, L4is unsubstituted tert-butylene.

[0333] 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, orlower 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.

[0334] In embodiments, a substituted ring formed when two R4substituents 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 R4substituents 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 R4substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0335] In embodiments, R4is independently halogen, -CCk, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -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, -0CCI3, -OCBr3, -OCF3, -0CI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCty, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0336] 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 -CCI3. In embodiments, R4is independently -CBr?. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2CI. In embodiments, R4is independently -CFFBr. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHCI2. In embodiments, R4is independently -CHBf2. In embodiments, 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 -OCCI3. In embodiments, R4is independently -OCBn. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2CI. In embodiments, R4is independently -OCH2Br. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCb. In embodiments, R4is independently -OCHBn. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently unsubstituted C1-C4 alkyl. 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.

[0337] 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.

[0338] 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.

[0339] In embodiments, R5is hydrogen. In embodiments, R5is halogen. In embodiments, R5is -F. In embodiments, R5is -Cl. In embodiments, R5is -Br. In embodiments, R5is -I. In embodiments, R5is -CCk. In embodiments, R5is -CBn. In embodiments, R5is -CF3. In embodiments, R5is -CI3. In embodiments, R5is -CH2CI. In embodiments, R5is -CFFBr. In embodiments, R5is -CH2F. In embodiments, R5is -CH2I. In embodiments, R5is -CHCI2. In embodiments, R5is -CHBr2. In embodiments, R5is -CHF2. In embodiments, R5is -CHI2. In embodiments, R5is -CN. In embodiments, R5is -OH. In embodiments, R5is -NH2. In embodiments, R5is -COOH. In embodiments, R5is -CONH2. In embodiments, R5is -NO2. In embodiments, R5is -SH. In embodiments, R5is -SO3H. In embodiments, R5is -OSO3H. In embodiments, R5is -SO2NH2. In embodiments, R5is -NHNH2. In embodiments, R3is -ONH2. In embodiments, R5is -NHC(O)NHNH2. In embodiments, R5is -NHC(O)NH2. Inembodiments, R5is -NHSO2H. In embodiments, R5is -NHC(O)H. In embodiments, R5is -NHC(O)OH. In embodiments, R5is -NHOH. In embodiments, R5is -OCCk. In embodiments, R5is -OCBn. In embodiments, R5is -OCF3. In embodiments, R5is -OCI3. In embodiments, R5is -OCH2CI. In embodiments, R5is -OCH2Br. In embodiments, R5is -OCH2F. In embodiments, R5is -OCH2I. In embodiments, R5is -OCHCI2. In embodiments, R5is -OCHBr2. In embodiments, R5is -OCHF2. In embodiments, R5is -OCHI2. In embodiments, R5is unsubstituted C1-C4 alkyl. In embodiments, R5is unsubstituted methyl. In embodiments, R5is unsubstituted ethyl. In embodiments, R5is unsubstituted propyl. In embodiments, R5is unsubstituted n-propyl. In embodiments, R5is unsubstituted isopropyl. In embodiments, R5is unsubstituted butyl. In embodiments, R5is unsubstituted n-butyl. In embodiments, R5is unsubstituted isobutyl. In embodiments, R5is unsubstituted tert-butyl.

[0340] 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.

[0341] In embodiments, R6is hydrogen. In embodiments, R6is halogen. In embodiments, R6is -F. In embodiments, R6is -Cl. In embodiments, R6is -Br. In embodiments, R6is -I. In embodiments, R6is -CCI3. In embodiments, R6is -CBr,. In embodiments, R6is -CF3. In embodiments, R6is -CI3. In embodiments, R6is -CH2CI. In embodiments, R6is -CFBBr. In embodiments, R6is -CH2F. In embodiments, R6is -CH2I. In embodiments, R6is -CHCI2. In embodiments, R6is -CHBr2. In embodiments, R6is -CHF2. In embodiments, R6is -CHI2. In embodiments, R6is -CN. In embodiments, R6is -OH. In embodiments, R6is -NH2. In embodiments, R6is -COOH. In embodiments, R6is -CONH2. In embodiments, R6is -NO2. In embodiments, R6is -SH. In embodiments, R6is -SO3H. In embodiments, R6is -OSO3H. In embodiments, R6is -SO2NH2. In embodiments, R6is -NHNH2. In embodiments, R6is-ONH2. In embodiments, R6is -NHC(0)NHNH2. In embodiments, R6is -NHC(O)NH2. In embodiments, R6is -NHSO2H. In embodiments, R6is -NHC(O)H. In embodiments, R6is -NHC(O)OH. In embodiments, R6is -NHOH. In embodiments, R6is -OCCI3. In embodiments, R6is -OCBn. In embodiments, R6is -OCF3. In embodiments, R6is -OCI3. In embodiments, R6is -OCH2CI. In embodiments, R6is -OCIhBr. In embodiments, R6is -OCH2F. In embodiments, R6is -OCH2I. In embodiments, R6is -OCHCh. In embodiments, R6is -OCHBr2. In embodiments, R6is -OCHF2. In embodiments, R6is -OCHI2. In embodiments, R6is unsubstituted C1-C4 alkyl. In embodiments, R6is unsubstituted methyl. In embodiments, R6is unsubstituted ethyl. In embodiments, R6is unsubstituted propyl. In embodiments, R6is unsubstituted n-propyl. In embodiments, R6is unsubstituted isopropyl. In embodiments, R6is unsubstituted butyl. In embodiments, R6is unsubstituted n-butyl. In embodiments, R6is unsubstituted isobutyl. In embodiments, R6is unsubstituted tert-butyl.

[0342] In embodiments, a substituted R7(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 R7is 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 R7is substituted, it is substituted with at least one substituent group. In embodiments, when R7is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7is substituted, it is substituted with at least one lower substituent group.

[0343] In embodiments, R7is hydrogen. In embodiments, R7is halogen. In embodiments, R7is -F. In embodiments, R7is -Cl. In embodiments, R7is -Br. In embodiments, R7is -I. In embodiments, R7is -CCI3. In embodiments, R7is -CBr,. In embodiments, R7is -CF3. In embodiments, R7is -CI3. In embodiments, R7is -CH2CI. In embodiments, R7is -CFbBr. In embodiments, R7is -CH2F. In embodiments, R7is -CH2I. In embodiments, R7is -CHCh. In embodiments, R7is -CHBr2. In embodiments, R7is -CHF2. In embodiments, R7is -CHI2. In embodiments, R7is -CN. In embodiments, R7is -OH. In embodiments, R7is -NH2. In embodiments, R7is -COOH. In embodiments, R7is -CONH2. In embodiments, R7is -NO2. In embodiments, R7is -SH. In embodiments, R7is -SO3H. In embodiments, R7is -OSO3H.In embodiments, R7is -SO2NH2. In embodiments, R7is -NHNH2. In embodiments, R7is -ONH2. In embodiments, R7is -NHC(O)NHNH2. In embodiments, R7is -NHC(O)NH2. In embodiments, R7is -NHSO2H. In embodiments, R7is -NHC(O)H. In embodiments, R7is -NHC(O)OH. In embodiments, R7is -NHOH. In embodiments, R7is -OCCI3. In embodiments, R7is -OCBn. In embodiments, R7is -OCF3. In embodiments, R7is -OCI3. In embodiments, R7is -OCH2CI. In embodiments, R7is -OCFBBr. In embodiments, R7is -OCH2F. In embodiments, R7is -OCH2I. In embodiments, R7is -OCHCh. In embodiments, R7is -OCHBr2. In embodiments, R7is -OCHF2. In embodiments, R7is -OCHI2. In embodiments, R7is unsubstituted C1-C4 alkyl. In embodiments, R7is unsubstituted methyl. In embodiments, R7is unsubstituted ethyl. In embodiments, R7is unsubstituted propyl. In embodiments, R7is unsubstituted n-propyl. In embodiments, R7is unsubstituted isopropyl. In embodiments, R7is unsubstituted butyl. In embodiments, R7is unsubstituted n-butyl. In embodiments, R7is unsubstituted isobutyl. In embodiments, R7is unsubstituted tert-butyl.

[0344] In embodiments, a substituted R8(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 R8is 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 R8is substituted, it is substituted with at least one substituent group. In embodiments, when R8is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8is substituted, it is substituted with at least one lower substituent group.

[0345] In embodiments, R8is hydrogen. In embodiments, R8is unsubstituted C1-C4 alkyl. In embodiments, R8is unsubstituted methyl. In embodiments, R8is unsubstituted ethyl. In embodiments, R8is unsubstituted propyl. In embodiments, R8is unsubstituted n-propyl. In embodiments, R8is unsubstituted isopropyl. In embodiments, R8is unsubstituted butyl. In embodiments, R8is unsubstituted n-butyl. In embodiments, R8is unsubstituted isobutyl. In embodiments, R8is unsubstituted tert-butyl.

[0346] In embodiments, a substituted R9(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 R9is 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 R9is substituted, it is substituted with at least one substituent group. In embodiments, when R9is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R9is substituted, it is substituted with at least one lower substituent group.

[0347] In embodiments, R9is hydrogen. In embodiments, R9is unsubstituted C1-C4 alkyl. In embodiments, R9is unsubstituted methyl. In embodiments, R9is unsubstituted ethyl. In embodiments, R9is unsubstituted propyl. In embodiments, R9is unsubstituted n-propyl. In embodiments, R9is unsubstituted isopropyl. In embodiments, R9is unsubstituted butyl. In embodiments, R9is unsubstituted n-butyl. In embodiments, R9is unsubstituted isobutyl. In embodiments, R9is unsubstituted tert-butyl.

[0348] In embodiments, E2is: .g., C1-C8, C1-C6, C1-C4, or C1-C2).

[0350] L5is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR50-, -C(O)NR50-, -NR50C(O)-, -NR50C(O)O-, -OC(O)NR50-, -NR50C(O)NR50A-, -S(O)2-, -NR50S(O)2-, -S(O)2NR50-, 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).

[0351] R15is hydrogen, halogen, -CX153, -CHX152, -CH2X15, -OCX153, -OCH2X15, -OCHX152, -CN, -SOn15R15D, -SOv15NR15AR15B, ^NR15CNR15AR15B, ^ONR15AR15B,^NR15DC(O)NR15CNR15AR15B, -NR15CC(O)NR15AR15B, -N(O)m15, -NR15AR15B, -C(O)R15C, -C(O)OR15C, -OC(O)R15C, -OC(O)OR15C, -C(O)NR15AR15B, -OC(O)NR15AR15B, -OR15D, -SR15D, -NR15ASO2R15D, -NR15AC(O)R15C, -NR15AC(O)OR15C, -NR15AOR15C, -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).

[0352] R15A, R15B, R15C, R15D, R50, and R50Aare independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -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 ...

Claims

WHAT IS CLAIMED IS:

1. A Ras GTPase family protein comprising a cysteine residue at an amino acid position equivalent to position 23 of RalA (SEQ ID NO: 2), position 12 of RaplA (SEQ ID NO: 3), or position 15 of Rheb (SEQ ID NO: 4); wherein the Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras.

2. The Ras GTPase family protein of claim 1, having at least 95% sequence identity to RalA (SEQ ID NO: 2).

3. The Ras GTPase family protein of claim 2, wherein the cysteine residue is position 23 of RalA (SEQ ID NO: 2).

4. The Ras GTPase family protein of claim 1, having at least 95% sequence identity to RaplA (SEQ ID NO: 3).

5. The Ras GTPase family protein of claim 4, wherein the cysteine residue is at position 12 of RaplA (SEQ ID NO: 3).

6. The Ras GTPase family protein of claim 1, having at least 95% sequence identity to Rheb (SEQ ID NO: 4).

7. The Ras GTPase family protein of claim 6, wherein the cysteine residue is at position 15 of Rheb (SEQ ID NO: 4).

8. The Ras GTPase family protein of one of claims 2 to 7, comprising at least one further amino acid mutation relative to SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

9. The Ras GTPase family protein of claim 8, comprising a phenylalanine at position 96 of SEQ ID NO: 3.

10. The Ras GTPase family protein of claim 1, bound to a Switch II Binding Pocket inhibitor.

11. The Ras GTPase family protein of claim 10, wherein the Switch II Binding Pocket inhibitor has the formula:R1-L1-L2-L3-E1(I), or a pharmaceutically acceptable salt thereof; whereinR1is a Switch II Binding Pocket binding moiety;bond or a divalent linkerL2is a bond or a divalent linker;L3is a bond or a divalent linker; and prior to covalently bonding to said cysteine residue, E1is an electrophilic moiety capable of forming a covalent bond with said cysteine residue.

12. The Ras GTPase family protein of claim 10, wherein the Switch IIBinding Pocket inhibitor has the formula:

13. A Rho GTPase family protein comprising a cysteine residue at an amino acid position equivalent to position 12 of Rael (SEQ ID NO: 5) or position 14 of RhoA (SEQ ID NO: 6).

14. The Rho GTPase family protein of claim 13, having at least 95% sequence identity to Rael (SEQ ID NO: 5).

15. The Rho GTPase family protein of claim 14, wherein the cysteine residue is position 12 of Rael (SEQ ID NO: 5).

16. The Rho GTPase family protein of claim 13, having at least 95% sequence identity to RhoA (SEQ ID NO: 6).

17. The Rho GTPase family protein of claim 16, wherein the cysteine residue is at position 14 of RhoA (SEQ ID NO: 6).

18. The Rho GTPase family protein of one of claims 14 to 17, comprising at least one further amino acid mutation relative to SEQ ID NO: 5 or SEQ ID NO: 6.

19. The Rho GTPase family protein of claim 18, comprising a tyrosine at position 96 of SEQ ID NO: 5.

20. The Rho GTPase family protein of claim 18, comprising a try ptophan at position 96 of SEQ ID NO: 5.

21. The Rho GTPase family protein of claim 18, comprising a glutamine at position 100 of SEQ ID NO: 5.

22. The Rho GTPase family protein of claim 18, comprising a histidine at position 96 of SEQ ID NO: 5.

23. The Rho GTPase family protein of claim 18, comprising a serine at position 29 of SEQ ID NO: 5.

24. The Rho GTPase family protein of claim 13, bound to a Switch II Binding Pocket inhibitor.

25. The Rho GTPase family protein of claim 24, wherein the Switch II Binding Pocket inhibitor has the formula:R1-L1-L2-L3-E1(I), or a pharmaceutically acceptable salt thereof; whereinR1is a Switch II Binding Pocket binding moiety;L1is a bond or a divalent linker;L2is a bond or a divalent linker;L3is a bond or a divalent linker; and prior to covalently bonding to said cysteine residue, E1is an electrophilic moiety capable of forming a covalent bond with said cysteine residue.

26. The Rho GTPase family protein of claim 24, wherein the Switch II Binding Pocket inhibitor has the formula:

27. A Rab GTPase family protein with a cysteine residue at an amino acid position equivalent to position 20 of RablA (SEQ ID NO: 7) or position 30 of Rab5C (SEQ ID NO: 8).

28. The Rab GTPase family protein of claim 27, having at least 95% sequence identity to RablA (SEQ ID NO: 7).

29. The Rab GTPase family protein of claim 28, wherein the cysteine residue is position 20 of RablA (SEQ ID NO: 7).

30. The Rab GTPase family protein of claim 27, having at least 95% sequence identity to Rab5C (SEQ ID NO: 8).

31. The Rab GTPase family protein of claim 30, wherein the cysteine residue is at position 30 of Rab5C (SEQ ID NO: 8).

32. The Rab GTPase family protein of one of claims 28 to 31, comprising at least one further amino acid mutation relative to SEQ ID NO: 7 or SEQ ID NO: 8.

33. The Rab GTPase family protein of claim 32, comprising a glutamine at position 108 of SEQ ID NO: 7.

34. The Rab GTPase family protein of claim 27, bound to a Switch II Binding Pocket inhibitor.

35. The Rab GTPase family protein of claim 34, wherein the Switch II Binding Pocket inhibitor has the formula:R1-L1-L2-L3-E1(I), or a pharmaceutically acceptable salt thereof; whereinR1is a Switch II Binding Pocket binding moiety;L1is a bond or a divalent linker;L2is a bond or a divalent linker;L3is a bond or a divalent linker; and prior to covalently bonding to said cysteine residue, E1is an electrophilic moiety capable of forming a covalent bond with said cysteine residue.

36. The Rab GTPase family protein of claim 34, wherein the Switch IIBinding Pocket inhibitor has the formula:

37. A method of determining a phenotype of a cell, comprising:(i) contacting a cell expressing the Ras GTPase family protein of claim 1 with a Switch II Binding Pocket inhibitor; and(ii) determining a change in phenotype of the cell relative to the absence of the Switch II Binding Pocket inhibitor.

38. A method of determining a phenotype of a cell, comprising:(i) contacting a cell expressing the Rho GTPase family protein of claim13 with a Switch II Binding Pocket inhibitor; and(ii) determining a change in the phenotype of the cell relative to the absence of the Switch II Binding Pocket inhibitor.

39. A method of determining a phenotype of a cell, comprising:(i) contacting a cell expressing the Rab GTPase family protein of claim 27 with a Switch II Binding Pocket inhibitor; and(ii) determining a change in the phenotype of the cell relative to the absence of the Switch II Binding Pocket inhibitor.

40. The method of one of claims 37 to 39, wherein step (ii) comprises transcriptomics or proteomics.

41. The method of one of claims 37 to 39, wherein the change in phenotype is a change in cellular expression, cellular proliferation, cell morphology, actine cytoskeleton arrangement, organelle trafficking, or endolysosomal trafficking.

42. The method of one of claims 37 to 39, wherein the Switch II BindingPocket inhibitor has the formula:R1-L1-L2-L3-E1(I), or a pharmaceutically acceptable salt thereof; whereinR1is a Switch II Binding Pocket binding moiety;L1is a bond or a divalent linkerL2is a bond or a divalent linker;L3is a bond or a divalent linkerprior to covalently bonding to said cysteine residue, E1is an electrophilic moiety capable of forming a covalent bond with said cysteine residue.

43. The method of claim 42, wherein R1is hydrogen, 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.

44. The method of claim 42, wherein R1is substituted or unsubstituted fused ring aryl or substituted or unsubstituted fused ring heteroaryl.

45. The method of claim 42, wherein R1is R3-substituted or unsubstituted aryl or R3-substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B, -NR3DC(O)NR3CNR3AR3B, -NR3CC(O)NR3AR3B, -N(0)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted 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;R3A, R3B, R3C, and R3Dare independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X3is independently -F, -Cl, -Br, or -I; n3 is an integer from 0 to 4; and m3 and v3 are independently 1 or 2.

46. The method of claim 42, wherein R1is R3-substituted pyridinyl, R3-substituted pyrimidinyl, R3-substituted thiophenyl, R3-substituted furanyl, R3-substituted indolyl, R3-substituted benzoxadiazolyl, R3-substituted benzodioxolyl, R3-substituted benzodioxanyl, R3-substituted thianaphthanyl, R3-substituted pyrrolopyridinyl, R3-substituted indazolyl, R3-substituted quinolinyl, R3-substituted quinoxalinyl, R3-substituted pyridopyrazinyl, R3-substituted quinazolinonyl, R3-substituted benzoisoxazolyl, R3-substituted imidazopyridinyl, R3-substituted benzofuranyl, R3-substituted benzothiophenyl, R3-substituted phenyl, R3-substituted naphthyl, R3-substituted biphenyl, R3-substituted pyrrolyl, R1-substituted pyrazolyl, R3-substituted imidazolyl, R'-substiluled pyrazinyl, R3-substituted oxazolyl, R3-substituted isoxazolyl, R3-substituted thiazolyl, R3-substituted furylthienyl, R3-substituted pyridyl, R3-substituted pyrimidyl, R3-substituted benzothiazolyl, R3-substituted purinyl, R3-substituted benzimidazolyl, R3-substituted isoquinolyl, R3-substituted thiadiazolyl, R3-substituted oxadiazolyl, R3-substituted pyrrolyl, R3-substituted diazolyl, R3-substituted triazolyl, R3-substituted tetrazolyl, R3-substituted benzothiadiazolyl, R3-substituted isothiazolyl, R3-substituted pyrazolopyrimidinyl, R3-substituted pyrrolopynmidinyl, R3-substituted benzotriazolyl, or R3-substituted quinolyl;R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B,-NR3DC(O)NR3CNR3AR3B, -NR3CC(O)NR3AR3B, -N(0)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -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; 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;R3A, R3B:R3C, and R3Dare independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCb, -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; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X3is independently -F, -Cl, -Br, or -I; n3 is an integer from 0 to 4; and m3 and v3 are independently 1 or 2.

47. The method of claim 42, wherein R1is unsubstituted pyridinyl, unsubstituted pyrimidinyl, unsubstituted thiophenyl, unsubstituted furanyl, unsubstituted indolyl, unsubstituted benzoxadiazolyl, unsubstituted benzodioxolyl, unsubstituted benzodioxanyl, unsubstituted thianaphthanyl, unsubstituted pyrrolopyridinyl, unsubstituted indazolyl, unsubstituted quinolinyl, unsubstituted quinoxalinyl, unsubstituted pyridopyrazinyl, unsubstituted quinazolinonyl, unsubstituted benzoisoxazolyl, unsubstituted imidazopyridinyl, unsubstituted benzofuranyl, unsubstituted benzothiophenyl, unsubstituted phenyl, unsubstituted naphthyl, unsubstituted biphenyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, unsubstituted pyrazinyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted thiazolyl, unsubstituted furylthienyl, unsubstituted pyridyl, unsubstituted pyrimidyl, unsubstituted benzothiazolyl, unsubstituted purinyl, unsubstituted benzimidazolyl, unsubstituted isoquinolyl, unsubstituted thiadiazolyl, unsubstituted oxadiazolyl, unsubstituted pyrrolyl, unsubstituted diazolyl, unsubstituted triazolyl, unsubstituted tetrazolyl, unsubstituted14 benzothiadiazolyl, unsubstituted isothiazolyl, unsubstituted pyrazolopyrimidinyl, unsubstituted15 pyrrol opyrimidinyl, unsubstituted benzotriazolyl, or unsubstituted quinolyl.R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3,-OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B,-NR3DC(O)NR3CNR3AR3B, -NR3CC(O)NR3AR3B, -N(0)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -0R3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, 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;R3A, R3B, R3C, and R3Dare independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH,-CONH2, -OCCI3, -OCBr3, -0CF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCb,-OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X3is independently -F, -Cl, -Br, or -I; n3 is an integer from 0 to 4; m3 and v3 are independently 1 or 2; and z3 is an integer from 0 to 7.

49. The method of claim 42, whereinL1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10A-, -S(O)2-, -NR10S(O)2-,-S(O)2NR10-, 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;L2is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20A-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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;L3is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, -NR30C(O)O-, -OC(O)NR30-, -NR30C(O)NR30A-, -S(O)2-, -NR30S(O)2-, -S(O)2NR30-, 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; andRio, R1OA, R20, R20A, R30, and R30Aare independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -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.

50. The method of claim 49, wherein L1, L2, or L3is substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

51. The method of claim 49, wherein L1, L2, or L3is substituted or unsubstituted spirocyclic cycloalkylene or substituted or unsubstituted spirocyclic heterocycloalkylene.

52. The method of claim 42, wherein E1is:R11, R12, R13, and R14are independently hydrogen, halogen, -CCI3, -CBn, -CF3,-CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -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, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cy cloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; andX11and X12are independently -F, -Cl, -Br, or -I.

53. The method of claim 42, wherein the Switch II Binding Pocket inhibitor has the formula:

54. A GTPase family protein covalently bound to a Switch II Binding Pocket inhibitor at an amino acid position equivalent to position 12 of K-Ras; wherein said GTPase family protein is a Ras GTPase family protein, a Rho GTPase family protein, or a Rab GTPase family protein; and wherein said Ras GTPase family protein is not K-Ras, H-Ras, or N-Ras.

55. The covalently bound GTPase family protein of claim 54, wherein the GTPase family protein is ERAS, RASD1, RASD2, RASL10B, RASL1 IB, RASL12, RHEB, RHEBL1, GEM, REM2, RH0BTB1, RH0BTB2, RH0BTB3, RHOH, RND3, RAB1A, RAB IB, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB8A, RAB8B, RABL2A, RABL2B, RAB10, RABI 1 A, RAB11B, RAB12, RAB 13. RAB14, RAB15, RAB18, RAB19, RAB20, RAB22A, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB31, RAB33A, RAB33B, RAB35, RAB37, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, or RAB41.

56. The covalently bound GTPase family protein of claim 54, having a cysteine residue, a serine residue, a threonine residue, an arginine residue, a glutamine residue, an asparagine residue, a methionine residue, a glutamic acid residue, or an aspartic acid residue at said amino acid position.

57. The covalently bound GTPase family protein of claim 56, wherein the Switch II Binding Pocket inhibitor has the formula:R1-L1-L2-L3-E2(II), or a pharmaceutically acceptable salt thereof; whereinR1is a Switch II Binding Pocket binding moiety;L1is a bond or a divalent linker;L2is a bond or a divalent linker;L3is a bond or a divalent linker; and prior to covalently bonding, E2is an electrophilic moiety capable of forming a covalent bond with said cysteine residue, said serine residue, said threonine residue, said arginine residue, said glutamine residue, said asparagine residue, said methionine residue, or said glutamic acid residue.

58. The covalently bound GTPase family protein of claim 57, wherein E2isR11, R12, R13, and R14are independently hydrogen, halogen, -CCI3, -CBr3, -CF3,-CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -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; andX11and X12are independently -F, -Cl, -Br, or -I.

59. The covalently bound GTPase family protein of claim 57, wherein E2comprises a P-lactone.

60. The covalently bound GTPase family protein of claim 57, wherein E2comprises a P-lactam.

61. The covalently bound GTPase family protein of claim 57, wherein E2isRing A is a cycloalkyl or heterocycloalkyl;L4is a bond or substituted or unsubstituted alkylene;X is 0 or S;Y is 0, S, or NR9;R4is independently oxo, halogen, -CCh, -CBrs, -CF3, -CI3, -CH2CI, -CEEBr, -CH2F, -CH2I, -CHCb, -CHBr2, -CHF2, -CHE, -CN, -OH, -NH2, -C00H, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -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 R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z4 is an integer from 0 to 10;R5, R6, and R7are independently hydrogen, halogen, -CCh, -CBr,. -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -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; andR8and R9are independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl.

62. The covalently bound GTPase family protein of claim 61, wherein E2is:

63. The covalently bound GTPase family protein of claim 57, wherein E2is:whereinL4is a bond or substituted or unsubstituted alkylene;L5is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR50-, -C(O)NR50-, -NR50C(O)-, -NR50C(O)O-, -OC(O)NR50-, -NR50C(O)NR50A-, -S(O)2-, -NR50S(O)2-, -S(O)2NR30-, 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;R15is hydrogen, halogen, -CX153, -CHX152, -CH2X15, -OCX153, -OCH2X15, -OCHX152, -CN, -SOni5R15D, -SOvi5NR15AR15B, -NR15CNR15AR15B, -ONR15AR15B, -NR15DC(O)NR15CNR15AR15B, -NR15CC(O)NR15AR15B, -N(0)mi5, -NR15AR15B, -C(O)R15C, -C(0)0R15C, -0C(0)R15C, -0C(0)0R15C, -C(O)NR15AR15B, -OC(O)NR15AR15B, -OR15D, -SR15D, -NR15ASO2R15D, -NR15AC(O)R15C, -NR15AC(O)OR15C, -NR15AOR15C, -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;R15A, R15B, R15C, R15D, R50, and R50Aare independently hydrogen, halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH,-NH2, -COOH, -CONH2, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; R15Aand R13Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X15is independently -Cl, -Br, -I, or -F; nl5 is an integer from 0 to 4; and ml 5 and vl5 are independently 1 or 2.

64. The covalently bound GTPase family protein of claim 57, wherein -L2-L3-E2- is:R16is hydrogen, halogen, -CX163, -CHX162, -CH2X16, -OCX163, -OCH2X16,-OCHX162, -CN, -SOni6R16D, -SOV16NR16AR16B, -NR16CNR16AR16B, -ONR16AR16B,-NR16DC(O)NR16CNR16AR16B, -NR16CC(O)NR16AR16B, -N(O)mi6, -NR16AR16B, -C(O)R16C, -C(O)OR16C, -OC(O)R16C, -OC(O)OR16C, -C(O)NR16AR16B, -OC(O)NR16AR16B, -OR16D, -SR16D, -NR16ASO2R16D-NR16AC(O)R16C, -NR16AC(O)OR16C, -NR16AOR16C, -PR16AR16B,-P(O)R16AR16B, -OP(O)OR16AOR16B, -SiR16AR16BR16C, 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;R16A, R16B. R16c, and R16Dare independently hydrogen, halogen, -CCh, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCh, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; R16Aand R16Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X16is independently -F, -Cl, -Br, or -I; nl6 is an integer from 0 to 4; and ml 6 and vl6 are independently 1 or 2.

66. The covalently bound GTPase family protein of claim 65, wherein R16is hydrogen, -CH3, -CH2CH3, -CH2CH(CH3)2, -CF3, -Si(CH3)3, -P(O)(CH3)2, -S(O)2CH3,67. A method of inhibiting a GTPase family protein in a cell, comprising contacting the cell with a Switch II Binding Pocket inhibitor; wherein the GTPase family protein is a Ras GTPase family protein, a RhoGTPase family protein, or a Rab GTPase family protein; and wherein the GTPase family protein is not K-Ras, H-Ras, or N-Ras.

68. The method of claim 67, wherein the Switch II Binding Pocket inhibitor has the formula:R1-L1-L2-L3-R2(III), or a pharmaceutically acceptable salt thereof; whereinR1is a Switch II Binding Pocket binding moiety;L1is a bond or a divalent linker;L2is a bond or a divalent linker;L3is a bond or a divalent linker; andR2is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -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, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E2; andE2is an electrophilic moiety capable of forming a covalent bond with a cysteine residue, a serine residue, a threonine residue, an arginine residue, a glutamine residue, an asparagine residue, a methionine residue, or a glutamic acid residue.

69. The method of claim 67, wherein the GTPase family protein is a Ras GTPase family protein.

70. The method of claim 69, wherein the Ras GTPase family protein is ERAS, RASD1, RASD2, RASL10B, RASL11B, RASL12, RHEB, RHEBL1, GEM, or REM2.

71. The method of claim 69, wherein the Ras GTPase family protein is DIRAS1, DIRAS2, DIRAS3, MRAS, NKIRAS1, NKIRAS2, RALA, RALB, RAP1A, RAP2A, RAP2B, RAP2C, RAL10A, RASL11A, REMI, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RRAD, REM, RIT1, or RIT2.

72. The method of one of claims 67 to 71, wherein the cell is in situ.

73. The method of one of claims 67 to 71, wherein the cell is in a nonhuman animal model.

74. The method of one of claims 67 to 71, wherein the cell is in a subject.

75. The method of claim 74, wherein the subject has cancer or aRASopathy.

76. The method of claim 75, wherein the cancer is pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer, cholangiocarcinoma, uterine endometrial cancer, neuroblastoma, malignant melanoma, leukemia, lymphoma, or salivary gland cancer.

77. The method of claim 75, wherein the RASopathy is Costello syndrome, Noonan syndrome, or neurofibromatosis.

78. The method of claim 67, wherein the GTPase family protein is a Rho GTPase family protein.

79. The method of claim 78, wherein the Rho GTPase family protein is RHOBTB1, RHOBTB2, RHOBTB3, RHOH, or RND3.

80. The method of claim 78, wherein the Rho GTPase family protein is RHO A, RHOB, RHOC, RHOD, RHOF, RHOG, RHOJ, RHOQ, RHOU, RHOV, RND1, RND2, RAC1, RAC2, RAC3, or CDC42.

81. The method of one of claims 67, 68, and 78 to 80, wherein the cell is in situ.

82. The method of one of claims 67, 68, and 78 to 80, wherein the cell is in a non-human animal model.

83. The method of one of claims 67, 68, and 78 to 80, wherein the cell is in a subject.

84. The method of claim 74, wherein the subject has cancer, a neurological disease, an inflammatory disease, a cardiovascular disease, pulmonary hypertension, systemic sclerosis, or neutrophil immunodeficiency.

85. The method of claim 84, wherein the cancer is Burkitt lymphoma, T- cell lymphoma, Kaposi’s sarcoma, urothelial carcinoma, prostate cancer, testicular cancer,gastric cell carcinoma, breast cancer, non-small cell lung cancer, squamous cell carcinoma, glioblastoma, or melanoma.

86. The method of claim 84, wherein the neurological disease is Alzheimer’s disease, Huntington’s disease, epilepsy, or Parkinson’s disease.

87. The method of claim 84, wherein the inflammatory disease is psoriasis, rheumatoid arthritis, or atherosclerosis.

88. The method of claim 84, wherein the cardiovascular disease is angina, myocardial infarction, aortic aneurysm, or cardiac hypertrophy.

89. The method of claim 67, wherein the GTPase family protein is a Rab GTPase family protein.

90. The method of claim 89, wherein the Rab GTPase family protein is RABI A, RAB IB, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB8A, RAB8B, RABL2A, RABL2B, RAB10, RAB11A, RABI IB, RAB12, RAB 13. RAB14, RAB15, RAB18, RAB19, RAB20, RAB22A, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB31, RAB33A, RAB33B, RAB35, RAB37, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, or RAB41.

91. The method of claim 89, wherein the Rab GTPase family protein is RAB4A, RAB4B, RAB7B, RAB7L1, RAB9, RAB9B, RABL4, RAB17, RAB21, RAB23, RAB28, RAB29, RAB30, RAB32, RAB34, RAB36, RAB38, RAB42, or RAB4392. The method of one of claims 67, 68, and 89 to 91, wherein the cell is in situ.

93. The method of one of claims 67, 68, and 89 to 91, wherein the cell is in a non-human animal model.

94. The method of one of claims 67, 68, and 89 to 91, wherein the cell is in a subject.

95. The method of claim 94, wherein the subject has cancer, a neurological disease, or choroideremia.

96. The method of claim 94, wherein the cancer is ovarian cancer, breast cancer, renal cancer, gastric cancer, liver cancer, non-small cell lung cancer, bladder cancer, glioblastoma, prostate cancer, pancreatic cancer, renal cell carcinoma, or oral squamous cell carcinoma.

97. The method of claim 94, wherein the neurological disease is Charcot- Marie-Tooth disease, Warburg Micro syndrome, Carpenter syndrome, Griscelli syndrome, X- linked intellectual disability, or Alzheimer’s disease.

98. The method of one of claims 70, 79, and 90, wherein R2is E2.

99. The method of one of claims 71, 80, and 91, wherein R2is hydrogen, halogen, -CCh, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHCh, -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, -OCCh, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCb, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl.

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