GTPase inhibitors and their uses

Abstract

Among other things, GTPase inhibitors and uses thereof are described herein.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 400,620, filed August 24, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (048536-743001WO_Sequence_Listing_ST26.xml, size: 13,874 bytes, and creation date: August 2, 2023) are incorporated herein by reference in their entirety.

[0003] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under K00 CA253758 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0004] KRAS mutation is one of the most common carcinogenic drivers in human cancer.Although the development of small molecule inhibitors for G12C mutation has been successful, the allele-specific inhibition of other KRAS hotspot mutations remains difficult.In particular, the present invention discloses solutions to these and other problems in the art. Summary of the Invention

[0005] In one aspect, the formula:

[0006] [ka] or a pharmaceutically acceptable salt thereof.

[0007] R 1is the switch II binding pocket binding moiety.

[0008] L 1 is a bond or a bivalent linker.

[0009] L 2 is a bond or substituted or unsubstituted alkylene.

[0010] L 3 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 30 -, -C(O)NR 30 -, -NR 30 C(O)-, -NR 30 C(O)O-, -OC(O)NR 30 -, -NR 30 C(O)NR 30 -, -S(O)2-, -NR 30 S(O)2-, -S(O)2NR 30 -, 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.

[0011] R 3 is hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -CN, -SO n3 R 3D , -SO v3 NR 3A R 3B , -NR 3C NR 3A R 3B , -ONR 3A R 3B , -NR 3C C(O)NR 3A R 3B , -N(O) m3 , -NR 3A R 3B, -C(O)R 3C , -C(O)OR 3C , -OC(O)R 3C , -OC(O)OR 3C , -C(O)NR 3A R 3B , -OC(O)NR 3A R 3B , -OR 3D , -SR 3D , -NR 3A SO2R 3D , -NR 3A C(O)R 3C , -NR 3A C(O)OR 3C , -NR 3A OR 3C , -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.

[0012] R 30 are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCHI, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0013] R 3A , R 3B , R 3C , and R 3Dare independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted; 3A and R 3B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0014] each X 3 are independently -Cl, -Br, -I, or -F. The symbol n3 is an integer of 0 to 4. The symbols m3 and v3 are independently 1 or 2.

[0015] In one aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0016] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0017] In one aspect, there is provided a method of treating a K-Ras(G12R) associated disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, there is provided a method of treating an H-Ras(G12R)-associated disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0019] In one aspect, there is provided a method of treating an N-Ras(G12R)-associated disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0020] In one aspect, a method for modulating the level of activity of a Ras protein in a cell is provided, the method comprising contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, a method of attaching a compound to an arginine residue of a protein is provided, the method comprising contacting the compound with the arginine residue, wherein the compound has the formula:

[0022] [ka] or a salt thereof. 1 , L 2 , L 3 , and R 3 is as described herein, including the embodiments. 2 is a switch II binding pocket binding moiety, a phosphatase PTP domain binding moiety, an SH2 domain binding moiety, a pseudokinase KSR domain binding moiety, or a pseudokinase STRADα domain binding moiety.

[0023] In one aspect, a method of attaching a compound to an arginine residue is provided, the method comprising contacting a compound with the arginine residue, wherein the compound has the formula:

[0024] [ka] or a salt thereof. 1 and R 3 is as described herein, including the embodiments.

[0025] R 4 is hydrogen, halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NR 4C NR 4A R 4B , -ONR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C , -OC(O)OR 4C , -C(O)NR 4A R 4B , -OC(O)NR 4A R 4B , -OR 4D , -SR 4D , -NR 4A SO2R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -NR 4A OR 4C , -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.

[0026] R 4A , R4B , R 4C , and R 4D are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 4A and R 4B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0027] each X 4 are independently -Cl, -Br, -I, or -F. The symbol n4 is an integer of 0 to 4. The symbols m4 and v4 are independently 1 or 2.

[0028] In one aspect, there is provided a Switch II GTPase protein covalently bound to a compound described herein, or a salt thereof, wherein the compound is covalently bound to an arginine residue in the Switch II GTPase protein.

[0029] In one aspect, the formula:

[0030] [ka] or a salt thereof, covalently bonded to an arginine residue. 1 , R 3 , and R 4 is as described herein, including the embodiments. 11 is hydrogen, —C(O)CH3, or a first protein moiety. 12is —OH or a second protein moiety. [Brief explanation of the drawings]

[0031] [Figure 1A] Synthesis of α,β-diketoamide 3. [Figure 1B] Scheme showing the reaction between an arginine residue and an α,β-diketoamide. [Figure 1C] Intact protein mass spectra of K-Ras(G12R)·GDP and K-Ras(G12R)·GDP·3 adducts. [Figure 2A] Time-dependent covalent modification of wild-type K-Ras and CysLight K-Ras(G12R) by compound 3 (50 μM). [Figure 2B] Reaction between K-Ras mutants and compound 3 (50 μM, 16 h). [Figure 2C] Reaction between K-Ras(G12R)·GDP and compound 3 (50 μM) at various pH values. [Figure 2D] Differential scanning fluorimetry of K-Ras(G12R)·GDP and K-Ras(G12R)·GDP·3 adducts. [Figure 3A] Crystal structure of the K-Ras(G12R)·GDP·4 adduct. The Fo-Fc omission map is shown with a gray mesh (σ = 2.0) for compound 4 and arginine 12. [Figure 3B] Scheme showing the reaction between compound 4 and the Arg12 residue. [Figure 3C] Comparison of the structures of unliganded K-Ras(G12R)·GDP (PDB:4QL3) and K-Ras(G12R)·GDP·4 adducts. [Figure 3D] Comparison of the structures of K-Ras(G12C)·GDP·MRTX849 (PDB:6UT0) and K-Ras(G12R)·GDP·4 adducts. [Figure 4A] Sos- or EDTA-mediated nucleotide exchange of K-Ras(G12R) and K-Ras(G12R)·3 adducts. [Figure 4B]Covalent modification of endogenous and exogenous K-Ras(G12R) in cell lysates. [Figure 5A] Biochemical characterization of compound 4. Differential scanning fluorimetry of K-Ras(G12R)·GDP and its adduct with compound 4. [Figure 5B] Biochemical characterization of compound 4. Reaction between K-Ras(G12R)·GDP and compound 4 (50 μM) at various pH values. [Figure 5C] Biochemical characterization of compound 4. Total protein mass analysis of K-Ras(G12R) GDP incubated with 100 μM 4 at pH 7.5 for 1 and 24 h. [Figure 6A] Cellular activity of compound 3. Immunoblot analysis of phospho-ERK signaling in TCC-PAN-2 cells treated with compound 3. [Figure 6B] Cellular activity of compound 3. Growth inhibition of BaF3 / G12R cells (±IL-3), TCC-Pan-2 cells, and A375 cells by compound 3. [Figure 7] Growth inhibition of BaF3 / G12R cells (±IL-3) by compound 4. [Figure 8] The permeability of Compound 3 was evaluated in a parallel artificial membrane permeability assay (PAMPA). Three permeability controls were included: chloramphenicol (high), diclofenac (medium), and theophylline (low). MRTX849 was included as a reference compound. [Figure 9] Direct targeting of arginine with 1,2-dicarbonyl compounds. Labeling conditions: 4 μM K-Ras Cyslight, 100 μM compound, 20 mM HEPES 7.5, 150 mM NaCl, 1 mM MgCl2. [Figure 10A] The diketone warhead is reactive with arginine. Chemical structure of ZZY-04-084. [Figure 10B] The diketone warhead is reactive with arginine. Covalent labeling of Src protein detected by mass spectrometry. [Figure 10C]The diketone warhead is reactive with arginine. Covalent labeling of Src protein detected by fluorescence. [Figure 11] Overlaid crystal structures of c-Src bound to relevant inhibitors and KSR2. The pseudokinase contains a mutation of the native lysine to an arginine. [Figure 12] Targeting the natural arginine in the VAIR motif in KSR. [Figure 13A] The compounds react selectively with the pseudokinase KSR. Chemical structures of ZZY-04-076, ZZY-04-084, ZZY-04-090, and ZZY-05-057. [Figure 13B] The compound reacts selectively with the pseudokinase KSR. Experimental conditions: approximately 10 ng / μL protein + 10 μM compound, 23° C., 1 hour. [Figure 14-1] Targeting Arg692 in KSR. [Figure 14-2] Targeting Arg692 in KSR. [Figure 15] STRADα has two arginines in the ATP pocket. The compound engages in both binary and ternary complexes of STRADα, but not LKB1. [Figure 16-1] Arg crosslinks with Cys but not Lys in the presence of 2,3-butanedione. The SH2 domain and the phosphatase active site contain an Arg-Cys dyad. Experimental conditions: 0.1 M NAc-Arg, 0.1 M 2,3-butanedione, 0.1 M additive, 0.5 M pH 8.0 Na-phosphate buffer, 23°C, 24 hours. [Figure 16-2] Arg crosslinks with Cys but not Lys in the presence of 2,3-butanedione. The SH2 domain and the phosphatase active site contain an Arg-Cys dyad. Experimental conditions: 0.1 M NAc-Arg, 0.1 M 2,3-butanedione, 0.1 M additive, 0.5 M pH 8.0 Na-phosphate buffer, 23°C, 24 hours. [Figure 17-1]Selected compounds modify the SHP2 PTP domain, which contains a ligand-binding capable arginine, in the assays tested. [Figure 17-2] Selected compounds modify the SHP2 PTP domain, which contains a ligand-binding capable arginine, in the assays tested. DETAILED DESCRIPTION OF THE INVENTION

[0032] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known to the chemical arts.

[0033] Substituents, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0034] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, linear (i.e., unbranched) or branched carbon chains (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which may include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C1-C6). 10means 1 to 10 carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. The 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, and the like, as well as homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those having one or more double 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 higher homologs and isomers. Alkoxy is an alkyl attached to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. An alkenyl contains one or more double bonds. An alkynyl contains one or more triple bonds.

[0035] The term "alkylene," by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from alkyl, exemplified by, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with 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 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from an alkene. The term "alkynylene," by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from an alkyne. In embodiments, an alkylene is fully saturated. In embodiments, an alkylene is monounsaturated. In embodiments, an alkylene is polyunsaturated. An alkenylene contains one or more double bonds. An alkynylene contains one or more triple bonds.

[0036] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, stable linear or branched chains, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (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 a non-cyclizing 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)-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. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain two, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain five, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain up to eight, 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 specified, a heteroalkyl containing at least one double bond. A heteroalkenyl can optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds.The term "heteroalkynyl," by itself or in combination with another term, means, unless otherwise specified, a heteroalkynyl containing at least one triple bond. A heteroalkynyl can optionally contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds. In embodiments, a heteroalkyl is fully saturated. In embodiments, a heteroalkyl is monounsaturated. In embodiments, a heteroalkyl is polyunsaturated.

[0037] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). 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)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule via a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —SOR′. When “heteroalkyl” is recited followed by a specific heteroalkyl group, such as —NR′R″, it is understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from a heteroalkene. The term “heteroalkynylene,” by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from a heteroalkyne. In embodiments, a heteroalkylene is fully saturated. In embodiments, a heteroalkylene is monounsaturated. In embodiments, heteroalkylene is polyunsaturated. Heteroalkenylene contains one or more double bonds. Heteroalkynylene contains one or more triple bonds.

[0038] 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, mean a divalent radical derived from a cycloalkyl and a 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.

[0039] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkyl ring, and the multiple rings being connected to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings.

[0040] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to multiple rings fused together, at least one of which is a cycloalkenyl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the cycloalkenyl ring of the multiple rings.

[0041] In embodiments, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In embodiments, the heterocycloalkyl group is fully saturated. A bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a heterocycloalkyl ring, and the rings are attached to the parent molecular moiety through any atom contained within the heterocycloalkyl ring of the multiple rings.

[0042] 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.

[0043] The term "acyl," unless otherwise specified, means -C(O)R, where R is 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.

[0044] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the aryl ring of the multiple rings. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is a heteroaromatic ring, and the multiple rings are bonded to the parent molecular moiety through any atom contained within the heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, one ring having 5 members and the other ring having 6 members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and at least one ring being a heteroaryl ring. Also, a 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and at least one ring being a heteroaryl ring. A heteroaryl group can be attached to the rest of the molecule through a carbon atom or a 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, benzoxazolyl, 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- Examples of suitable aryl and heteroaryl ring systems include 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 aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean divalent radicals derived from aryl and heteroaryl, respectively. Heteroaryl group substituents may be -O-bonded to a ring heteroatom nitrogen.

[0045] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring can be the same or different. The individual rings within a spirocyclic ring can be substituted or unsubstituted and can have different substituents than the other individual rings within a set of spirocyclic rings. The possible substituents for the individual rings within a spirocyclic ring are the possible substituents for the same ring (e.g., the substituents for a cycloalkyl ring or heterocycloalkyl ring) when not part of a spirocyclic ring. The spirocyclic ring can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group can be any of the groups listed immediately above, including having all rings of one type (e.g., all rings can be substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may optionally be different.

[0046] symbol

[0047] [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0048] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0049] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0050] [ka] It has.

[0051] The alkylarylene moiety may be substituted (e.g., by a substituent) at the alkylene portion or in the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH, -SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In embodiments, the alkylarylene is unsubstituted.

[0052] 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.

[0053] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from zero to (2m'+1), where m' is the total number of carbon atoms in such radical, and include -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR' It can be one or more of a variety of groups selected from, but not limited to, R", -NR"C(O)R', -NR'C(O)NR"R'", -NR"C(O)R', -NRC(NR'R"R'")=NR"", -NRC(NR'R")=NR'", -S(O)R', -S(O)R', -S(O)NR'R", -NRSO2R', -NR'NR"R'", -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO2, -NR'S02R", -NR'C(O)R", -NR'C(O)OR", -NR'OR". 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 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected when more than one of these groups is present, as are each R', R'', R''', and R'''' group. 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 that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0054] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups vary and include, for example, —OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′C(O)NR″R′″, —NR″C(O)R′, —NR-C(NR′R″R′″)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —NR′NR and R' is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected for each R', R'', R''', and R'''' group when more than one of these groups is present.

[0055] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be designated as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) may also be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown to be attached to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0056] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but 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 form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0057] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can form a ring 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 from 1 to 4). One of the single bonds in 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'') dwherein s and d are independently integers 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.

[0058] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0059] As used herein, a "substituent" 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, -OCH F2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, - NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 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., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCH F2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, - NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 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., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCH F2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, - NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 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., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each substituted with at least one substituent selected from the following: 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, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0060] As used herein, a "size-limited substituent" or "size-limited substituent group" refers to a group selected from all of the substituents described above for "substituent," and each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 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; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0061] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0062] In some embodiments, each substituent described in the compounds herein is substituted with at least one substituent. 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 is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0063] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 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; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 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; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0064] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 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 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section below, in a Figure, or in a Table.

[0065] 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., 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., 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).

[0066] 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, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0067] 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-limiting substituent, and when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0068] 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, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0069] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one substituent, size-limiting substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0070] In the recited claims or formula descriptions herein, each R substituent or L linker described as "substituted" (also referred to herein as an "open substitution" or "openly substituted" R substituent or L linker for an "open" R substituent or L linker), without reference to the identity of any chemical moieties that make up the "substituted" group, the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituents, as defined below.

[0071] The first substituent can be, for example, R 1 But R 1.1 and R 2 But R 2.1 and R 3 But R 3.1 and R 4 But R 4.1 and R 5 But R 5.1 and may be substituted with one or more first substituents represented by the formula: 100 But R 100.1As a further example, R 1A But R 1A.1 and R 2A But R 2A.1 and R 3A But R 3A.1 and R 4A But R 4A.1 and R 5A But R 5A.1 and may be substituted with one or more first substituents represented by the formula: 100A But R 100A.1 As a further example, L 1 But R L1.1 and L may be substituted with one or more first substituents represented by 2 But R L2.1 and L may be substituted with one or more first substituents represented by 3 But R L3.1 and L may be substituted with one or more first substituents represented by 4 But R L4.1 and L may be substituted with one or more first substituents represented by 5 But R L5.1 and may be substituted with one or more first substituents represented by the formula: 100 But R L100.1 Thus, each numbered R or L group described herein (alternatively, R WW or L WW and "WW" represents the listed superscript number of the subject R or L group) are generally referred to herein as R WW.1 or R LWW.1 Each first substituent (e.g., R 1.1 , R 2.1 , R 3.1 , R4.1 , R 5.1 ...R 100.1 ;R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ...R 100A.1 ;R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ...R L100.1 ) may be substituted with one or more second substituents (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ...R 100.2 ;R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ...R 100A.2 ;R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ...R L100.2 ) may be further substituted. Therefore, as used herein, R WW.1 Each first substituent may alternatively be represented as R WW.2 The alkyl group may be further substituted with one or more second substituents, which may alternatively be represented as:

[0072] Finally, each second substituent (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ...R 100.2 ;R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ...R 100A.2 ;R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ...R L100.2) may be one or more third substituents (e.g., R 1.3 , R 2.3 , R 3.3 , R 4.3 , R 5.3 ...R 100.3 ;R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.3 ...R 100A.3 ;R L1.3 , R L2.3 , R L3.3 , R L4.3 , R L5.3 ...R L100.3 ) may be further substituted. Therefore, as used herein, R WW.2 Each second substituent may alternatively be represented as R WW.3 Each of the first substituents may be optionally different. Each of the second substituents may be optionally different. Each of the third substituents may be optionally different.

[0073] Thus, as used herein, R WW represents an openly substituted substituent as listed in the claims or in the formula descriptions herein. "WW" represents the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the R group in question. Similarly, L WW is an open-substituted linker as described in the claims or formula descriptions herein. Additionally, "WW" represents the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject L group. As noted above, in embodiments, each R WW may be unsubstituted, and is referred to herein as R WW.1 and each first substituent R WW.1 may be unsubstituted, and is referred to herein as R WW.2 Each of the groups may be independently substituted with one or more second substituents, referred to herein as R WW.3Similarly, each L may be independently substituted with one or more third substituents, referred to as WW The linker may be unsubstituted and is referred to herein as R LWW.1 and each first substituent R LWW.1 may be unsubstituted, and is referred to herein as R LWW.2 Each of the groups may be independently substituted with one or more second substituents, referred to herein as R LWW.3 Each of the first substituents is optionally different. Each of the second substituents is optionally different. Each of the third substituents is optionally different. For example, R WW When is phenyl, the phenyl group may be one or more R WW.1 Optionally substituted by groups, such as R WW.1 R WW.2 In the case of substituted or unsubstituted alkyl, examples of the groups so formed include one or more R WW.2 and R itself optionally substituted with WW.2 is one or more R WW.3 For example, R WW R is a methyl group WW.1 When the methyl group is phenyl substituted by, the methyl group may be further substituted with, but not limited to,

[0074] [ka] It is possible to form a group comprising:

[0075] R WW.1 are independently oxo, halogen, -CX WW.1 3. -CHX WW.1 2. -CH2X WW.1 , -OCX WW.1 3. -OCH2X WW.1 , -OCHX WW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.2 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.2 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.2 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), R WW.2 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.2 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or R WW.2 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW.1 are independently oxo, halogen, -CX WW.1 3. -CHX WW.1 2. -CH2X WW.1 , -OCX WW.1 3. -OCH2X WW.1 , -OCHX WW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C C1-C6, C1-C4, C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). WW.1 is independently -F, -Cl, -Br, or -I.

[0076] R WW.2 are independently oxo, halogen, -CX WW.2 3. -CHX WW.2 2. -CH2X WW.2 , -OCX WW.2 3. -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.3 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, C1-C2), R WW.3 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.3 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), R WW.3substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.3 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or R WW.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW.2 are independently oxo, halogen, -CX WW.2 3. -CHX WW.2 2. -CH2X WW.2 , -OCX WW.2 3. -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C C1-C6, C1-C4, C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). WW.2 is independently -F, -Cl, -Br, or -I.

[0077] R WW.3 are independently oxo, halogen, -CX WW.3 3. -CHX WW.3 2. -CH2X WW.3 , -OCX WW.3 3. -OCH2X WW.3 , -OCHX WW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C C1-C6, C1-C4, C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). WW.3 is independently -F, -Cl, -Br, or -I.

[0078] Two different R WW When substituents 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 is referred to herein as R WW.1 and each first substituent R WW.1 may be unsubstituted, and is referred to herein as R WW.2 and each second substituent R WW.2 may be unsubstituted, and is referred to herein as R WW.3 and each third substituent R WW.3 are unsubstituted. Each first substituent is optionally different. Each second substituent is optionally different. Each third substituent is optionally different. Two different R WW In the context where the substituents are joined together to form an open substituted ring, R WW.1 , R WW.2, and R WW.3 The "WW" symbol in WW Refers to a specified number of one of the substituents. For example, R 100A and R 100B are optionally linked together to form an open substituted ring, R WW.1 is R 100A.1 and R WW.2 is R 100A.2 and R WW.3 is R 100A.3 Alternatively, R 100A and R 100B are optionally linked together to form an open substituted ring, R WW.1 is R 100B.1 and R WW.2 is R 100B.2 and R WW.3 is R 100B.3 R in this paragraph WW.1 , R WW.2 , and R WW.3 is as defined in the previous paragraph.

[0079] R LWW.1 are independently oxo, halogen, -CX LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 , -OCX LWW.1 3. -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.2 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.2 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R LWW.2 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), R LWW.2substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.2 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or R LWW.2 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). LWW.1 are independently oxo, halogen, -CX LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 , -OCX LWW.1 3. -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C C1-C6, C1-C4, C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). LWW.1 is independently -F, -Cl, -Br, or -I.

[0080] R LWW.2 are independently oxo, halogen, -CX LWW.2 3. -CHX LWW.2 2. -CH2X LWW.2 , -OCX LWW.2 3. -OCH2X LWW.2 , -OCHX LWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.3 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, C1-C2), R LWW.3 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.3 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), R LWW.3 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.3 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or R LWW.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). LWW.2 are independently oxo, halogen, -CX LWW.2 3. -CHX LWW.2 2. -CH2X LWW.2 , -OCX LWW.2 3. -OCH2X LWW.2 , -OCHX LWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C C1-C6, C1-C4, C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). LWW.2 is independently -F, -Cl, -Br, or -I.

[0081] R LWW.3 are independently oxo, halogen, -CX LWW.3 3. -CHX LWW.3 2. -CH2X LWW.3 , -OCX LWW.3 3. -OCH2X LWW.3 , -OCHX LWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C C1-C6, C1-C4, C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). LWW.3 is independently -F, -Cl, -Br, or -I.

[0082] Any R group (R WW If an R group (R WW The groups) are independently oxo, halogen, -CX WW 3. -CHX WW 2. -CH2X WW , -OCX WW 3. -OCH2X WW , -OCHX WW 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.1 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, C1-C2), R WW.1 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.1 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, C5-C6), R WW.1 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.1 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or R WW.1 X is defined herein as substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW are independently -F, -Cl, -Br, -I. Again, "WW" represents the superscript number of the R group in question (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1 , R WW.2 , and R WW.3 is as defined above.

[0083] Any L linker group (i.e., L) listed in the chain or formula descriptions herein WW If the L group (L WW groups) are independently a bond, -O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, R LWW.1 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, C1-C2), R LWW.1 substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R LWW.1 Substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, C5-C6), R LWW.1 substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.1 Substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or R LWW.1 R is defined herein as a substituted or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). Additionally, "WW" represents the listed superscript numbers (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject L group. LWW.1 , and R LWW.2 and R LWW.3 is as defined above.

[0084] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. 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 geometric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0085] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0086] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0087] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0088] Unless otherwise specified, 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.

[0089] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0090] 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 contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0091] It should be noted that throughout this application, options, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0092] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the resulting association between atoms or molecules of a bioconjugate reactive group or bioconjugate reactive moiety. The association can be direct or indirect. For example, provided herein, conjugates between a first bioconjugate reactive group (e.g., -NH, -COOH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine side chain-containing amino acid, or carboxylate) can be direct, e.g., through a covalent bond or linker (e.g., a first linker to a second linker), or indirect, e.g., through a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effect), hydrophobic interactions, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups), including, but not limited to, nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, activated esters), electrophilic substitution (e.g., enamine reaction), and addition across carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed, for example, in 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, DC, 1982.In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., an -N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amine). In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (eg, a -sulfo-N-hydroxysuccinimide moiety) is covalently attached to a second bioconjugate reactive group (eg, an amine).

[0093] Useful bioconjugate reactive groups for use in the bioconjugate chemistry herein include: (a) carboxyl groups and their various derivatives, including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters; (b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, and the like; (c) haloalkyl groups, where the halide can be subsequently displaced with a nucleophilic group, such as an amine, carboxylate anion, thiol anion, carbanion, or alkoxide ion, resulting in the covalent attachment of a new group at the halogen atom; (d) dienophile groups, such as maleimide or maleimide groups, that can participate in Diels-Alder reactions; and (e) groups that can be subsequently derivatized via the formation of carbonyl derivatives, such as imines, hydrazones, semicarbazones, or oximes, or via mechanisms such as Grignard addition or alkyllithium addition. (f) sulfonyl halide groups, for example, for subsequent reaction with amines to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or attached to metals such as gold, or reacted with maleimides; (h) amine or sulfhydryl groups (e.g., those present in cysteine), which can be acylated, alkylated, or oxidized; (i) alkenes, which can undergo, for example, cycloaddition, acylation, Michael addition, etc.; (j) alkyl groups, such as amines and hydroxyl groups, which can be acylated, alkylated, or oxidized; (k) epoxides that can react with hydroxyl compounds, (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis, (l) metal-silicon oxide linkages, (m) metal linkages to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphodiester bonds, (n) azides coupled to alkynes using copper-catalyzed cycloaddition click chemistry, and (o) biotin conjugates that can react with avidin or streptavidin to form avidin-biotin or streptavidin-biotin complexes.

[0094] Bioconjugate reactive groups can be selected so that they do not contribute to or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups can be protected from participating in crosslinking reactions by the presence of protecting groups. In embodiments, bioconjugates include molecular entities resulting from the reaction of an unsaturated bond, such as a maleimide, with a sulfhydryl group.

[0095] As used herein, "biomolecule" is used in its conventional sense to refer to a molecule found in nature or a derivative thereof, including macromolecules such as proteins, carbohydrates, lipids, and nucleic acids, and small molecules such as primary metabolites, secondary metabolites, and natural products. A biomolecule may exist as a moiety attached to the remainder of a compound. Biomolecules include, but are not limited to, nucleic acids (e.g., DNA and RNA), peptide nucleic acids, sugars, peptides, proteins, antibodies, aptamers, lipids, and small molecule affinity ligands (e.g., inhibitors, biotin, and haptens). As used herein, "biomolecular moiety" refers to the radical of a biomolecule.

[0096] "Analog," "analogue," or "derivative" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the substitution of one atom with an atom of a different element, or the presence of a particular functional group, or the substitution of one functional group with another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0097] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group can be substituted with one or more of any or all of the named substituents. For example, when a group such as an alkyl group or heteroaryl group is "unsubstituted C1-C20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is selected from the group consisting of one or more unsubstituted C1-C 20 It may contain alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0098] Furthermore, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group occurs in a description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituents are R 13.A , R 13.B , R 13.C , R 13.D can be distinguished from R 13.A , R 13.B , R 13.C , R 13.D Each of these is R 13 and optionally defined differently within the definition of . When an R moiety, group, or substituent disclosed herein is attached via a single bond representation and the R moiety, group, or substituent is oxo, one of ordinary skill in the art will immediately recognize that the oxo is attached via a double bond in accordance with the normal rules of chemical valence.

[0099] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted by one or more of several substituents, these substituents are selected to comply with the principles of chemical bonding and to bring about a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0100] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound 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 salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., 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.

[0101] Therefore, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0102] 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.

[0103] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0104] Certain compounds of the present disclosure may exist in unsolvated forms and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polycrystalline or amorphous forms. Generally, 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.

[0105] A polypeptide or cell is "recombinant" if it is artificial or engineered, or if it is derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-naturally occurring or non-wild-type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in the genome of a recombinant organism, so that it is not associated with nucleotide sequences that normally flank the polynucleotide as 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. Similarly, a polynucleotide sequence not found in nature, e.g., a variant of a naturally occurring gene, is recombinant.

[0106] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation).

[0107] As used herein, a "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with certain dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells may include prokaryotic and eukaryotic 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, such as mammalian cells, insect cells (e.g., Spodoptera), and human cells. Cells may be useful if they are naturally non-adherent or have been treated to prevent them from adhering to surfaces, for example, by trypsinization.

[0108] The term "treating" or "treatment" refers to any indication of success in treatment or improvement of an injury, disease, condition, or state, including any objective or subjective parameter, such as relief, remission, a decrease in symptoms, or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, or improving the patient's physical or mental health. The treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, certain methods provided herein successfully treat cancer by reducing the incidence of cancer and / or by 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 its conjugations includes prevention of an injury, lesion, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In an embodiment, the treating or treatment is not a prophylactic treatment.

[0109] An "effective amount" is an amount sufficient for a compound to achieve a predetermined purpose (e.g., achieve the effect of being administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom or symptoms of a disease, which may also be referred to as a "therapeutically effective amount" when referred to in this context. "Alleviation" of a symptom(s) (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of the symptom, or elimination of the symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have an intended prophylactic effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, a "function-interfering amount" refers to the amount of antagonist required to interfere with the function of an enzyme or protein compared to the absence of the antagonist. As used herein, an "activity-increasing amount" refers to the amount of agonist required to increase the activity of an enzyme compared to the absence of the agonist. As used herein, a "function-increasing amount" refers to the amount of agonist required to increase the function of an enzyme or protein compared to the absence of the agonist.The exact amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill 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).

[0110] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or reagent is treated the same as in a parallel experiment except for the omission of the experimental procedure, reagent, or variable. In some cases, a control is used as a standard of comparison in evaluating experimental efficacy. In some embodiments, a control is a measurement of a protein activity (e.g., a signaling pathway) in the absence of a compound described herein (including in any embodiment, example, figure, or table).

[0111] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two distinct species (e.g., chemical compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or physically contact each other. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or may be produced from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0112] The term "contacting" can include allowing two species to react, interact, or come into physical contact, where the two species can be a compound described herein and a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular 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., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) involved in a signaling pathway.

[0113] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to proteins, refer to the conversion of a protein from an initial, inactive, or inactivated state to a biologically active derivative. These terms refer to activating, or activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease.

[0114] The terms "agonist," "activator," "up-regulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared 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 more, greater than expression or activity in the absence of the agonist.

[0115] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to cellular component-inhibitor interactions, mean to adversely affect (e.g., decrease) the activity or function of the cellular component (e.g., decrease a signal transduction pathway stimulated by the cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) compared to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means adversely affecting (e.g., decreasing) the concentration or level of the cellular component compared to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to the alleviation of a disease or disease symptom. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction or signaling pathway (e.g., a decrease in a pathway involving the cellular component). Thus, inhibiting includes, at least in part, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating a signaling pathway or enzymatic activity or the amount of a cellular component.

[0116] The terms "inhibitor," "suppressor," "antagonist," or "down-regulator" refer interchangeably to a substance capable of detectably reducing the expression or activity of a given gene or protein. An antagonist can reduce expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared 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 more lower than the expression or activity in the absence of the antagonist.

[0117] 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 molecule's target compared to the absence of the composition (e.g., the target can be a cellular component (e.g., a 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)).

[0118] The term "expression" includes any step involved in the production of a 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 proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0119] The term "modulate" is used according to its plain and ordinary meaning to refer 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 effect of a modulator on a target protein, modulating means changing the property or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0120] "Patient," "patient in need thereof," "subject," or "subject in need thereof" refers to an organism suffering from or susceptible 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, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In an embodiment, the patient is a human. In an embodiment, the patient in need thereof is a human. In an embodiment, the subject is a human. In an embodiment, the subject in need thereof is a human.

[0121] "Disease" or "condition" refers to an existence or state of health of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, melanoma, thyroid cancer, or bladder cancer). In embodiments, the disease is a RASopathy (e.g., capillary dysplasia-AV dysplasia syndrome, autoimmune lymphoproliferative syndrome, cardiomyocutaneous syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, Noonan syndrome, Costello syndrome, or Legius syndrome).

[0122] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. Further examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0123] The term "leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by the distorted proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease—acute or chronic; (2) the type of cells involved—myeloid (myeloid), lymphatic (lymphoid), or monocytic; and (3) the increased or non-increasing number of abnormal cells in the blood—leukemia or non-leukemia (subleukemia). Exemplary leukemias that may be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, and non-leukemia. leukemia), leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphoid leukemia, Examples of leukemia include lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0124] As used herein, the term "lymphoma" refers to a group of cancers affecting hematopoietic and lymphatic tissues. It develops primarily in lymphocytes, which are blood cells found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate at which the cancer grows and the type of cell involved. NHL includes aggressive (high-grade) and indolent (low-grade) types. Based on the type of cell involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with the compounds or methods 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.

[0125] The term "sarcoma" generally refers to a tumor composed of closely packed cells that are composed of a substance like embryonic connective tissue and that is generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, and fibroblastic sarcoma. These include alveolar sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0126] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0127] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinic cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, carcinoma adenomatous, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid cell carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, and compact carcinoma. durum, embryonal carcinoma, encephalomyocellular carcinoma, epidermoid carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in epidermis, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucus-secreting carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, mucous carcinoma (carcinoma mucosum), mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinomacarcinoma, globular cell carcinoma, spindle cell carcinoma, porocytic carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, carcinoma tuberosum, nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0128] 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 part of the body. "Metastatic cancer" is also referred to as "stage IV cancer." Cancer begins at a site of origin, e.g., the breast, called a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and invade surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system and circulate through the system to other parts and tissues of the body. Clinically detectable secondary tumors formed from cancer cells of the primary tumor are called metastatic or secondary tumors. 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 in the breast site will consist of abnormal lung cells, not abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Therefore, the term metastatic cancer refers to a disease in which a subject has or has had a primary tumor, and has one or more secondary tumors.The term non-metastatic cancer or a subject with non-metastatic cancer refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors.For example, metastatic lung cancer refers to a disease in a subject who has or has had a history of a primary lung tumor, and has one or more secondary tumors, for example, in a second location or multiple locations in the breast.

[0129] The terms "skin metastasis" and "cutaneous metastasis" refer to secondary malignant cell growth in the skin, where the malignant cells originate from a primary cancer site (e.g., breast). In skin metastasis, cancerous cells from the primary cancer site migrate to the skin, where they can divide and cause lesions. Skin metastasis can result from the migration of cancer cells from a breast cancer tumor to the skin.

[0130] The term "visceral metastasis" refers to secondary malignant cell growth in an internal organ (e.g., heart, lung, liver, pancreas, intestine) or body cavity (e.g., pleura, peritoneum), where the malignant cells originate from the primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from the primary cancer site migrate to a visceral organ, where they may divide and cause lesions. Visceral metastasis can result from the migration of cancer cells from a liver cancer tumor or a head and neck tumor to a visceral organ.

[0131] As used herein, the term "RASopathy" refers to a disease caused by a germline mutation in a gene encoding a component 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 an epidermal nevus. In embodiments, the RASopathy is Schimmelpenning syndrome. In embodiments, the RASopathy is a sebaceous nevus. In embodiments, the RASopathy is clubfoot (e.g., congenital clubfoot). 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 hyperplasia, hemihyperplasia-multifocal lipomatosis, congenital lipomatous hyperplasia, vascular malformation, epidermal nevus, spinal and skeletal syndrome, macrodactyly syndrome, megalencephaly 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 cardio-facio-cutaneous 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.In an embodiment, the RASopathy is a disease as described in Hafner, C. et al. Cell Cycle 12(1), 43-50, which is incorporated herein by reference in its entirety for all purposes.

[0132] 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. In embodiments, the switch II GTPase protein-associated disease is cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, melanoma, thyroid cancer, or bladder cancer).

[0133] As used herein, the term "K-Ras(G12R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G12R). In embodiments, the K-Ras(G12R)-associated disease is cancer (e.g., pancreatic cancer, lung cancer, or colorectal cancer). In embodiments, the K-Ras(G12R)-associated disease is a RASopathy.

[0134] As used herein, the term "H-Ras(G12R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G12R). In embodiments, the H-Ras(G12R)-associated disease is cancer. In embodiments, the H-Ras(G12R)-associated disease is a RASopathy.

[0135] As used herein, the term "N-Ras(G12R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of N-Ras(G12R). In embodiments, the N-Ras(G12R)-associated disease is cancer. In embodiments, the N-Ras(G12R)-associated disease is a RASopathy.

[0136] As used herein, the term "K-Ras(G13R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G13R). In embodiments, the K-Ras(G13R)-associated disease is cancer. In embodiments, the K-Ras(G13R)-associated disease is a RASopathy.

[0137] As used herein, the term "H-Ras(G13R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G13R). In embodiments, the H-Ras(G13R)-associated disease is cancer (e.g., melanoma). In embodiments, the H-Ras(G13R)-associated disease is a RASopathy.

[0138] As used herein, the term "N-Ras(G13R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of N-Ras(G13R). In embodiments, the N-Ras(G13R)-associated disease is cancer. In embodiments, the N-Ras(G13R)-associated disease is a RASopathy.

[0139] As used herein, the term "K-Ras(Q61R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(Q61R). In embodiments, the K-Ras(Q61R)-associated disease is cancer. In embodiments, the K-Ras(Q61R)-associated disease is a RASopathy.

[0140] As used herein, the term "H-Ras(Q61R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(Q61R). In embodiments, the H-Ras(Q61R)-associated disease is cancer (e.g., thyroid cancer or bladder cancer). In embodiments, the H-Ras(Q61R)-associated disease is a RASopathy.

[0141] As used herein, the term "N-Ras(Q61R)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of N-Ras(Q61R). In embodiments, the N-Ras(Q61R)-associated disease is cancer (e.g., melanoma or thyroid cancer). In embodiments, the N-Ras(Q61R)-associated disease is a RASopathy.

[0142] The term "drug" is used according to its ordinary meaning to refer to a substance that has a physiological effect (e.g., a beneficial effect, useful for treating a subject) when introduced into or onto a subject (e.g., into or onto the body of a subject or patient). The drug moiety is the radical of the drug.

[0143] 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 include: 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr,149 PM 153 Sm、 154-158 God 161 Tb 166 Dy 166 Ho 169 Err 175 sun 177 sun 186 Re 188 Re 189 Re 194 Ir 198 I 199 I 211 And 211 Pb、 212 Hello 212 Pb、 213 Hello 223 Ra 225 Ac、Cr、V、Mn、Fe、Co、Ni、Cu、La、Ce、Pr、Nd、Pm、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb、Lu、 32P, a fluorophore (e.g., a fluorescent dye), a modified oligonucleotide (e.g., the portion described in PCT / US2015 / 022063, incorporated herein by reference), an electron-dense reagent, an enzyme (e.g., commonly used in ELISA), biotin, digoxigenin, a paramagnetic molecule, a paramagnetic nanoparticle, an ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticle, a USPIO nanoparticle aggregate, a superparamagnetic iron oxide ("SPIO") nanoparticle, a SPIO nanoparticle aggregate, a single-crystal iron oxide nanoparticle, a single-crystal iron oxide, a nanoparticle contrast agent, a liposome, or a gadolinium chelate (Gadolinium chelate). Other delivery vehicles containing molecules such as chelate, "Gd-chelate"), gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma-emitting radionuclide, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., microbubble shells comprising albumin, galactose, lipids, and / or polymers), air, heavy gases, perfluorocarbons, nitrogen, octafluoropropane, perfluorocarbons, Microbubble gas cores including perflexane lipid microspheres, 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 that can be made detectable by, for example, incorporating a radioactive label into a peptide or an antibody that specifically reacts with a target peptide.

[0144] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents according to embodiments of the present disclosure include: 18 F, 32 P,33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, and 225Paramagnetic ions that can be used as additional imaging agents in accordance with embodiments of the present disclosure include, but are not limited to, ions of transition metals and lanthanide metals (e.g., metals with atomic numbers 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.

[0145] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0146] The term "preparation" is intended to include formulations of an active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and is therefore associated with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0147] As used herein, the term "about" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range that covers + / - 10% of the particular value. In embodiments, about includes the specified value.

[0148] As used herein, the term "administering" is used according to its plain and ordinary meaning and refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-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, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Concomitant administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally or topically, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols.

[0149] The compounds described herein can be used in combination with each other, with other active agents known to be useful in treating diseases associated with cells expressing disease-associated cellular components, or in combination with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agent.

[0150] In some embodiments, simultaneous 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. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agent and / or adjunct agent may be linked or conjugated to each other.

[0151] In therapeutic use for the treatment of disease, the compounds utilized in the pharmaceutical compositions of the present invention may be administered at an initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. Daily dosage ranges 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. However, dosages may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound or drug being used. For example, dosages can be empirically determined taking into account the type and stage of disease (e.g., cancer or RASopathy) diagnosed in a particular patient. In accordance with the present invention, the dosage administered to a patient should be sufficient to effect 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 associated with the administration of the compound in a particular patient. Determination of the appropriate dosage for a particular situation is within the ability of one of ordinary skill in the art. Generally, treatment is started with a smaller dosage that is less than the optimal dose of compound.Then, dosage is gradually increased until the optimal effect is reached under the circumstances.For convenience, if desired, total daily dosage can be divided and administered in portions throughout the day.

[0152] In the context of a substance or substance activity or function related to a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term "related" or "associated with" means that the substance or substance activity or function causes (in whole or in part) the disease (e.g., cancer or RASopathy) or causes (in whole or in part) a symptom of the disease, or that a symptom of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., a cellular component). As used herein, something that is described as associated with a disease, if it is a causative agent, can be a target for treating the disease.

[0153] As used herein, the term "aberrant" refers to something that is different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater than or less than the average of a normal control or normal, non-disease control sample. Abnormal activity can also refer to an amount of activity that results in disease, and restoring the abnormal activity to a normal or non-disease-associated amount (e.g., by administering a compound or using the methods described herein) results in a reduction of the disease or one or more symptoms.

[0154] As used herein, the term "electrophilic" refers to a chemical group that can accept electron density. An "electrophilic substituent," "electrophilic chemical moiety," or "electrophilic moiety" refers to an electron-deficient chemical group, substituent, or moiety (a monovalent chemical group) that can accept an electron pair or electron density to react with an electron-donating group, such as a nucleophile, by forming a bond.

[0155] As used herein, "nucleophile" refers to a chemical group that can donate electron density.

[0156] The term "isolated," when applied to a nucleic acid or protein, means that the nucleic acid or protein is essentially free from other cellular components with which it is associated in its natural state. It can be, for example, in a homogeneous state, 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 present as the predominant species in a preparation is substantially purified.

[0157] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. 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 refer to compounds that have a structure that differs from the general chemical structure of an amino acid but function similarly 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 that are not found in nature.

[0158] 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. Similarly, nucleotides may be referred to by their commonly accepted single-letter codes.

[0159] The term "amino acid side chain" refers to the side chain of an amino acid. For example, when an amino acid has the formula

[0160] [ka] where -LR is an amino acid side chain. As an example, L-arginine has the formula

[0161] [ka] and the L-arginine side chain has

[0162] [ka] is.

[0163] As used herein, the term "arginine" refers to the amino acid residue of the side chain

[0164] [ka] or an amino acid having a post-translational modification thereof. In embodiments, the post-translational modification is methylation, citrullination, phosphorylation, ADP-ribosylation, carbonylation, or glycation. In embodiments, the arginine is monomethylarginine (MMA). In embodiments, the arginine is symmetric dimethylarginine (SDMA). In embodiments, the arginine is asymmetric dimethylarginine (ADMA). In embodiments, the arginine is 5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine (MG-H1). In embodiments, the arginine is carboxyethylarginine (CEA). In embodiments, the arginine is carboxymethylarginine (CMA). In embodiments, the arginine is as described in Slade, DJ et al. Biopolymers 101(2), 133-143 (2014), which is incorporated herein by reference in its entirety for all purposes. In embodiments, the arginine is a post-translationally modified arginine as described above. In embodiments, the arginine is not post-translationally modified and has a side chain

[0165] [ka] It has.

[0166] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which may, in embodiments, be conjugated to moieties not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0167] The "position" of an amino acid or nucleotide base is indicated by a number sequentially identifying each amino acid (or nucleotide base) in a reference sequence based on its position relative to the N-terminus (or 5'-terminus). Due to deletions, insertions, truncations, fusions, etc., which must be considered when determining optimal alignment, the number of amino acid residues in a test sequence, determined simply by counting from the N-terminus, is generally not necessarily the same as the number of corresponding positions in the reference sequence. For example, if a variant has a deletion compared to the aligned reference sequence, there will be no amino acid in the variant corresponding to the position in the reference sequence at the site of the deletion. If there is an insertion in the aligned reference sequence, the insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0168] When used in the context of the numbering of a given amino acid or polynucleotide sequence, the term "numbered with reference to" or "corresponding to" refers to the numbering of residues in a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0169] An amino acid residue in a protein "corresponds" to a given residue if it occupies the same essential structural position in the protein as the given residue. For example, a selected residue in a selected protein corresponds to G12 of K-Ras if the selected residue occupies the same essential spatial or other structural relationship as G12 of K-Ras. In some embodiments, when a selected protein is aligned for maximum homology with K-Ras, the position in the aligned selected protein that aligns with G12 is said to correspond to G12. Instead of primary sequence alignment, three-dimensional structural alignment can also be used, for example, when the structure of a selected protein is aligned with K-Ras for maximum identity and the overall structure is compared. In this case, the amino acid that occupies the same essential position in the structural model as G12 is said to correspond to the G12 residue.

[0170] The term "protein complex" is used according to its plain and ordinary meaning and refers to a protein associated with an additional substance (e.g., another protein, a protein subunit, or a compound). A protein complex typically has a 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., a compound) is via a non-covalent interaction. In embodiments, a protein complex refers to a group of two or more polypeptide chains. The proteins in a protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

[0171] The term "protein aggregate" is used according to its plain and ordinary meaning to refer to an abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with disease (e.g., amyloidosis). Typically, a protein misfolds as a result of a change in amino acid sequence or an alteration in the native environment that disrupts normal non-covalent interactions, and if this misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that can form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, the protein aggregates are referred to as aggresomes.

[0172] The term "switch II" as used herein refers to a protein domain of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras) formed by residues corresponding to residues 60-76 of K-Ras, H-Ras, or N-Ras (e.g., K-Ras switch II refers to residues 60-76 of K-Ras, H-Ras switch II refers to residues 60-76 of H-Ras, and N-Ras switch II refers to residues 60-76 of N-Ras). A "switch II binding pocket" is a cavity bounded, at least in part, by the amino acid residues that form switch II. In some embodiments, a "switch II binding pocket" is a cavity in the GDP-bound form of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras) that is bounded, at least in part, by the amino acid residues that form switch II. A "switch II binding pocket binding moiety" is a portion of a compound (eg, as described herein) that binds to the switch II binding pocket.

[0173] As used herein, the term "switch II GTPase protein" refers to a GTPase protein that comprises a switch II. In embodiments, the switch II GTPase protein comprises a switch II binding pocket. In embodiments, the switch II GTPase protein is a Ras protein. In embodiments, the switch II GTPase protein is K-Ras. In embodiments, the switch II GTPase protein is H-Ras. In embodiments, the switch II GTPase protein is N-Ras. In embodiments, the switch II GTPase protein is ARF1 (e.g., UniProt P84077). In embodiments, the switch II GTPase protein is ARF3 (e.g., UniProt P61204). In embodiments, the switch II GTPase protein is ARF4 (e.g., UniProt P18085). In embodiments, the switch II GTPase protein is ARF5 (e.g., UniProt P84085). In embodiments, the switch II GTPase protein is ARF6 (e.g., UniProt P62330). In embodiments, the switch II GTPase protein is TRIM23 (e.g., UniProt P36406). In embodiments, the switch II GTPase protein is ARL1 (e.g., UniProt P40616). In embodiments, the switch II GTPase protein is ARL2 (e.g., UniProt P36404). In embodiments, the switch II GTPase protein is ARL3 (e.g., UniProt P36405). In embodiments, the switch II GTPase protein is ARL4A (e.g., UniProt P40617). In embodiments, the switch II GTPase protein is ARL4B. In embodiments, the switch II GTPase protein is ARL5. In embodiments, the switch II GTPase protein is ARL6 (e.g., UniProt Q9H0F7). In embodiments, the Switch II GTPase protein is ARL7. In embodiments, the Switch II GTPase protein is ARL8.In embodiments, the switch II GTPase protein is ARL9 (e.g., UniProt Q6T311). In embodiments, the switch II GTPase protein is ARL12. In embodiments, the switch II GTPase protein is ARL11 (e.g., UniProt Q969Q4). In embodiments, the switch II GTPase protein is ARF7. In embodiments, the switch II GTPase protein is 339231 (e.g., UniProt Q0P5N6). In embodiments, the switch II GTPase protein is DKFZp761. In embodiments, the switch II GTPase protein is ARFRP1 (e.g., UniProt Q13795). In embodiments, the switch II GTPase protein is ARFRP2 (e.g., UniProt Q9NXU5). In embodiments, the switch II GTPase protein is ARL10A (e.g., UniProt Q8N8L6). In embodiments, the Switch II GTPase protein is ARL10B (e.g., UniProt Q96BM9). In embodiments, the Switch II GTPase protein is ARL10C. In embodiments, the Switch II GTPase protein is 344988. In embodiments, the Switch II GTPase protein is SARA1 (e.g., UniProt Q6FID4). In embodiments, the Switch II GTPase protein is SARA2.

[0174] As used herein, the term "switch II GTPase protein arginine residue" refers to an arginine residue of a switch II GTPase protein. In embodiments, the switch II GTPase protein arginine residue is an arginine residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein arginine residue is an arginine residue corresponding to position 13 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein arginine residue is an arginine residue corresponding to position 61 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein arginine residue is a native switch II GTPase protein arginine residue. In embodiments, the switch II GTPase protein arginine residue is a mutant switch II GTPase protein arginine residue. In embodiments, the mutant switch II GTPase protein arginine residue is arginine residue 12 of K-Ras(G12R), H-Ras(G12R), or N-Ras(G12R). In embodiments, the mutant switch II GTPase protein arginine residue is arginine residue 13 of K-Ras(G13R), H-Ras(G13R), or N-Ras(G13R). In embodiments, the mutant switch II GTPase protein arginine residue is arginine residue 61 of K-Ras(Q61R), H-Ras(Q61R), or N-Ras(Q61R).

[0175] The term "Ras" refers to one or more of the family of human Ras GTPase proteins (e.g., K-Ras, H-Ras, N-Ras), including homologs, isoforms, and functional fragments thereof.

[0176] The term "K-Ras" refers to the protein encoded by the KRAS gene in humans. The K-Ras protein is a GTPase that converts guanosine triphosphate to guanosine diphosphate. Mutations (e.g., amino acid substitutions) in the K-Ras protein can result in various malignancies (e.g., lung adenocarcinoma, pancreatic cancer, or colorectal cancer). The term "K-Ras" can 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 an embodiment, K-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM (SEQ ID NO: 1).

[0177] The term "H-Ras" refers to an enzyme encoded by the HRAS gene in humans. The H-Ras protein is a GTPase that converts guanosine triphosphate to guanosine diphosphate. Mutations (e.g., amino acid substitutions) in the H-Ras protein can result in various malignancies (e.g., bladder cancer, thyroid cancer, salivary gland duct cancer, epithelial cancer, or kidney cancer). The term "H-Ras" can refer to the nucleotide sequence or protein sequence of human HRAS (e.g., Entrez 3265, UniProt P01112, RefSeq NM_001130442.2, RefSeq NM_001318054.1, RefSeq NM_005343.3, RefSeq NM_00176795.4, RefSeq NP_001123914.1, RefSeq NP_001304983.1, RefSeq NP_005334.1, or RefSeq NP_789765.1). In embodiments, H-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVLVGNKCDLAARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDESGPGCMSCKCVLS (SEQ ID NO: 2).

[0178] The term "N-Ras" refers to the enzyme encoded by the NRAS gene in humans. The N-Ras protein is a GTPase that converts guanosine triphosphate to guanosine diphosphate. The term "N-Ras" can refer to the nucleotide sequence or protein sequence of human NRAS (e.g., Entrez 4893, UniProt P01111, RefSeq NM_002524.4, or RefSeq NP_002515.1). In embodiments, N-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDLPTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQGCMGLPCVVM (SEQ ID NO: 3).

[0179] In embodiments, the switch II binding pocket is bound at least in part by one or more of V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and / or I100 of K-Ras, or equivalent residues in a homologous, related (e.g., H-Ras or N-Ras), or mutant Ras protein. Compounds described herein (including embodiments, examples, and figures) that bind to or contact amino acids that form the switch II binding pocket are "switch II binding pocket binding compounds," and portions of compounds that bind to or contact amino acids that form the switch II binding pocket are "switch II binding pocket binding moieties."

[0180] In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts one amino acid forming the switch II binding pocket. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts multiple amino acids forming the switch II binding pocket. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts one amino acid selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts a plurality of K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts two K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts three K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts four K-Ras amino acids selected from amino acids in mutant K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts five K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts six K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts seven K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts eight K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts nine K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts ten K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 11 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 12 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 13 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 14 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or a homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety is a mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), a related Ras (e.g., H-Ras, H-Ras(G12R), H-Ras(G13R), H-Ras(Q61R), N-Ras, N-Ras(G12R), N-Ras(G13R), or N-Ras(Q61R)), or K-Ras residues V7, V9, G10, P34. , T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99 and I100.

[0181] As used herein, the term "phosphatase PTP domain" refers to the protein domain of a protein tyrosine phosphatase formed by residues corresponding to residues 1-279 of human PTP1B, including the arginine residue. In embodiments, the phosphatase PTP domain is as described in Andersen, J. Net al. Mol. Cell Biol. 21(21), 7117-7136 (2001), which is incorporated herein by reference in its entirety for all purposes. A "phosphatase PTP domain binding moiety" is a portion of a compound (e.g., as described herein) that binds to a phosphatase PTP domain.

[0182] The term "PTP1B" or "tyrosine protein phosphatase 1B" refers to a member of the protein tyrosine phosphatase family that in humans is encoded by the PTPN1 gene. The term "PTP1B" can refer to the nucleotide sequence or protein sequence of human PTP1B (e.g., Entrez 5770, UniProt P18031, RefSeq NM_002827.4, or RefSeq NP_002818.1). In embodiments, PTP1B has the following sequence: MEMEKEFEQIDKSGSWAAIYQDIRHEASDFPCRVAKLPKNKNRNRYRDVSPFDHSRIKLHQEDNDYINASLIKMEEAQRSYILTQGPLPNTCGHFWEMVWEQKSRGVVML NRVMEKGSLKCAQYWPQKEEKEMIFEDTNLKLTLISEDIKSYYTVRQLELENLTTQETREILHFHYTTWPDFGVPESPASFLNFLFKVRESGSLSPEHGPVVVHCSAGIGR SGTFCLADTCLLLMDKRKDPSSVDIKKVLLEMRKFRMGLIQTADQLRFSYLAVIEGAKFIMGDSSVQDQWKELSHEDLEPPPEHIPPPPRPPKRILEPHNGKCREFFPNHQWVKEETQEDKDCPIKEEKGSPLNAAPYGIESMSQDTEVRSRVVGGSLRGAQAASPAKGEPSLPEKDEDHALSYWKPFLVNMCVATVLTAGAYLCYRFLFNSNT (SEQ ID NO: 4).

[0183] As used herein, the term "SH2 domain" refers to the protein domain of the Src oncoprotein formed by residues corresponding to residues 151-248 of the human Src oncoprotein, including the arginine residue. In embodiments, the SH2 domain is as described in Roskoski, R. Jr. Biochem. Biophys. Res. Commun. 324(4), 1155-1164 (2004), which is incorporated by reference in its entirety for all purposes. An "SH2 domain-binding moiety" is a portion of a compound (e.g., as described herein) that binds to an SH2 domain.

[0184] The term "Src" or "proto-oncogene tyrosine-protein kinase Src" refers to the non-receptor tyrosine kinase protein encoded by the SRC gene in humans. The term "Src" may refer to the nucleotide sequence or protein sequence of human Src (e.g., Entrez 6714, UniProt P12931, RefSeq NM_005417.4, RefSeq NM_198291.2, RefSeq NP_005408.1, or RefSeq NP_938033.1). In embodiments, Src has the following amino acid sequence: (SEQ ID NO: 5).

[0185] As used herein, the term "pseudokinase KSR domain" or "pseudokinase kinase suppressor of Ras domain" refers to a protein domain of the KSR2 protein formed by residues corresponding to residues 634-950 of the human KSR2 protein, including an arginine residue. In embodiments, the pseudokinase KSR domain is as described in Brennan, D.F. et al. Nature 472, 366-369 (2011) and Xing, L. et al. Bioorg. Med. Chem. 23(19), 6520-6527, which are incorporated by reference in their entirety for all purposes. A "pseudokinase KSR domain binding moiety" is a portion of a compound (e.g., as described herein) that binds to a pseudokinase KSR domain.

[0186] The term "KSR2" or "kinase suppressor of Ras2" refers to the protein encoded by the KSR2 gene in humans. The term "KSR2" may refer to the nucleotide sequence or protein sequence of human KSR2 (e.g., Entrez 283455, UniProt Q6VAB6, RefSeq NM_173598.6, or RefSeq NP_775869.4). In embodiments, KSR2 has the following amino acid sequence: (SEQ ID NO: 6).

[0187] As used herein, the term "pseudokinase STRADα domain" refers to the protein domain of a STRADα protein formed by residues corresponding to residues 59-431 of the STRADα protein, including the arginine residue. In embodiments, the pseudokinase STRADα domain is as described in Zeqiraj, E. et al. PLOS Biology 7(6), e1000126 (2009) and Xing, L. et al. Bioorg. Med. Chem. 23(19), 6520-6527, which are incorporated by reference in their entirety for all purposes. A "pseudokinase STRADα domain binding moiety" is a portion of a compound (e.g., as described herein) that binds to a pseudokinase STRADα domain.

[0188] The term "STRADα" or "STE20-related kinase adaptor protein alpha" refers to the protein that in humans is encoded by the STRADA gene. The term "STRADα" refers to the nucleotide sequence or protein sequence of human STRADα (e.g., Entrez 92335, UniProt Q7RTN6, RefSeq NM_001003786.2, RefSeq NM_001003787.2, RefSeq NM_001003788.2, RefSeq NM_001165969.1, RefSeq NM_001165970.1, RefSeq NM_153335.5, RefSeq NP_001003786.1, RefSeq NP_001003787.1, RefSeq NP_001003788.1, RefSeq NP_001159441.1, RefSeq NP_001159442.1, or RefSeq NP_699166.2). In embodiments, STRADα has the following amino acid sequence: MSFLVSKPERIRRWVSEKFIVEGLRDLELFGEQPPGDTRRKTNDASSESIASFSKQEVMSSFLPEGGCYELLTVIGKGFEDLMTVNLARYKPTGEYVTVRRINLEACSN EMVTFLQGELHVSKLFNHPNIVPYRATFIADNELWVVTSFMAYGSAKDLICTHFMDGMNELAIAYILQGVLKALDYIHHMGYVHRSVKASHILISVDGKVYLSGLRSNLS MISHGQRQRVVHDFPKYSVKVLPWLSPEVLQQNLQGYDAKSDIYSVGITACELANGHVPFKDMPATQMLLEKLNGTVPCLLDTSTIPAEELTMSPSRSVANSGLSDSLTTSTPRPSNGDSPSHPYHRTFSPHFHHFVEQCLQRNPDARPSASTLLNHSFFKQIKRRASEALPELLRPVTPITNFEGSQSQDHSGIFGLVTNLEELEVDDWEF (SEQ ID NO: 7).

[0189] Terms such as "selective" or "selectivity" with respect to a compound or agent refer to the ability of the compound or agent to preferentially increase or decrease the activity of a particular molecular target (e.g., a protein, enzyme, etc.) over one or more different molecular targets (e.g., a compound that is selective for mutant K-Ras(G12R) preferentially inhibits K-Ras(G12R) over other K-Ras proteins (e.g., wild-type K-Ras)). In embodiments, a "Ras(G12R)-selective compound" refers to a compound (e.g., a compound described herein) that is selective for Ras(G12R).

[0190] II. Compounds In one aspect, the formula:

[0191] [ka] or a pharmaceutically acceptable salt thereof.

[0192] R 1 is the switch II binding pocket binding moiety.

[0193] L 1 is a bond or a bivalent linker.

[0194] L 2 is a bond or a substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).

[0195] L 3 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 30 -, -C(O)NR 30 -, -NR 30 C(O)-, -NR 30 C(O)O-, -OC(O)NR 30 -, -NR 30 C(O)NR 30 -, -S(O)2-, -NR 30 S(O)2-, -S(O)2NR 30 -, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0196] R 3 is hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -CN, -SO n3 R 3D , -SO v3 NR3A R 3B , -NR 3C NR 3A R 3B , -ONR 3A R 3B , -NR 3C C(O)NR 3A R 3B , -N(O) m3 , -NR 3A R 3B , -C(O)R 3C , -C(O)OR 3C , -OC(O)R 3C , -OC(O)OR 3C , -C(O)NR 3A R 3B , -OC(O)NR 3A R 3B , -OR 3D , -SR 3D , -NR 3A SO2R 3D , -NR 3A C(O)R 3C , -NR 3A C(O)OR 3C , -NR 3A OR 3C , -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0197] R 30are independently hydrogen, -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( For example, C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (for example, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (for example, C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (for example, 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (for example, C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0198] R 3A , R 3B , R 3C , and R 3Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl( For example, C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (for example, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (for example, C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (for example, 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (for example, C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 3A and R 3B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0199] each X 3 is independently -Cl, -Br, -I, or -F.

[0200] The symbol n3 is an integer of 0 to 4.

[0201] The symbols m3 and v3 are independently 1 or 2.

[0202] In embodiments, the compound has the formula:

[0203] [ka] or a pharmaceutically acceptable salt thereof. 1 , L 2 , L 3 , R 1 , and R 3 is as described herein, including the embodiments.

[0204] In embodiments, the compound has the formula:

[0205] [ka] L 1 , L 2 , L 3 , R 1 , and R 3 is as described herein, including the embodiments.

[0206] In embodiments, the compound has the formula:

[0207] [ka] L 1 , L 2 , L 3 , R 1 , and R 3 is as described herein, including the embodiments.

[0208] In an embodiment, the substitution L 2 (e.g., substituted alkylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 2 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2 When L is substituted, it is substituted with at least one substituent. 2 When L is substituted, it is substituted with at least one size-limited substituent. 2When is substituted, it is substituted with at least one lower substituent.

[0209] In an embodiment, L 2 is a bond or unsubstituted C1-C4 alkylene. 2 is a bond. In embodiments, L 2 is unsubstituted C1-C4 alkylene. 2 is unsubstituted methylene. In embodiments, L 2 is unsubstituted ethylene. In embodiments, L 2 is unsubstituted propylene. In embodiments, L 2 is unsubstituted n-propylene. In embodiments, L 2 is unsubstituted isopropylene. In embodiments, L 2 is unsubstituted butylene. In embodiments, L 2 is unsubstituted n-butylene. In embodiments, L 2 is unsubstituted isobutylene. In embodiments, L 2 is unsubstituted tert-butylene.

[0210] In an embodiment, the substitution L 3 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 3 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3 When L is substituted, it is substituted with at least one substituent. 3 When L is substituted, it is substituted with at least one size-limited substituent. 3 When is substituted, it is substituted with at least one lower substituent.

[0211] In an embodiment, L 3is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O)—, —NHS(O)—, —S(O)NH—, 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.

[0212] In an embodiment, L 3 is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O)—, —NHS(O)—, —S(O)NH—, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted 2- to 6-membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3- to 8-membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5- to 10-membered heteroarylene.

[0213] In an embodiment, L 3 is a bond. In embodiments, L 3 is -C(O)-.

[0214] In embodiments, the substitution R 30 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 30 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 30 When R is substituted, it is substituted with at least one substituent. 30When R is substituted, it is substituted with at least one size-limited substituent. 30 When is substituted, it is substituted with at least one lower substituent.

[0215] In embodiments, R 30 are independently hydrogen. In embodiments, R 30 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 30 is independently unsubstituted methyl. In embodiments, R 30 is independently unsubstituted ethyl. In embodiments, R 30 is independently unsubstituted propyl. In embodiments, R 30 is independently unsubstituted n-propyl. In embodiments, R 30 is independently unsubstituted isopropyl. In embodiments, R 30 is independently unsubstituted butyl. In embodiments, R 30 is independently unsubstituted n-butyl. In embodiments, R 30 is independently unsubstituted isobutyl. In embodiments, R 30 is independently unsubstituted tert-butyl.

[0216] In embodiments, the compound has the formula:

[0217] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0218] In embodiments, the compound has the formula:

[0219] [ka] L 1 , R 1 , and R 3is as described herein, including the embodiments.

[0220] In embodiments, the compound has the formula:

[0221] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0222] In embodiments, the compound has the formula:

[0223] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0224] In embodiments, the compound has the formula:

[0225] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0226] In embodiments, the compound has the formula:

[0227] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0228] In embodiments, the compound has the formula:

[0229] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0230] In embodiments, the compound has the formula:

[0231] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0232] In embodiments, the compound has the formula:

[0233] [ka] L 1 , R 1 , and R 3 is as described herein, including the embodiments.

[0234] In embodiments, the substitution R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3 When R is substituted, it is substituted with at least one substituent. 3 When R is substituted, it is substituted with at least one size-limited substituent. 3When is substituted, it is substituted with at least one lower substituent.

[0235] In embodiments, the substitution R 3A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3A When R is substituted, it is substituted with at least one substituent. 3A When R is substituted, it is substituted with at least one size-limited substituent. 3A When is substituted, it is substituted with at least one lower substituent.

[0236] In embodiments, the substitution R 3B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3B When R is substituted, it is substituted with at least one substituent. 3B When R is substituted, it is substituted with at least one size-limited substituent. 3B When is substituted, it is substituted with at least one lower substituent.

[0237] In embodiments, R 3A and R 3BThe substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and R 3A and R 3B When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 3A and R 3B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. In embodiments, R 3A and R 3B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 3A and R 3B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0238] In embodiments, the substitution R 3C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3C When R is substituted, it is substituted with at least one substituent. 3C When R is substituted, it is substituted with at least one size-limited substituent. 3C When is substituted, it is substituted with at least one lower substituent.

[0239] In embodiments, the substitution R 3D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3D When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3D When R is substituted, it is substituted with at least one substituent. 3D When R is substituted, it is substituted with at least one size-limited substituent. 3D When is substituted, it is substituted with at least one lower substituent.

[0240] In embodiments, R 3 represents 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, - OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0241] In embodiments, R 3 is hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 3 is hydrogen or unsubstituted methyl. In embodiments, R 3 is hydrogen. In embodiments, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted n-propyl. In embodiments, R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted butyl. In embodiments, R 3 is unsubstituted n-butyl. In embodiments, R 3 is unsubstituted isobutyl. In embodiments, R 3 is unsubstituted tert-butyl.

[0242] In embodiments, R 3 is halogen. In embodiments, R 3 is -F. In an embodiment, R 3 is —Cl. In embodiments, R 3 is -Br. In embodiments, R 3 is -I. In an embodiment, R 3 is —CCl. In embodiments, R 3 is —CBr. In embodiments, R 3 is —CF. In embodiments, R 3 is -CI3. In an embodiment, R 3 is —CH2Cl. In embodiments, R 3 is —CHBr. In embodiments, R 3 is —CHF. In embodiments, R 3is -CH2I. In embodiments, R 3 is —CHCl. ​​In embodiments, R 3 is —CHBr. In embodiments, R 3 is -CHF2. In an embodiment, R 3 is -CHI2. In embodiments, R 3 is -CN. In embodiments, R 3 is —OH. In embodiments, R 3 is —NH. In embodiments, R 3 is —COOH. In embodiments, R 3 is -CONH. In an embodiment, R 3 is —NO. In an embodiment, R 3 is -SH. In embodiments, R 3 is —SO3H. In embodiments, R 3 is —OSO3H. In embodiments, R 3 is —SO 2 NH 2 . In an embodiment, R 3 is -NHNH. In embodiments, R 3 is -ONH2. In embodiments, R 3 is —NHC(O)NHNH. In embodiments, R 3 is —NHC(O)NH. In embodiments, R 3 is —NHSO2H. In embodiments, R 3 is —NHC(O)H. In embodiments, R 3 is —NHC(O)OH. In embodiments, R 3 is —NHOH. In embodiments, R 3 is —OCCl. In embodiments, R 3 is —OCBr. In embodiments, R 3 is -OCF3. In an embodiment, R 3 is -OCI3. In an embodiment, R 3 is —OCH2Cl. In embodiments, R 3 is —OCHBr. In embodiments, R 3 is -OCHF. In embodiments, R 3is -OCH2I. In embodiments, R 3 is —OCHCl. ​​In embodiments, R 3 is —OCHBr. In embodiments, R 3 is -OCHF. In an embodiment, R 3 is -OCHI2. In embodiments, R 3 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 3 is unsubstituted cyclopropyl. In embodiments, R 3 is unsubstituted cyclobutyl. In embodiments, R 3 is unsubstituted cyclopentyl. In embodiments, R 3 is unsubstituted cyclohexyl. In embodiments, R 3 is unsubstituted cycloheptyl. In embodiments, R 3 is unsubstituted cyclooctyl. In embodiments, R 3 is unsubstituted phenyl.

[0243] In embodiments, R 3A is hydrogen. In embodiments, R 3A is unsubstituted C1-C4 alkyl. In embodiments, R 3A is unsubstituted methyl. In embodiments, R 3A is unsubstituted ethyl. In embodiments, R 3A is unsubstituted propyl. In embodiments, R 3A is unsubstituted n-propyl. In embodiments, R 3A is unsubstituted isopropyl. In embodiments, R 3A is unsubstituted butyl. In embodiments, R 3A is unsubstituted n-butyl. In embodiments, R 3A is unsubstituted isobutyl. In embodiments, R 3A is unsubstituted tert-butyl.

[0244] In embodiments, R 3B is hydrogen. In embodiments, R 3B is unsubstituted C1-C4 alkyl. In embodiments, R 3Bis unsubstituted methyl. In embodiments, R 3B is unsubstituted ethyl. In embodiments, R 3B is unsubstituted propyl. In embodiments, R 3B is unsubstituted n-propyl. In embodiments, R 3B is unsubstituted isopropyl. In embodiments, R 3B is unsubstituted butyl. In embodiments, R 3B is unsubstituted n-butyl. In embodiments, R 3B is unsubstituted isobutyl. In embodiments, R 3B is unsubstituted tert-butyl.

[0245] In embodiments, R 3C is hydrogen. In embodiments, R 3C is unsubstituted C1-C4 alkyl. In embodiments, R 3C is unsubstituted methyl. In embodiments, R 3C is unsubstituted ethyl. In embodiments, R 3C is unsubstituted propyl. In embodiments, R 3C is unsubstituted n-propyl. In embodiments, R 3C is unsubstituted isopropyl. In embodiments, R 3C is unsubstituted butyl. In embodiments, R 3C is unsubstituted n-butyl. In embodiments, R 3C is unsubstituted isobutyl. In embodiments, R 3C is unsubstituted tert-butyl.

[0246] In embodiments, R 3D is hydrogen. In embodiments, R 3D is unsubstituted C1-C4 alkyl. In embodiments, R 3D is unsubstituted methyl. In embodiments, R 3D is unsubstituted ethyl. In embodiments, R 3D is unsubstituted propyl. In embodiments, R 3D is unsubstituted n-propyl. In embodiments, R 3D is unsubstituted isopropyl. In embodiments, R3D is unsubstituted butyl. In embodiments, R 3D is unsubstituted n-butyl. In embodiments, R 3D is unsubstituted isobutyl. In embodiments, R 3D is unsubstituted tert-butyl.

[0247] In an embodiment, L 1 -L 101 -L 102 -L 103 -L 104 -L 105 -It is.

[0248] In an embodiment, L 101 is R 1 is directly connected to the

[0249] L 101 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 101 -, -C(O)NR 101 -, -NR 101 C(O)-, -NR 101 C(O)O-, -OC(O)NR 101 -, -NR 101 C(O)NR 101 -, -NR 101 C(NH)NR 101 -, -S(O)2-, -NR 101 S(O)2-, -S(O)2NR 101 -, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0250] L 102 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 102 -, -C(O)NR 102 -, -NR 102 C(O)-, -NR 102 C(O)O-, -OC(O)NR 102 -, -NR 102 C(O)NR 102 -, -NR 102 C(NH)NR 102 -, -S(O)2-, -NR 102 S(O)2-, -S(O)2NR 102 -, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0251] L 103 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 103 -, -C(O)NR 103 -, -NR 103 C(O)-, -NR 103 C(O)O-, -OC(O)NR 103 -, -NR 103 C(O)NR 103 -, -NR 103 C(NH)NR 103 -, -S(O)2-, -NR 103 S(O)2-, -S(O)2NR 103-, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0252] L 104 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 104 -, -C(O)NR 104 -, -NR 104 C(O)-, -NR 104 C(O)O-, -OC(O)NR 104 -, -NR 104 C(O)NR 104 -, -NR 104 C(NH)NR 104 -, -S(O)2-, -NR 104 S(O)2-, -S(O)2NR 104 -, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0253] L 105is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 105 -, -C(O)NR 105 -, -NR 105 C(O)-, -NR 105 C(O)O-, -OC(O)NR 105 -, -NR 105 C(O)NR 105 -, -NR 105 C(NH)NR 105 -, -S(O)2-, -NR 105 S(O)2-, -S(O)2NR 105 -, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0254] Each R 101 , R 102 , R 103 , R 104 , and R 105are 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, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0255] In an embodiment, the substitution L 101 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 101 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 101 When L is substituted, it is substituted with at least one substituent. 101 When L is substituted, it is substituted with at least one size-limited substituent. 101When is substituted, it is substituted with at least one lower substituent.

[0256] In an embodiment, L 101 is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O)2—, —NHS(O)2—, —S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituent, 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C8), 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0257] In an embodiment, L 101 is a bond. In embodiments, L 101 is —C(O)—. In embodiments, L 101 is —C(O)O—. In embodiments, L 101 is -OC(O)-. In embodiments, L 101 is —O—. In embodiments, L 101 is -S-. In embodiments, L 101 is -NR 101 In an embodiment, L 101 is —NH—. In embodiments, L 101 is -C(O)NR 101 In an embodiment, L 101 is —C(O)NH—. In embodiments, L 101 is -NR 101 In embodiments, L 101 is —NHC(O)—. In embodiments, L101 is -NR 101 C(O)O—. In embodiments, L 101 is —NHC(O)O—. In embodiments, L 101 is -OC(O)NR 101 In an embodiment, L 101 is —OC(O)NH—. In embodiments, L 101 is -NR 101 C(O)NR 101 In an embodiment, L 101 is —NHC(O)NH—. In embodiments, L 101 is -NR 101 C(NH)NR 101 In an embodiment, L 101 is —NHC(NH)NH—. In embodiments, L 101 is -S(O)-. In embodiments, L 101 is -NR 101 In one embodiment, L 101 is -NHS(O)-. In embodiments, L 101 is -S(O)NR 101 In an embodiment, L 101 is —S(O)NH—. In embodiments, L 101 is a substituted or unsubstituted C1-C6 alkylene. 101 is substituted or unsubstituted methylene. 101 is substituted or unsubstituted ethylene. In embodiments, L 101 is substituted or unsubstituted propylene. In embodiments, L 101 is substituted or unsubstituted n-propylene. In embodiments, L 101 is substituted or unsubstituted isopropylene. In embodiments, L 101 is substituted or unsubstituted butylene. In embodiments, L 101 is substituted or unsubstituted n-butylene. 101 is substituted or unsubstituted isobutylene. In embodiments, L 101 is substituted or unsubstituted tert-butylene. 101is substituted or unsubstituted pentylene. In embodiments, L 101 is substituted or unsubstituted hexylene. In embodiments, L 101 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 101 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 101 is substituted or unsubstituted azetidinyl. In embodiments, L 101 is substituted or unsubstituted piperazinyl. In embodiments, L 101 teeth,

[0258] [ka] In an embodiment, L 101 teeth,

[0259] [ka] In an embodiment, L 101 teeth,

[0260] [ka] is.

[0261] In embodiments, the substitution R 101 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 101 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 101 When R is substituted, it is substituted with at least one substituent. 101 When R is substituted, it is substituted with at least one size-limited substituent. 101When is substituted, it is substituted with at least one lower substituent.

[0262] In embodiments, R 101 are independently hydrogen. In embodiments, R 101 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 101 is independently unsubstituted methyl. In embodiments, R 101 is independently unsubstituted ethyl. In embodiments, R 101 is independently unsubstituted propyl. In embodiments, R 101 is independently unsubstituted n-propyl. In embodiments, R 101 is independently unsubstituted isopropyl. In embodiments, R 101 is independently unsubstituted butyl. In embodiments, R 101 is independently unsubstituted n-butyl. In embodiments, R 101 is independently unsubstituted isobutyl. In embodiments, R 101 is independently unsubstituted tert-butyl.

[0263] In an embodiment, the substitution L 102 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 102 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 102 When L is substituted, it is substituted with at least one substituent. 102 When L is substituted, it is substituted with at least one size-limited substituent. 102 When is substituted, it is substituted with at least one lower substituent.

[0264] In an embodiment, L 102is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O)2—, —NHS(O)2—, —S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituent, 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C8), 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0265] In an embodiment, L 102 is a bond. In embodiments, L 102 is —C(O)—. In embodiments, L 102 is —C(O)O—. In embodiments, L 102 is -OC(O)-. In embodiments, L 102 is —O—. In embodiments, L 102 is -S-. In embodiments, L 102 is -NR 102 In an embodiment, L 102 is —NH—. In embodiments, L 102 is -C(O)NR 102 In an embodiment, L 102 is —C(O)NH—. In embodiments, L 102 is -NR 102 In embodiments, L 102 is —NHC(O)—. In embodiments, L 102 is -NR 102 C(O)O—. In embodiments, L 102 is —NHC(O)O—. In embodiments, L102 is -OC(O)NR 102 In an embodiment, L 102 is —OC(O)NH—. In embodiments, L 102 is -NR 102 C(O)NR 102 In an embodiment, L 102 is —NHC(O)NH—. In embodiments, L 102 is -NR 102 C(NH)NR 102 In an embodiment, L 102 is —NHC(NH)NH—. In embodiments, L 102 is -S(O)-. In embodiments, L 102 is -NR 102 In one embodiment, L 102 is -NHS(O)-. In embodiments, L 102 is -S(O)NR 102 In an embodiment, L 102 is —S(O)NH—. In embodiments, L 102 is a substituted or unsubstituted C1-C6 alkylene. 102 is substituted or unsubstituted methylene. 102 is substituted or unsubstituted ethylene. In embodiments, L 102 is substituted or unsubstituted propylene. In embodiments, L 102 is substituted or unsubstituted n-propylene. In embodiments, L 102 is substituted or unsubstituted isopropylene. In embodiments, L 102 is substituted or unsubstituted butylene. In embodiments, L 102 is substituted or unsubstituted n-butylene. 102 is substituted or unsubstituted isobutylene. In embodiments, L 102 is substituted or unsubstituted tert-butylene. 102 is substituted or unsubstituted pentylene. In embodiments, L 102 is substituted or unsubstituted hexylene. In embodiments, L 102is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 102 is substituted or unsubstituted phenylene.

[0266] In embodiments, the substitution R 102 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 102 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 102 When R is substituted, it is substituted with at least one substituent. 102 When R is substituted, it is substituted with at least one size-limited substituent. 102 When is substituted, it is substituted with at least one lower substituent.

[0267] In embodiments, R 102 are independently hydrogen. In embodiments, R 102 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 102 is independently unsubstituted methyl. In embodiments, R 102 is independently unsubstituted ethyl. In embodiments, R 102 is independently unsubstituted propyl. In embodiments, R 102 is independently unsubstituted n-propyl. In embodiments, R 102 is independently unsubstituted isopropyl. In embodiments, R 102 is independently unsubstituted butyl. In embodiments, R 102 is independently unsubstituted n-butyl. In embodiments, R 102 is independently unsubstituted isobutyl. In embodiments, R 102 is independently unsubstituted tert-butyl.

[0268] In an embodiment, the substitution L 103 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 103 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 103 When L is substituted, it is substituted with at least one substituent. 103 When L is substituted, it is substituted with at least one size-limited substituent. 103 When is substituted, it is substituted with at least one lower substituent.

[0269] In an embodiment, L 103 is a bond. In embodiments, L 103 is —C(O)—. In embodiments, L 103 is —C(O)O—. In embodiments, L 103 is -OC(O)-. In embodiments, L 103 is —O—. In embodiments, L 103 is -S-. In embodiments, L 103 is -NR 103 In an embodiment, L 103 is —NH—. In embodiments, L 103 is -C(O)NR 103 In an embodiment, L 103 is —C(O)NH—. In embodiments, L 103 is -NR 103 In embodiments, L 103 is —NHC(O)—. In embodiments, L 103 is -NR 103 C(O)O—. In embodiments, L 103 is —NHC(O)O—. In embodiments, L 103 is -OC(O)NR 103In an embodiment, L 103 is —OC(O)NH—. In embodiments, L 103 is -NR 103 C(O)NR 103 In an embodiment, L 103 is —NHC(O)NH—. In embodiments, L 103 is -NR 103 C(NH)NR 103 In an embodiment, L 103 is —NHC(NH)NH—. In embodiments, L 103 is -S(O)-. In embodiments, L 103 is -NR 103 In one embodiment, L 103 is -NHS(O)-. In embodiments, L 103 is -S(O)NR 103 In an embodiment, L 103 is —S(O)NH—. In embodiments, L 103 is a substituted or unsubstituted C1-C6 alkylene. 103 is substituted or unsubstituted methylene. 103 is substituted or unsubstituted ethylene. In embodiments, L 103 is substituted or unsubstituted propylene. In embodiments, L 103 is substituted or unsubstituted n-propylene. In embodiments, L 103 is substituted or unsubstituted isopropylene. In embodiments, L 103 is substituted or unsubstituted butylene. In embodiments, L 103 is substituted or unsubstituted n-butylene. 103 is substituted or unsubstituted isobutylene. In embodiments, L 103 is substituted or unsubstituted tert-butylene. 103 is substituted or unsubstituted pentylene. In embodiments, L 103 is substituted or unsubstituted hexylene. In embodiments, L 103 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 103is substituted or unsubstituted phenylene.

[0270] In embodiments, the substitution R 103 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 103 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 103 When R is substituted, it is substituted with at least one substituent. 103 When R is substituted, it is substituted with at least one size-limited substituent. 103 When is substituted, it is substituted with at least one lower substituent.

[0271] In embodiments, R 103 are independently hydrogen. In embodiments, R 103 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 103 is independently unsubstituted methyl. In embodiments, R 103 is independently unsubstituted ethyl. In embodiments, R 103 is independently unsubstituted propyl. In embodiments, R 103 is independently unsubstituted n-propyl. In embodiments, R 103 is independently unsubstituted isopropyl. In embodiments, R 103 is independently unsubstituted butyl. In embodiments, R 103 is independently unsubstituted n-butyl. In embodiments, R 103 is independently unsubstituted isobutyl. In embodiments, R 103 is independently unsubstituted tert-butyl.

[0272] In an embodiment, the substitution L 104(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 104 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 104 When L is substituted, it is substituted with at least one substituent. 104 When L is substituted, it is substituted with at least one size-limited substituent. 104 When is substituted, it is substituted with at least one lower substituent.

[0273] In an embodiment, L 104 is a bond. In embodiments, L 104 is —C(O)—. In embodiments, L 104 is —C(O)O—. In embodiments, L 104 is -OC(O)-. In embodiments, L 104 is —O—. In embodiments, L 104 is -S-. In embodiments, L 104 is -NR 104 In an embodiment, L 104 is —NH—. In embodiments, L 104 is -C(O)NR 104 In an embodiment, L 104 is —C(O)NH—. In embodiments, L 104 is -NR 104 In embodiments, L 104 is —NHC(O)—. In embodiments, L 104 is -NR 104 C(O)O—. In embodiments, L 104 is —NHC(O)O—. In embodiments, L 104 is -OC(O)NR 104 In an embodiment, L 104is —OC(O)NH—. In embodiments, L 104 is -NR 104 C(O)NR 104 In an embodiment, L 104 is —NHC(O)NH—. In embodiments, L 104 is -NR 104 C(NH)NR 104 In an embodiment, L 104 is —NHC(NH)NH—. In embodiments, L 104 is -S(O)-. In embodiments, L 104 is -NR 104 In one embodiment, L 104 is -NHS(O)-. In embodiments, L 104 is -S(O)NR 104 In an embodiment, L 104 is —S(O)NH—. In embodiments, L 104 is a substituted or unsubstituted C1-C6 alkylene. 104 is substituted or unsubstituted methylene. 104 is substituted or unsubstituted ethylene. In embodiments, L 104 is substituted or unsubstituted propylene. In embodiments, L 104 is substituted or unsubstituted n-propylene. In embodiments, L 104 is substituted or unsubstituted isopropylene. In embodiments, L 104 is substituted or unsubstituted butylene. In embodiments, L 104 is substituted or unsubstituted n-butylene. 104 is substituted or unsubstituted isobutylene. In embodiments, L 104 is substituted or unsubstituted tert-butylene. 104 is substituted or unsubstituted pentylene. In embodiments, L 104 is substituted or unsubstituted hexylene. In embodiments, L 104 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 104 is substituted or unsubstituted phenylene.

[0274] In embodiments, the substitution R 104 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 104 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 104 When R is substituted, it is substituted with at least one substituent. 104 When R is substituted, it is substituted with at least one size-limited substituent. 104 When is substituted, it is substituted with at least one lower substituent.

[0275] In embodiments, R 104 are independently hydrogen. In embodiments, R 104 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 104 is independently unsubstituted methyl. In embodiments, R 104 is independently unsubstituted ethyl. In embodiments, R 104 is independently unsubstituted propyl. In embodiments, R 104 is independently unsubstituted n-propyl. In embodiments, R 104 is independently unsubstituted isopropyl. In embodiments, R 104 is independently unsubstituted butyl. In embodiments, R 104 is independently unsubstituted n-butyl. In embodiments, R 104 is independently unsubstituted isobutyl. In embodiments, R 104 is independently unsubstituted tert-butyl.

[0276] In an embodiment, the substitution L 105(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 105 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 105 When L is substituted, it is substituted with at least one substituent. 105 When L is substituted, it is substituted with at least one size-limited substituent. 105 When is substituted, it is substituted with at least one lower substituent.

[0277] In an embodiment, L 105 is a bond. In embodiments, L 105 is —C(O)—. In embodiments, L 105 is —C(O)O—. In embodiments, L 105 is -OC(O)-. In embodiments, L 105 is —O—. In embodiments, L 105 is -S-. In embodiments, L 105 is -NR 105 In an embodiment, L 105 is —NH—. In embodiments, L 105 is -C(O)NR 105 In an embodiment, L 105 is —C(O)NH—. In embodiments, L 105 is -NR 105 In embodiments, L 105 is —NHC(O)—. In embodiments, L 105 is -NR 105 C(O)O—. In embodiments, L 105 is —NHC(O)O—. In embodiments, L 105 is -OC(O)NR 105 In an embodiment, L 105is —OC(O)NH—. In embodiments, L 105 is -NR 105 C(O)NR 105 In an embodiment, L 105 is —NHC(O)NH—. In embodiments, L 105 is -NR 105 C(NH)NR 105 In an embodiment, L 105 is —NHC(NH)NH—. In embodiments, L 105 is -S(O)-. In embodiments, L 105 is -NR 105 In one embodiment, L 105 is -NHS(O)-. In embodiments, L 105 is -S(O)NR 105 In an embodiment, L 105 is —S(O)NH—. In embodiments, L 105 is a substituted or unsubstituted C1-C6 alkylene. 105 is substituted or unsubstituted methylene. 105 is substituted or unsubstituted ethylene. In embodiments, L 105 is substituted or unsubstituted propylene. In embodiments, L 105 is substituted or unsubstituted n-propylene. In embodiments, L 105 is substituted or unsubstituted isopropylene. In embodiments, L 105 is substituted or unsubstituted butylene. In embodiments, L 105 is substituted or unsubstituted n-butylene. 105 is substituted or unsubstituted isobutylene. In embodiments, L 105 is substituted or unsubstituted tert-butylene. 105 is substituted or unsubstituted pentylene. In embodiments, L 105 is substituted or unsubstituted hexylene. In embodiments, L 105 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 105 is substituted or unsubstituted phenylene.

[0278] In embodiments, the substitution R 105 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 105 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 105 When R is substituted, it is substituted with at least one substituent. 105 When R is substituted, it is substituted with at least one size-limited substituent. 105 When is substituted, it is substituted with at least one lower substituent.

[0279] In embodiments, R 105 are independently hydrogen. In embodiments, R 105 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 105 is independently unsubstituted methyl. In embodiments, R 105 is independently unsubstituted ethyl. In embodiments, R 105 is independently unsubstituted propyl. In embodiments, R 105 is independently unsubstituted n-propyl. In embodiments, R 105 is independently unsubstituted isopropyl. In embodiments, R 105 is independently unsubstituted butyl. In embodiments, R 105 is independently unsubstituted n-butyl. In embodiments, R 105 is independently unsubstituted isobutyl. In embodiments, R 105 is independently unsubstituted tert-butyl.

[0280] In an embodiment, L 1is a bond, a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, or a substituted or unsubstituted phenylene. 1 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 1 is substituted or unsubstituted piperazinylene. In embodiments, L 1 teeth,

[0281] [ka] In an embodiment, L 1 teeth,

[0282] [ka] In an embodiment, L 1 teeth,

[0283] [ka] In an embodiment, L 1 teeth,

[0284] [ka] In an embodiment, L 1 teeth,

[0285] [ka] In an embodiment, L 1 teeth,

[0286] [ka] In an embodiment, L 1 teeth,

[0287] [ka] In an embodiment, L1 teeth,

[0288] [ka] is.

[0289] In embodiments, R 1 -L 10 -R 10 is.

[0290] L 10 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 100 -, -C(O)NR 100 -, -NR 100 C(O)-, -NR 100 C(O)O-, -OC(O)NR 100 -, -NR 100 C(O)NR 100 -, -NR 100 C(NH)NR 100 -, -S(O)2-, -NR 100 S(O)2-, -S(O)2NR 100 -, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0291] R 100are 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, -OCH2 F, -OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0292] R 10 is hydrogen, halogen, -CX 10 3. -CHX 10 2. -CH2X 10 , -OCX 10 3. -OCH2X 10 , -OCHX 10 2, -CN, -SO n10 R 10D , -SO v10 NR 10A R 10B , -NR 10C NR 10A R 10B , -ONR 10A R 10B , -NHC(O)NR 10C NR 10A R 10B , -NHC(O)NR10A R 10B , -N(O) m10 , -NR 10A R 10B , -C(O)R 10C , -C(O)OR 10C , -C(O)NR 10A R 10B , -OR 10D , -SR 10D , -NR 10A SO2R 10D , -NR 10A C(O)R 10C , -NR 10A C(O)OR 10C , -NR 10A OR 10C , -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0293] R 10A , R 10B , R 10C , and R 10Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl( For example, C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (for example, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (for example, C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (for example, 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (for example, C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 10A and R 10B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0294] each X 10 is independently -F, -Cl, -Br, or -I.

[0295] The symbol n10 is an integer of 0-4.

[0296] The symbols m10 and v10 are independently 1 or 2.

[0297] In an embodiment, the substitution L 10(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 10 When L is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10 When L is substituted, it is substituted with at least one substituent. 10 When L is substituted, it is substituted with at least one size-limited substituent. 10 When is substituted, it is substituted with at least one lower substituent.

[0298] In an embodiment, L 10 is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O)2—, —NHS(O)2—, —S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituent, 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C8), 10 or phenylene), or substituted or unsubstituted heteroarylene (for example, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0299] In an embodiment, L 10 is a bond. In embodiments, L 10 is —C(O)—. In embodiments, L 10is —C(O)O—. In embodiments, L 10 is -OC(O)-. In embodiments, L 10 is —O—. In embodiments, L 10 is -S-. In embodiments, L 10 is -NR 100 In an embodiment, L 10 is —NH—. In embodiments, L 10 is -C(O)NR 100 In an embodiment, L 10 is —C(O)NH—. In embodiments, L 10 is -NR 100 In embodiments, L 10 is —NHC(O)—. In embodiments, L 10 is -NR 100 C(O)O—. In embodiments, L 10 is —NHC(O)O—. In embodiments, L 10 is -OC(O)NR 100 In an embodiment, L 10 is —OC(O)NH—. In embodiments, L 10 is -NR 100 C(O)NR 100 In an embodiment, L 10 is —NHC(O)NH—. In embodiments, L 10 is -NR 100 C(NH)NR 100 In an embodiment, L 10 is —NHC(NH)NH—. In embodiments, L 10 is -S(O)-. In embodiments, L 10 is -NR 100 In one embodiment, L 10 is -NHS(O)-. In embodiments, L 10 is -S(O)NR 100 In an embodiment, L 10 is —S(O)NH—. In embodiments, L 10 is a substituted or unsubstituted C1-C6 alkylene. 10is substituted or unsubstituted methylene. 10 is substituted or unsubstituted ethylene. In embodiments, L 10 is substituted or unsubstituted propylene. In embodiments, L 10 is substituted or unsubstituted n-propylene. In embodiments, L 10 is substituted or unsubstituted isopropylene. In embodiments, L 10 is substituted or unsubstituted butylene. In embodiments, L 10 is substituted or unsubstituted n-butylene. 10 is substituted or unsubstituted isobutylene. In embodiments, L 10 is substituted or unsubstituted tert-butylene. 10 is substituted or unsubstituted pentylene. In embodiments, L 10 is substituted or unsubstituted hexylene. In embodiments, L 10 is a substituted or unsubstituted 2- to 6-membered heteroalkylene.

[0300] In embodiments, the substitution R 100 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 100 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 100 When R is substituted, it is substituted with at least one substituent. 100 When R is substituted, it is substituted with at least one size-limited substituent. 100 When is substituted, it is substituted with at least one lower substituent.

[0301] In embodiments, R 100 are independently hydrogen. In embodiments, R 100is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 100 is independently unsubstituted methyl. In embodiments, R 100 is independently unsubstituted ethyl. In embodiments, R 100 is independently unsubstituted propyl. In embodiments, R 100 is independently unsubstituted n-propyl. In embodiments, R 100 is independently unsubstituted isopropyl. In embodiments, R 100 is independently unsubstituted butyl. In embodiments, R 100 is independently unsubstituted n-butyl. In embodiments, R 100 is independently unsubstituted isobutyl. In embodiments, R 100 is independently unsubstituted tert-butyl.

[0302] In embodiments, the substitution R 10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10 When R is substituted, it is substituted with at least one substituent. 10 When R is substituted, it is substituted with at least one size-limited substituent. 10 When is substituted, it is substituted with at least one lower substituent.

[0303] In embodiments, the substitution R 10A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10A When R is substituted, it is substituted with at least one substituent. 10A When R is substituted, it is substituted with at least one size-limited substituent. 10A When is substituted, it is substituted with at least one lower substituent.

[0304] In embodiments, the substitution R 10B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10B When R is substituted, it is substituted with at least one substituent. 10B When R is substituted, it is substituted with at least one size-limited substituent. 10B When is substituted, it is substituted with at least one lower substituent.

[0305] In embodiments, R 10A and R 10B The substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group, and R 10A and R 10BWhen the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 10A and R 10B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. In embodiments, R 10A and R 10B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 10A and R 10B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0306] In embodiments, the substitution R 10C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10C When R is substituted, it is substituted with at least one substituent. 10C When R is substituted, it is substituted with at least one size-limited substituent. 10C When is substituted, it is substituted with at least one lower substituent.

[0307] In embodiments, the substitution R 10D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R10D When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10D When R is substituted, it is substituted with at least one substituent. 10D When R is substituted, it is substituted with at least one size-limited substituent. 10D When is substituted, it is substituted with at least one lower substituent.

[0308] In embodiments, R 10 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 10 is a substituted or unsubstituted (C3-C8) cycloalkyl, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted (C6-C 10 ) aryl, or substituted or unsubstituted 5-10 membered heteroaryl. In embodiments, R 10 is a substituted C3-C8 cycloalkyl. In embodiments, R 10 is a substituted 3-8 membered heterocycloalkyl. In embodiments, R 10 is substituted C6~C 10 In embodiments, R 10 is substituted phenyl. In embodiments, R 10 is a substituted 5-10 membered heteroaryl. In embodiments, R 10 is substituted pyrimidyl. In embodiments, R 10 is a substituted tetrahydropyridopyrimidyl. In embodiments, R 10 is a substituted pyridopyrimidyl. In embodiments, R 10 is a substituted quinazolinyl. In embodiments, R 10 is a substituted pyrazolyl. In embodiments, R 10 is a substituted piperazinyl.

[0309] In embodiments, R10A is hydrogen. In embodiments, R 10A is unsubstituted C1-C4 alkyl. In embodiments, R 10A is unsubstituted methyl. In embodiments, R 10A is unsubstituted ethyl. In embodiments, R 10A is unsubstituted propyl. In embodiments, R 10A is unsubstituted n-propyl. In embodiments, R 10A is unsubstituted isopropyl. In embodiments, R 10A is unsubstituted butyl. In embodiments, R 10A is unsubstituted n-butyl. In embodiments, R 10A is unsubstituted isobutyl. In embodiments, R 10A is unsubstituted tert-butyl.

[0310] In embodiments, R 10B is hydrogen. In embodiments, R 10B is unsubstituted C1-C4 alkyl. In embodiments, R 10B is unsubstituted methyl. In embodiments, R 10B is unsubstituted ethyl. In embodiments, R 10B is unsubstituted propyl. In embodiments, R 10B is unsubstituted n-propyl. In embodiments, R 10B is unsubstituted isopropyl. In embodiments, R 10B is unsubstituted butyl. In embodiments, R 10B is unsubstituted n-butyl. In embodiments, R 10B is unsubstituted isobutyl. In embodiments, R 10B is unsubstituted tert-butyl.

[0311] In embodiments, R 10C is hydrogen. In embodiments, R 10C is unsubstituted C1-C4 alkyl. In embodiments, R 10C is unsubstituted methyl. In embodiments, R 10C is unsubstituted ethyl. In embodiments, R 10Cis unsubstituted propyl. In embodiments, R 10C is unsubstituted n-propyl. In embodiments, R 10C is unsubstituted isopropyl. In embodiments, R 10C is unsubstituted butyl. In embodiments, R 10C is unsubstituted n-butyl. In embodiments, R 10C is unsubstituted isobutyl. In embodiments, R 10C is unsubstituted tert-butyl.

[0312] In embodiments, R 10D is hydrogen. In embodiments, R 10D is unsubstituted C1-C4 alkyl. In embodiments, R 10D is unsubstituted methyl. In embodiments, R 10D is unsubstituted ethyl. In embodiments, R 10D is unsubstituted propyl. In embodiments, R 10D is unsubstituted n-propyl. In embodiments, R 10D is unsubstituted isopropyl. In embodiments, R 10D is unsubstituted butyl. In embodiments, R 10D is unsubstituted n-butyl. In embodiments, R 10D is unsubstituted isobutyl. In embodiments, R 10D is unsubstituted tert-butyl.

[0313] In embodiments, R 1 teeth,

[0314] [ka] In an embodiment, R 1 teeth,

[0315] [ka] In an embodiment, R 1 teeth,

[0316] [ka] In an embodiment, R 1 teeth,

[0317] [ka] In an embodiment, R 1 teeth,

[0318] [ka] In an embodiment, R 1 teeth,

[0319] [ka] In an embodiment, R 1 teeth,

[0320] [ka] In an embodiment, R 1 teeth,

[0321] [ka] In an embodiment, R 1 teeth,

[0322] [ka] In an embodiment, R 1 teeth,

[0323] [ka] In an embodiment, R 1 teeth,

[0324] [ka] In an embodiment, R 1 teeth,

[0325] [ka] In an embodiment, R 1 teeth,

[0326] [ka] In an embodiment, R 1 teeth,

[0327] [ka] is.

[0328] R 6 are 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, -OCH2 F, -OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0329] R 7 are 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, -OCH2 F, -OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0330] R 8are independently a 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 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0331] The symbol z6 is an integer of 0-7.

[0332] The symbol z7 is an integer from 0 to 7.

[0333] The symbol z8 is an integer of 0 to 5.

[0334] In embodiments, the substitution R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6 When R is substituted, it is substituted with at least one substituent. 6 When R is substituted, it is substituted with at least one size-limited substituent. 6 When is substituted, it is substituted with at least one lower substituent.

[0335] In embodiments, R 6 are independently a 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 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0336] In embodiments, R 6 is independently oxo. In embodiments, R 6is independently halogen. In an embodiment, R 6 is independently -F. In an embodiment, R 6 is independently -Cl. In an embodiment, R 6 is independently -Br. In an embodiment, R 6 is independently -I. In an embodiment, R 6 is independently —CCl. In embodiments, R 6 is independently —CBr. In an embodiment, R 6 is independently —CF. In an embodiment, R 6 is independently -CI. In an embodiment, R 6 is independently —CH2Cl. In an embodiment, R 6 is independently —CHBr. In an embodiment, R 6 is independently -CHF. In an embodiment, R 6 is independently -CH2I. In embodiments, R 6 is independently —CHCl. ​​In an embodiment, R 6 is independently —CHBr. In embodiments, R 6 is independently -CHF. In an embodiment, R 6 is independently -CHI. In embodiments, R 6 is independently —CN. In an embodiment, R 6 is independently —OH. In an embodiment, R 6 is independently —NH. In an embodiment, R 6 is independently —COOH. In an embodiment, R 6 is independently -CONH. In an embodiment, R 6 is independently —NO. In an embodiment, R 6 is independently -SH. In an embodiment, R 6 is independently —SO3H. In an embodiment, R 6 is independently —OSO3H. In embodiments, R 6 is independently —SO 2 NH 2 . In an embodiment, R 6is independently -NHNH. In embodiments, R 6 is independently -ONH. In embodiments, R 6 is independently —NHC(O)NHNH. In embodiments, R 6 is independently —NHC(O)NH. In embodiments, R 6 is independently —NHSO2H. In an embodiment, R 6 is independently —NHC(O)H. In an embodiment, R 6 is independently —NHC(O)OH. In embodiments, R 6 is independently —NHOH. In an embodiment, R 6 is independently —OCCl. In an embodiment, R 6 is independently —OCBr. In an embodiment, R 6 is independently -OCF. In an embodiment, R 6 is independently -OCI. In an embodiment, R 6 is independently —OCH2Cl. In an embodiment, R 6 is independently —OCHBr. In an embodiment, R 6 is independently —OCHF. In an embodiment, R 6 is independently -OCH2I. In embodiments, R 6 is independently —OCHCl. ​​In an embodiment, R 6 is independently —OCHBr. In embodiments, R 6 is independently -OCHF. In an embodiment, R 6 is independently -OCHI. In embodiments, R 6 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 6 is independently unsubstituted methyl. In embodiments, R 6 is independently unsubstituted ethyl. In embodiments, R 6 is independently unsubstituted propyl. In embodiments, R 6 is independently unsubstituted n-propyl. In embodiments, R 6is independently unsubstituted isopropyl. In embodiments, R 6 is independently unsubstituted butyl. In embodiments, R 6 is independently unsubstituted n-butyl. In embodiments, R 6 is independently unsubstituted isobutyl. In embodiments, R 6 is independently unsubstituted tert-butyl. In embodiments, R 6 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. 6 is independently a substituted 2-6 membered heteroalkyl. In embodiments, R 6 is independently unsubstituted methoxy. In embodiments, R 6 is independently unsubstituted ethoxy. In embodiments, R 6 is independently unsubstituted propoxy. In embodiments, R 6 is independently unsubstituted n-propoxy. In embodiments, R 6 is independently unsubstituted isopropoxy. In embodiments, R 6 is independently unsubstituted butoxy. In embodiments, R 6 is independently unsubstituted n-butoxy. In embodiments, R 6 is independently unsubstituted isobutoxy. In embodiments, R 6 is independently unsubstituted tert-butoxy. In embodiments, R 6 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0337] In embodiments, R 6 is independently halogen, —OH, unsubstituted C1-C4 alkyl, substituted 2-6 membered heteroalkyl, or substituted 5-6 membered heteroaryl. 6 is independently -F, -Cl, -OH, or unsubstituted methyl. In embodiments, R 6 is independently a 2-6 membered heteroalkyl substituted with a substituted heterocycloalkyl or an unsubstituted fused heterocycloalkyl. 6 is independently a substituted pyridyl.

[0338] In an embodiment, z6 is 0. In an embodiment, z6 is 1. In an embodiment, z6 is 2. In an embodiment, z6 is 3. In an embodiment, z6 is 4. In an embodiment, z6 is 5. In an embodiment, z6 is 6. In an embodiment, z6 is 7.

[0339] In embodiments, the substitution R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 7 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 7 When R is substituted, it is substituted with at least one substituent. 7 When R is substituted, it is substituted with at least one size-limited substituent. 7 When is substituted, it is substituted with at least one lower substituent.

[0340] In embodiments, R 7are independently a 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 to C8, C1 to C6, C1 to C4, or C1 to 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 to C8, C3 to C6, C4 to C6, or C5 to 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 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0341] In embodiments, R 7 is independently oxo. In embodiments, R 7 is independently halogen. In an embodiment, R 7 is independently -F. In an embodiment, R 7 is independently -Cl. In an embodiment, R 7 is independently -Br. In an embodiment, R 7 is independently -I. In an embodiment, R 7 is independently —CCl. In embodiments, R 7 is independently —CBr. In an embodiment, R 7 is independently —CF. In an embodiment, R 7 is independently -CI. In an embodiment, R7 is independently —CH2Cl. In an embodiment, R 7 is independently —CHBr. In an embodiment, R 7 is independently -CHF. In an embodiment, R 7 is independently -CH2I. In embodiments, R 7 is independently —CHCl. ​​In an embodiment, R 7 is independently —CHBr. In embodiments, R 7 is independently -CHF. In an embodiment, R 7 is independently -CHI. In embodiments, R 7 is independently —CN. In an embodiment, R 7 is independently —OH. In an embodiment, R 7 is independently —NH. In an embodiment, R 7 is independently —COOH. In an embodiment, R 7 is independently -CONH. In an embodiment, R 7 is independently —NO. In an embodiment, R 7 is independently -SH. In an embodiment, R 7 is independently —SO3H. In an embodiment, R 7 is independently —OSO3H. In embodiments, R 7 is independently —SO 2 NH 2 . In an embodiment, R 7 is independently -NHNH. In embodiments, R 7 is independently -ONH. In embodiments, R 7 is independently —NHC(O)NHNH. In embodiments, R 7 is independently —NHC(O)NH. In embodiments, R 7 is independently —NHSO2H. In an embodiment, R 7 is independently —NHC(O)H. In an embodiment, R 7 is independently —NHC(O)OH. In embodiments, R 7 is independently —NHOH. In an embodiment, R 7is independently —OCCl. In an embodiment, R 7 is independently —OCBr. In an embodiment, R 7 is independently -OCF. In an embodiment, R 7 is independently -OCI. In an embodiment, R 7 is independently —OCH2Cl. In an embodiment, R 7 is independently —OCHBr. In an embodiment, R 7 is independently —OCHF. In an embodiment, R 7 is independently -OCH2I. In embodiments, R 7 is independently —OCHCl. ​​In an embodiment, R 7 is independently —OCHBr. In embodiments, R 7 is independently -OCHF. In an embodiment, R 7 is independently -OCHI. In embodiments, R 7 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 7 is independently unsubstituted methyl. In embodiments, R 7 is independently unsubstituted ethyl. In embodiments, R 7 is independently unsubstituted propyl. In embodiments, R 7 is independently unsubstituted n-propyl. In embodiments, R 7 is independently unsubstituted isopropyl. In embodiments, R 7 is independently unsubstituted butyl. In embodiments, R 7 is independently unsubstituted n-butyl. In embodiments, R 7 is independently unsubstituted isobutyl. In embodiments, R 7 is independently unsubstituted tert-butyl. In embodiments, R 7 is independently an unsubstituted C2-C4 alkynyl. 7 is independently unsubstituted ethynyl. In embodiments, R 7 is independently unsubstituted propynyl. In embodiments, R 7is independently unsubstituted butynyl. In embodiments, R 7 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. 7 is independently unsubstituted methoxy. In embodiments, R 7 is independently unsubstituted ethoxy. In embodiments, R 7 is independently unsubstituted propoxy. In embodiments, R 7 is independently unsubstituted n-propoxy. In embodiments, R 7 is independently unsubstituted isopropoxy. In embodiments, R 7 is independently unsubstituted butoxy. In embodiments, R 7 is independently unsubstituted n-butoxy. In embodiments, R 7 is independently unsubstituted isobutoxy. In embodiments, R 7 is independently unsubstituted tert-butoxy.

[0342] In embodiments, R 7 are independently halogen, —CF, —CN, —OH, —NH, unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkynyl, unsubstituted 2-6 membered heteroalkyl, or unsubstituted C3-C8 cycloalkyl. 7 are independently -F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, unsubstituted ethynyl, unsubstituted methoxy, or unsubstituted cyclopropyl.

[0343] In embodiments, R 7 are independently halogen, —CF, —CN, —OH, —NH, unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkynyl, or unsubstituted C3-C8 cycloalkyl. 7 are independently -F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, unsubstituted ethynyl, or unsubstituted cyclopropyl.

[0344] In an embodiment, z7 is 0. In an embodiment, z7 is 1. In an embodiment, z7 is 2. In an embodiment, z7 is 3. In an embodiment, z7 is 4. In an embodiment, z7 is 5. In an embodiment, z7 is 6. In an embodiment, z7 is 7.

[0345] In embodiments, the substitution R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 8 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 8 When R is substituted, it is substituted with at least one substituent. 8 When R is substituted, it is substituted with at least one size-limited substituent. 8 When is substituted, it is substituted with at least one lower substituent.

[0346] In embodiments, R 8 is independently halogen. In an embodiment, R 8 is independently -F. In an embodiment, R 8 is independently -Cl. In an embodiment, R 8 is independently -Br. In an embodiment, R 8 is independently -I. In an embodiment, R 8 is independently —CCl. In embodiments, R 8 is independently —CBr. In an embodiment, R 8 is independently —CF. In an embodiment, R 8 is independently -CI. In an embodiment, R 8 is independently —CH2Cl. In an embodiment, R 8 is independently —CHBr. In an embodiment, R8 is independently -CHF. In an embodiment, R 8 is independently -CH2I. In embodiments, R 8 is independently —CHCl. ​​In an embodiment, R 8 is independently —CHBr. In embodiments, R 8 is independently -CHF. In an embodiment, R 8 is independently -CHI. In embodiments, R 8 is independently —CN. In an embodiment, R 8 is independently —OH. In an embodiment, R 8 is independently —NH. In an embodiment, R 8 is independently —COOH. In an embodiment, R 8 is independently -CONH. In an embodiment, R 8 is independently —NO. In an embodiment, R 8 is independently -SH. In an embodiment, R 8 is independently —SO3H. In an embodiment, R 8 is independently —OSO3H. In embodiments, R 8 is independently —SO 2 NH 2 . In an embodiment, R 8 is independently -NHNH. In embodiments, R 8 is independently -ONH. In embodiments, R 8 is independently —NHC(O)NHNH. In embodiments, R 8 is independently —NHC(O)NH. In embodiments, R 8 is independently —NHSO2H. In an embodiment, R 8 is independently —NHC(O)H. In an embodiment, R 8 is independently —NHC(O)OH. In embodiments, R 8 is independently —NHOH. In an embodiment, R 8 is independently —OCCl. In an embodiment, R 8 is independently —OCBr. In an embodiment, R 8is independently -OCF. In an embodiment, R 8 is independently -OCI. In an embodiment, R 8 is independently —OCH2Cl. In an embodiment, R 8 is independently —OCHBr. In an embodiment, R 8 is independently —OCHF. In an embodiment, R 8 is independently -OCH2I. In embodiments, R 8 is independently —OCHCl. ​​In an embodiment, R 8 is independently —OCHBr. In embodiments, R 8 is independently -OCHF. In an embodiment, R 8 is independently -OCHI. In embodiments, R 8 is independently an unsubstituted C1-C4 alkyl. In an embodiment, R 8 is independently unsubstituted methyl. In embodiments, R 8 is independently unsubstituted ethyl. In embodiments, R 8 is independently unsubstituted propyl. In embodiments, R 8 is independently unsubstituted n-propyl. In embodiments, R 8 is independently unsubstituted isopropyl. In embodiments, R 8 is independently unsubstituted butyl. In embodiments, R 8 is independently unsubstituted n-butyl. In embodiments, R 8 is independently unsubstituted isobutyl. In embodiments, R 8 is independently unsubstituted tert-butyl. In embodiments, R 8 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. 8 is independently unsubstituted methoxy. In embodiments, R 8 is independently unsubstituted ethoxy. In embodiments, R 8 is independently unsubstituted propoxy. In embodiments, R 8 is independently unsubstituted n-propoxy. In embodiments, R 8is independently unsubstituted isopropoxy. In embodiments, R 8 is independently unsubstituted butoxy. In embodiments, R 8 is independently unsubstituted n-butoxy. In embodiments, R 8 is independently unsubstituted isobutoxy. In embodiments, R 8 is independently unsubstituted tert-butoxy.

[0347] In embodiments, R 8 is independently halogen or unsubstituted C1-C4 alkyl. 8 is independently —Cl or unsubstituted methyl.

[0348] In an embodiment, z8 is 0. In an embodiment, z8 is 1. In an embodiment, z8 is 2. In an embodiment, z8 is 3. In an embodiment, z8 is 4. In an embodiment, z8 is 5.

[0349] In embodiments, R 1 teeth

[0350] [ka]

[0351] [ka] In an embodiment, R 1 teeth,

[0352] [ka] In an embodiment, R 1 teeth,

[0353] [ka] In an embodiment, R 1 teeth,

[0354] [ka] In an embodiment, R 1 teeth,

[0355] [ka] In an embodiment, R 1 teeth,

[0356] [ka] In an embodiment, R 1 teeth,

[0357] [ka] In an embodiment, R 1 teeth,

[0358] [ka] In an embodiment, R 1 teeth,

[0359] [ka] In an embodiment, R 1 teeth,

[0360] [ka] In an embodiment, R 1 teeth,

[0361] [ka] In an embodiment, R 1 teeth,

[0362] [ka] In an embodiment, R 1 teeth,

[0363] [ka] In an embodiment, R 1 teeth,

[0364] [ka] In an embodiment, R 1 teeth,

[0365] [ka] In an embodiment, R 1 teeth,

[0366] [ka] In an embodiment, R 1 teeth,

[0367] [ka] In an embodiment, R 1 teeth,

[0368] [ka] In an embodiment, R 1 teeth,

[0369] [ka] In an embodiment, R 1 teeth,

[0370] [ka] In an embodiment, R 1 teeth,

[0371] [ka] In an embodiment, R 1 teeth,

[0372] [ka] In an embodiment, R 1 teeth,

[0373] [ka] In an embodiment, R 1 teeth,

[0374] [ka] In an embodiment, R 1 teeth,

[0375] [ka] In an embodiment, R 1 teeth,

[0376] [ka] is.

[0377] In embodiments, R 1 is a monovalent form of ARS-1620. In embodiments, R 1 teeth,

[0378] [ka] In embodiments, R 1 teeth,

[0379] [ka] In an embodiment, R 1 is a monovalent form of a portion of ARS-1620, and R 1 does not contain a substituted piperazinyl moiety.

[0380] In embodiments, R 1 is a monovalent form of AMG-510. 1 is a monovalent form of a compound as described in Canon, J. et al. Nature 575, 217-223 (2019), which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0381] [ka] In embodiments, R 1 teeth,

[0382] [ka] In an embodiment, R 1 is a monovalent form of a moiety of AMG-510, where R 1 does not include the substituted piperazinyl moieties or equivalents of the compounds described in Canon, et al.

[0383] In embodiments, R 1 is a monovalent form of MRTX-849. 1 is a monovalent form of a compound as described in Fell, JB et al. J. Med. Chem. 63, 6679-6693 (2020), which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0384] [ka] In embodiments, R 1 teeth,

[0385] [ka] In an embodiment, R 1 teeth,

[0386] [ka] In an embodiment, R 1 teeth,

[0387] [ka] In an embodiment, R 1 is a monovalent form of a moiety of MRTX-849, where R 1 does not include the substituted piperazinyl moieties or equivalents of the compounds described in Fell, et al.

[0388] In embodiments, R 1 is a monovalent form of GDC-6036. In embodiments, R 1 is a monovalent form of a compound as described in WO2020097537, which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0389] [ka] In embodiments, R 1 teeth,

[0390] [ka] In an embodiment, R 1 teeth,

[0391] [ka] In an embodiment, R 1 teeth,

[0392] [ka] In an embodiment, R 1 is a monovalent form of a moiety of GDC-6036, where R 1 does not include the substituted piperazinyl moieties or equivalents of the compounds described in WO2020097537.

[0393] In embodiments, R 1 is a monovalent form of MRTX1133. In embodiments, R 1 is a monovalent form of a compound as described in Wang, X. et al. J. Med. Chem. 65, 3123-3133 (2022), which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0394] [ka] In embodiments, R 1 teeth,

[0395] [ka] In an embodiment, R 1 teeth,

[0396] [ka] In an embodiment, R 1 is a monovalent form of a moiety of MRTX1133, where R 1 does not contain the diazabicyclooctanyl moiety or equivalent of the compounds described in Wang, et al.

[0397] In embodiments, R 1 is a monovalent form of BBO-8520. In embodiments, R 1 is a putative monovalent form of BBO-8520. 1 is a monovalent form of a compound as described in WO2023004102, which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0398] [ka] In embodiments, R 1 teeth,

[0399] [ka] In an embodiment, R 1 teeth,

[0400] [ka] In an embodiment, R 1 teeth,

[0401] [ka] In an embodiment, R 1 teeth,

[0402] [ka] In an embodiment, R 1 is a monovalent form of a portion of BBO-8520, and R 1 is a compound described in WO 2023004102

[0403] [ka] or equivalents.

[0404] In embodiments, R 1 is a monovalent form of JDQ-443. In embodiments, R 1 is a monovalent form of a compound as described in WO2021120890, which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0405] [ka] In embodiments, R 1 teeth,

[0406] [ka] In an embodiment, R 1 is a monovalent form of a portion of JDQ-443, and R 1 does not contain the azaspiroheptanyl moiety or equivalent of the compounds described in WO2021120890.

[0407] In embodiments, R 1 is a monovalent form of BI-0474. In embodiments, R 1 is a monovalent form of a compound as described in Broker, J. et al. J. Med. Chem. 65, 14614-14629 (2022), which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0408] [ka] In embodiments, R 1 teeth,

[0409] [ka] In an embodiment, R 1 teeth,

[0410] [ka] In an embodiment, R 1 is a monovalent form of a moiety of BI-0474, where R 1 does not contain the piperazinyl moiety or equivalent of the compounds described in Broker, et al.

[0411] In embodiments, R 1 is a monovalent form of a compound as described in WO2021118877, which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0412] [ka] In an embodiment, R 1 is a monovalent form of a portion of the compounds described in WO2021118877, where R 1 does not contain the acryloyl moiety or equivalent of the compounds described in WO2021118877.

[0413] In embodiments, R 1 is a monovalent form of a compound as described in WO2021120045, which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0414] [ka] In an embodiment, R 1 is a monovalent form of a portion of the compounds described in WO2021120045, where R 1 does not include the substituted piperazinyl moieties or equivalents of the compounds described in WO2021120045.

[0415] In embodiments, R 1 is a monovalent form of sotorasib. In embodiments, R 1 is a monovalent form of a compound as described in U.S. Pat. Nos. 10,519,146, 11,236,091, and 11,426,404, which are incorporated by reference in their entireties for all purposes. 1 teeth,

[0416] [ka] In embodiments, R 1 teeth,

[0417] [ka] In an embodiment, R 1 is a monovalent form of a moiety of sotorasib, and R 1 does not include the substituted piperazinyl moieties or equivalents of the compounds described in U.S. Patent Nos. 10,519,146, 11,236,091, and 11,426,404.

[0418] In embodiments, R 1 is a monovalent form of adagrasib. In embodiments, R 1 is a monovalent form of a compound as described in WO 2021 / 037018, which is incorporated herein by reference in its entirety for all purposes. 1 teeth,

[0419] [ka] In embodiments, R 1 teeth,

[0420] [ka] In an embodiment, R 1 teeth,

[0421] [ka] In an embodiment, R 1 teeth,

[0422] [ka] In an embodiment, R 1 is a monovalent form of a moiety of adagrasib, where R 1 does not contain the substituted piperazinyl moiety or equivalent of the compounds described in WO 2021 / 037018.

[0423] In embodiments, R 1 is a monovalent form of MRTX1257. In embodiments, R 1 is a monovalent form of a compound as described in U.S. Patent Application Publication No. 2018 / 0072723, which is incorporated herein by reference in its entirety for all purposes. In embodiments, R 1 teeth,

[0424] [ka] In embodiments, R 1 teeth,

[0425] [ka] In an embodiment, R 1 teeth,

[0426] [ka] In an embodiment, R 1 teeth,

[0427] [ka] In an embodiment, R 1 is a monovalent form of a moiety of MRTX1257, where R 1 does not contain the substituted piperazinyl moieties or equivalents of the compounds described in U.S. Patent Application Publication No. 2018 / 0072723.

[0428] In embodiments, R 3 If is substituted, R 3 is R as explained in the description of "first substituent" in the definitions section above. 3.1 In an embodiment, R 3.1 If the substituent is substituted, R 3.1 The substituents are as described in the definitions section above under "first substituent," R 3.2 In an embodiment, R 3.2 If the substituent is substituted, R 3.2 The substituents are as described in the definitions section above under "first substituent," R 3.3 In the above embodiment, R 3 , R 3.1 , R 3.2 , and R 3.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 3 , R 3.1 , R 3.2 , and R 3.3 Corresponds to.

[0429] In embodiments, R 3A If is substituted, R 3Ais R as explained in the description of "first substituent" in the definitions section above. 3A.1 In an embodiment, R 3A.1 If the substituent is substituted, R 3A.1 The substituents are as described in the definitions section above under "first substituent," R 3A.2 In an embodiment, R 3A.2 If the substituent is substituted, R 3A.2 The substituents are as described in the definitions section above under "first substituent," R 3A.3 In the above embodiment, R 3A , R 3A.1 , R 3A.2 , and R 3A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 3A , R 3A.1 , R 3A.2 , and R 3A.3 Corresponds to.

[0430] In embodiments, R 3B If is substituted, R 3B is R as explained in the description of "first substituent" in the definitions section above. 3B.1 In an embodiment, R 3B.1 If the substituent is substituted, R 3B.1 The substituents are as described in the definitions section above under "first substituent," R 3B.2 In an embodiment, R 3B.2 If the substituent is substituted, R 3B.2The substituents are as described in the definitions section above under "first substituent," R 3B.3 In the above embodiment, R 3B , R 3B.1 , R 3B.2 , and R 3B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 3B , R 3B.1 , R 3B.2 , and R 3B.3 Corresponds to.

[0431] In embodiments, R 3A and R 3B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 3A.1 In an embodiment, R 3A.1 If the substituent is substituted, R 3A.1 The substituents are as described in the definitions section above under "first substituent," R 3A.2 In an embodiment, R 3A.2 If the substituent is substituted, R 3A.2 The substituents are as described in the definitions section above under "first substituent," R 3A.3 In the above embodiment, R 3A.1 , R 3A.2 , and R 3A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1, R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 3A.1 , R 3A.2 , and R 3A.3 Corresponds to.

[0432] In embodiments, R 3A and R 3B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 3B.1 In an embodiment, R 3B.1 If the substituent is substituted, R 3B.1 The substituents are as described in the definitions section above under "first substituent," R 3B.2 In an embodiment, R 3B.2 If the substituent is substituted, R 3B.2 The substituents are as described in the definitions section above under "first substituent," R 3B.3 In the above embodiment, R 3B.1 , R 3B.2 , and R 3B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 3B.1 , R 3B.2 , and R 3B.3 Corresponds to.

[0433] In embodiments, R 3C If is substituted, R 3Cis R as explained in the description of "first substituent" in the definitions section above. 3C.1 In an embodiment, R 3C.1 If the substituent is substituted, R 3C.1 The substituents are as described in the definitions section above under "first substituent," R 3C.2 In an embodiment, R 3C.2 If the substituent is substituted, R 3C.2 The substituents are as described in the definitions section above under "first substituent," R 3C.3 In the above embodiment, R 3C , R 3C.1 , R 3C.2 , and R 3C.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 3C , R 3C.1 , R 3C.2 , and R 3C.3 Corresponds to.

[0434] In embodiments, R 3D If is substituted, R 3D is R as explained in the description of "first substituent" in the definitions section above. 3D.1 In an embodiment, R 3D.1 If the substituent is substituted, R 3D.1 The substituents are as described in the definitions section above under "first substituent," R 3D.2 In an embodiment, R 3D.2 If the substituent is substituted, R 3D.2The substituents are as described in the definitions section above under "first substituent," R 3D.3 In the above embodiment, R 3D , R 3D.1 , R 3D.2 , and R 3D.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 3D , R 3D.1 , R 3D.2 , and R 3D.3 Corresponds to.

[0435] In embodiments, R 4 If is substituted, R 4 is R as explained in the description of "first substituent" in the definitions section above. 4.1 In an embodiment, R 4.1 If the substituent is substituted, R 4.1 The substituents are as described in the definitions section above under "first substituent," R 4.2 In an embodiment, R 4.2 If the substituent is substituted, R 4.2 The substituents are as described in the definitions section above under "first substituent," R 4.3 In the above embodiment, R 4 , R 4.1 , R 4.2 , and R 4.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4 , R 4.1 , R 4.2 , and R 4.3 Corresponds to.

[0436] In embodiments, R 4A If is substituted, R 4A is R as explained in the description of "first substituent" in the definitions section above. 4A.1 In an embodiment, R 4A.1 If the substituent is substituted, R 4A.1 The substituents are as described in the definitions section above under "first substituent," R 4A.2 In an embodiment, R 4A.2 If the substituent is substituted, R 4A.2 The substituents are as described in the definitions section above under "first substituent," R 4A.3 In the above embodiment, R 4A , R 4A.1 , R 4A.2 , and R 4A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4A , R 4A.1 , R 4A.2 , and R 4A.3 Corresponds to.

[0437] In embodiments, R 4B If is substituted, R 4Bis R as explained in the description of "first substituent" in the definitions section above. 4B.1 In an embodiment, R 4B.1 If the substituent is substituted, R 4B.1 The substituents are as described in the definitions section above under "first substituent," R 4B.2 In an embodiment, R 4B.2 If the substituent is substituted, R 4B.2 The substituents are as described in the definitions section above under "first substituent," R 4B.3 In the above embodiment, R 4B , R 4B.1 , R 4B.2 , and R 4B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4B , R 4B.1 , R 4B.2 , and R 4B.3 Corresponds to.

[0438] In embodiments, R 4A and R 4B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 4A.1 In an embodiment, R 4A.1 If the substituent is substituted, R 4A.1 The substituents are as described in the definitions section above under "first substituent," R 4A.2In an embodiment, R 4A.2 If the substituent is substituted, R 4A.2 The substituents are as described in the definitions section above under "first substituent," R 4A.3 In the above embodiment, R 4A.1 , R 4A.2 , and R 4A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 4A.1 , R 4A.2 , and R 4A.3 Corresponds to.

[0439] In embodiments, R 4A and R 4B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 4B.1 In an embodiment, R 4B.1 If the substituent is substituted, R 4B.1 The substituents are as described in the definitions section above under "first substituent," R 4B.2 In an embodiment, R 4B.2 If the substituent is substituted, R 4B.2 The substituents are as described in the definitions section above under "first substituent," R 4B.3 In the above embodiment, R 4B.1 , R 4B.2 , and R 4B.3are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 4B.1 , R 4B.2 , and R 4B.3 Corresponds to.

[0440] In embodiments, R 4C If is substituted, R 4C is R as explained in the description of "first substituent" in the definitions section above. 4C.1 In an embodiment, R 4C.1 If the substituent is substituted, R 4C.1 The substituents are as described in the definitions section above under "first substituent," R 4C.2 In an embodiment, R 4C.2 If the substituent is substituted, R 4C.2 The substituents are as described in the definitions section above under "first substituent," R 4C.3 In the above embodiment, R 4C , R 4C.1 , R 4C.2 , and R 4C.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4C , R 4C.1 , R 4C.2 , and R 4C.3 Corresponds to.

[0441] In embodiments, R4D If is substituted, R 4D is R as explained in the description of "first substituent" in the definitions section above. 4D.1 In an embodiment, R 4D.1 If the substituent is substituted, R 4D.1 The substituents are as described in the definitions section above under "first substituent," R 4D.2 In an embodiment, R 4D.2 If the substituent is substituted, R 4D.2 The substituents are as described in the definitions section above under "first substituent," R 4D.3 In the above embodiment, R 4D , R 4D.1 , R 4D.2 , and R 4D.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4D , R 4D.1 , R 4D.2 , and R 4D.3 Corresponds to.

[0442] In embodiments, R 6 If is substituted, R 6 is R as explained in the description of "first substituent" in the definitions section above. 6.1 In an embodiment, R 6.1 If the substituent is substituted, R 6.1 The substituents are as described in the definitions section above under "first substituent," R 6.2 In an embodiment, R6.2 If the substituent is substituted, R 6.2 The substituents are as described in the definitions section above under "first substituent," R 6.3 In the above embodiment, R 6 , R 6.1 , R 6.2 , and R 6.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 6 , R 6.1 , R 6.2 , and R 6.3 Corresponds to.

[0443] In embodiments, R 7 If is substituted, R 7 is R as explained in the description of "first substituent" in the definitions section above. 7.1 In an embodiment, R 7.1 If the substituent is substituted, R 7.1 The substituents are as described in the definitions section above under "first substituent," R 7.2 In an embodiment, R 7.2 If the substituent is substituted, R 7.2 The substituents are as described in the definitions section above under "first substituent," R 7.3 In the above embodiment, R 7 , R 7.1 , R 7.2 , and R 7.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , RWW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 7 , R 7.1 , R 7.2 , and R 7.3 Corresponds to.

[0444] In embodiments, R 8 If is substituted, R 8 is R as explained in the description of "first substituent" in the definitions section above. 8.1 In an embodiment, R 8.1 If the substituent is substituted, R 8.1 The substituents are as described in the definitions section above under "first substituent," R 8.2 In an embodiment, R 8.2 If the substituent is substituted, R 8.2 The substituents are as described in the definitions section above under "first substituent," R 8.3 In the above embodiment, R 8 , R 8.1 , R 8.2 , and R 8.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 8 , R 8.1 , R 8.2 , and R 8.3 Corresponds to.

[0445] In embodiments, R 10If is substituted, R 10 is R as explained in the description of "first substituent" in the definitions section above. 10.1 In an embodiment, R 10.1 If the substituent is substituted, R 10.1 The substituents are as described in the definitions section above under "first substituent," R 10.2 In an embodiment, R 10.2 If the substituent is substituted, R 10.2 The substituents are as described in the definitions section above under "first substituent," R 10.3 In the above embodiment, R 10 , R 10.1 , R 10.2 , and R 10.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 10 , R 10.1 , R 10.2 , and R 10.3 Corresponds to.

[0446] In embodiments, R 10A If is substituted, R 10A is R as explained in the description of "first substituent" in the definitions section above. 10A.1 In an embodiment, R 10A.1 If the substituent is substituted, R 10A.1 The substituents are as described in the definitions section above under "first substituent," R 10A.2 In an embodiment, R 10A.2If the substituent is substituted, R 10A.2 The substituents are as described in the definitions section above under "first substituent," R 10A.3 In the above embodiment, R 10A , R 10A.1 , R 10A.2 , and R 10A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 10A , R 10A.1 , R 10A.2 , and R 10A.3 Corresponds to.

[0447] In embodiments, R 10B If is substituted, R 10B is R as explained in the description of "first substituent" in the definitions section above. 10B.1 In an embodiment, R 10B.1 If the substituent is substituted, R 10B.1 The substituents are as described in the definitions section above under "first substituent," R 10B.2 In an embodiment, R 10B.2 If the substituent is substituted, R 10B.2 The substituents are as described in the definitions section above under "first substituent," R 10B.3 In the above embodiment, R 10B , R 10B.1 , R 10B.2 , and R 10B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , RWW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 10B , R 10B.1 , R 10B.2 , and R 10B.3 Corresponds to.

[0448] In embodiments, R 10A and R 10B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 10A.1 In an embodiment, R 10A.1 If the substituent is substituted, R 10A.1 The substituents are as described in the definitions section above under "first substituent," R 10A.2 In an embodiment, R 10A.2 If the substituent is substituted, R 10A.2 The substituents are as described in the definitions section above under "first substituent," R 10A.3 In the above embodiment, R 10A.1 , R 10A.2 , and R 10A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 10A.1 , R 10A.2 , and R 10A.3 Corresponds to.

[0449] In embodiments, R 10A and R10B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 10B.1 In an embodiment, R 10B.1 If the substituent is substituted, R 10B.1 The substituents are as described in the definitions section above under "first substituent," R 10B.2 In an embodiment, R 10B.2 If the substituent is substituted, R 10B.2 The substituents are as described in the definitions section above under "first substituent," R 10B.3 In the above embodiment, R 10B.1 , R 10B.2 , and R 10B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 10B.1 , R 10B.2 , and R 10B.3 Corresponds to.

[0450] In embodiments, R 10C If is substituted, R 10C is R as explained in the description of "first substituent" in the definitions section above. 10C.1 In an embodiment, R 10C.1 If the substituent is substituted, R 10C.1 The substituents are as described in the definitions section above under "first substituent," R 10C.2 In an embodiment, R 10C.2 If the substituent is substituted, R10C.2 The substituents are as described in the definitions section above under "first substituent," R 10C.3 In the above embodiment, R 10C , R 10C.1 , R 10C.2 , and R 10C.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 10C , R 10C.1 , R 10C.2 , and R 10C.3 Corresponds to.

[0451] In embodiments, R 10D If is substituted, R 10D is R as explained in the description of "first substituent" in the definitions section above. 10D.1 In an embodiment, R 10D.1 If the substituent is substituted, R 10D.1 The substituents are as described in the definitions section above under "first substituent," R 10D.2 In an embodiment, R 10D.2 If the substituent is substituted, R 10D.2 The substituents are as described in the definitions section above under "first substituent," R 10D.3 In the above embodiment, R 10D , R 10D.1 , R 10D.2 , and R 10D.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and RWW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 10D , R 10D.1 , R 10D.2 , and R 10D.3 Corresponds to.

[0452] In embodiments, R 20 If is substituted, R 20 is R as explained in the description of "first substituent" in the definitions section above. 20.1 In an embodiment, R 20.1 If the substituent is substituted, R 20.1 The substituents are as described in the definitions section above under "first substituent," R 20.2 In an embodiment, R 20.2 If the substituent is substituted, R 20.2 The substituents are as described in the definitions section above under "first substituent," R 20.3 In the above embodiment, R 20 , R 20.1 , R 20.2 , and R 20.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 20 , R 20.1 , R 20.2 , and R 20.3 Corresponds to.

[0453] In embodiments, R 20A If is substituted, R 20Ais R as explained in the description of "first substituent" in the definitions section above. 20A.1 In an embodiment, R 20A.1 If the substituent is substituted, R 20A.1 The substituents are as described in the definitions section above under "first substituent," R 20A.2 In an embodiment, R 20A.2 If the substituent is substituted, R 20A.2 The substituents are as described in the definitions section above under "first substituent," R 20A.3 In the above embodiment, R 20A , R 20A.1 , R 20A.2 , and R 20A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 20A , R 20A.1 , R 20A.2 , and R 20A.3 Corresponds to.

[0454] In embodiments, R 20B If is substituted, R 20B is R as explained in the description of "first substituent" in the definitions section above. 20B.1 In an embodiment, R 20B.1 If the substituent is substituted, R 20B.1 The substituents are as described in the definitions section above under "first substituent," R 20B.2 In an embodiment, R 20B.2 If the substituent is substituted, R 20B.2The substituents are as described in the definitions section above under "first substituent," R 20B.3 In the above embodiment, R 20B , R 20B.1 , R 20B.2 , and R 20B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 20B , R 20B.1 , R 20B.2 , and R 20B.3 Corresponds to.

[0455] In embodiments, R 20A and R 20B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 20A.1 In an embodiment, R 20A.1 If the substituent is substituted, R 20A.1 The substituents are as described in the definitions section above under "first substituent," R 20A.2 In an embodiment, R 20A.2 If the substituent is substituted, R 20A.2 The substituents are as described in the definitions section above under "first substituent," R 20A.3 In the above embodiment, R 20A.1 , R 20A.2 , and R 20A.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1, R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 20A.1 , R 20A.2 , and R 20A.3 Corresponds to.

[0456] In embodiments, R 20A and R 20B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be substituted with R 20B.1 In an embodiment, R 20B.1 If the substituent is substituted, R 20B.1 The substituents are as described in the definitions section above under "first substituent," R 20B.2 In an embodiment, R 20B.2 If the substituent is substituted, R 20B.2 The substituents are as described in the definitions section above under "first substituent," R 20B.3 In the above embodiment, R 20B.1 , R 20B.2 , and R 20B.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 20B.1 , R 20B.2 , and R 20B.3 Corresponds to.

[0457] In embodiments, R 20C If is substituted, R 20Cis R as explained in the description of "first substituent" in the definitions section above. 20C.1 In an embodiment, R 20C.1 If the substituent is substituted, R 20C.1 The substituents are as described in the definitions section above under "first substituent," R 20C.2 In an embodiment, R 20C.2 If the substituent is substituted, R 20C.2 The substituents are as described in the definitions section above under "first substituent," R 20C.3 In the above embodiment, R 20C , R 20C.1 , R 20C.2 , and R 20C.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 20C , R 20C.1 , R 20C.2 , and R 20C.3 Corresponds to.

[0458] In embodiments, R 20D If is substituted, R 20D is R as explained in the description of "first substituent" in the definitions section above. 20D.1 In an embodiment, R 20D.1 If the substituent is substituted, R 20D.1 The substituents are as described in the definitions section above under "first substituent," R 20D.2 In an embodiment, R 20D.2 If the substituent is substituted, R 20D.2The substituents are as described in the definitions section above under "first substituent," R 20D.3 In the above embodiment, R 20D , R 20D.1 , R 20D.2 , and R 20D.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 20D , R 20D.1 , R 20D.2 , and R 20D.3 Corresponds to.

[0459] In embodiments, R 30 If is substituted, R 30 is R as explained in the description of "first substituent" in the definitions section above. 30.1 In an embodiment, R 30.1 If the substituent is substituted, R 30.1 The substituents are as described in the definitions section above under "first substituent," R 30.2 In an embodiment, R 30.2 If the substituent is substituted, R 30.2 The substituents are as described in the definitions section above under "first substituent," R 30.3 In the above embodiment, R 30 , R 30.1 , R 30.2 , and R 30.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 30 , R 30.1 , R 30.2 , and R 30.3 Corresponds to.

[0460] In embodiments, R 100 If is substituted, R 100 is R as explained in the description of "first substituent" in the definitions section above. 100.1 In an embodiment, R 100.1 If the substituent is substituted, R 100.1 The substituents are as described in the definitions section above under "first substituent," R 100.2 In an embodiment, R 100.2 If the substituent is substituted, R 100.2 The substituents are as described in the definitions section above under "first substituent," R 100.3 In the above embodiment, R 100 , R 100.1 , R 100.2 , and R 100.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 100 , R 100.1 , R 100.2 , and R 100.3 Corresponds to.

[0461] In embodiments, R 101 If is substituted, R 101is R as explained in the description of "first substituent" in the definitions section above. 101.1 In an embodiment, R 101.1 If the substituent is substituted, R 101.1 The substituents are as described in the definitions section above under "first substituent," R 101.2 In an embodiment, R 101.2 If the substituent is substituted, R 101.2 The substituents are as described in the definitions section above under "first substituent," R 101.3 In the above embodiment, R 101 , R 101.1 , R 101.2 , and R 101.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 101 , R 101.1 , R 101.2 , and R 101.3 Corresponds to.

[0462] In embodiments, R 102 If is substituted, R 102 is R as explained in the description of "first substituent" in the definitions section above. 102.1 In an embodiment, R 102.1 If the substituent is substituted, R 102.1 The substituents are as described in the definitions section above under "first substituent," R 102.2 In an embodiment, R 102.2 If the substituent is substituted, R 102.2The substituents are as described in the definitions section above under "first substituent," R 102.3 In the above embodiment, R 102 , R 102.1 , R 102.2 , and R 102.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 102 , R 102.1 , R 102.2 , and R 102.3 Corresponds to.

[0463] In embodiments, R 103 If is substituted, R 103 is R as explained in the description of "first substituent" in the definitions section above. 103.1 In an embodiment, R 103.1 If the substituent is substituted, R 103.1 The substituents are as described in the definitions section above under "first substituent," R 103.2 In an embodiment, R 103.2 If the substituent is substituted, R 103.2 The substituents are as described in the definitions section above under "first substituent," R 103.3 In the above embodiment, R 103 , R 103.1 , R 103.2 , and R 103.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 103 , R 103.1 , R 103.2 , and R 103.3 Corresponds to.

[0464] In embodiments, R 104 If is substituted, R 104 is R as explained in the description of "first substituent" in the definitions section above. 104.1 In an embodiment, R 104.1 If the substituent is substituted, R 104.1 The substituents are as described in the definitions section above under "first substituent," R 104.2 In an embodiment, R 104.2 If the substituent is substituted, R 104.2 The substituents are as described in the definitions section above under "first substituent," R 104.3 In the above embodiment, R 104 , R 104.1 , R 104.2 , and R 104.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 104 , R 104.1 , R 104.2 , and R 104.3 Corresponds to.

[0465] In embodiments, R 105 If is substituted, R 105is R as explained in the description of "first substituent" in the definitions section above. 105.1 In an embodiment, R 105.1 If the substituent is substituted, R 105.1 The substituents are as described in the definitions section above under "first substituent," R 105.2 In an embodiment, R 105.2 If the substituent is substituted, R 105.2 The substituents are as described in the definitions section above under "first substituent," R 105.3 In the above embodiment, R 105 , R 105.1 , R 105.2 , and R 105.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 105 , R 105.1 , R 105.2 , and R 105.3 Corresponds to.

[0466] In embodiments, R 200 If is substituted, R 200 is R as explained in the description of "first substituent" in the definitions section above. 200.1 In an embodiment, R 200.1 If the substituent is substituted, R 200.1 The substituents are as described in the definitions section above under "first substituent," R 200.2 In an embodiment, R 200.2 If the substituent is substituted, R 200.2The substituents are as described in the definitions section above under "first substituent," R 200.3 In the above embodiment, R 200 , R 200.1 , R 200.2 , and R 200.3 are, respectively, R as explained in the description of "first substituent" in the definition section above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 200 , R 200.1 , R 200.2 , and R 200.3 Corresponds to.

[0467] In an embodiment, L 2 If is replaced, L 2 is R as described in the definitions section above in the description of "first substituent" L2.1 In an embodiment, R L2.1 If the substituent is substituted, R L2.1 The substituents are as described in the definitions section above under "first substituent," R L2.2 In an embodiment, R L2.2 If the substituent is substituted, R L2.2 The substituents are as described in the definitions section above under "first substituent," R L2.3 In the above embodiment, L is substituted with one or more third substituents represented by 2 , R L2.1 , R L2.2 , and R L2.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 2 , R L2.1 , R L2.2 , and R L2.3 Corresponds to.

[0468] In an embodiment, L 3 If is replaced, L 3 is R as described in the definitions section above in the description of "first substituent" L3.1 In an embodiment, R L3.1 If the substituent is substituted, R L3.1 The substituents are as described in the definitions section above under "first substituent," R L3.2 In an embodiment, R L3.2 If the substituent is substituted, R L3.2 The substituents are as described in the definitions section above under "first substituent," R L3.3 In the above embodiment, L is substituted with one or more third substituents represented by 3 , R L3.1 , R L3.2 , and R L3.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3 and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 3 , R L3.1 , R L3.2 , and R L3.3 Corresponds to.

[0469] In an embodiment, L 10 If is replaced, L 10is R as described in the definitions section above in the description of "first substituent" L10.1 In an embodiment, R L10.1 If the substituent is substituted, R L10.1 The substituents are as described in the definitions section above under "first substituent," R L10.2 In an embodiment, R L10.2 If the substituent is substituted, R L10.2 The substituents are as described in the definitions section above under "first substituent," R L10.3 In the above embodiment, L is substituted with one or more third substituents represented by 10 , R L10.1 , R L10.2 , and R L10.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3 and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 10 , R L10.1 , R L10.2 , and R L10.3 Corresponds to.

[0470] In an embodiment, L 20 If is replaced, L 20 is R as described in the definitions section above in the description of "first substituent" L20.1 In an embodiment, R L20.1 If the substituent is substituted, R L20.1 The substituents are as described in the definitions section above under "first substituent," R L20.2 In an embodiment, R L20.2 If the substituent is substituted, R L20.2The substituents are as described in the definitions section above under "first substituent," R L20.3 In the above embodiment, L is substituted with one or more third substituents represented by 20 , R L20.1 , R L20.2 , and R L20.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3 and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 20 , R L20.1 , R L20.2 , and R L20.3 Corresponds to.

[0471] In an embodiment, L 101 If is replaced, L 101 is R as described in the definitions section above in the description of "first substituent" L101.1 In an embodiment, R L101.1 If the substituent is substituted, R L101.1 The substituents are as described in the definitions section above under "first substituent," R L101.2 In an embodiment, R L101.2 If the substituent is substituted, R L101.2 The substituents are as described in the definitions section above under "first substituent," R L101.3 In the above embodiment, L is substituted with one or more third substituents represented by 101 , R L101.1 , R L101.2 , and R L101.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3and has a value corresponding to the value of L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 101 , R L101.1 , R L101.2 , and R L101.3 Corresponds to.

[0472] In an embodiment, L 102 If is substituted, L 102 is R as described in the definitions section above in the description of "first substituent" L102.1 In an embodiment, R L102.1 If the substituent is substituted, R L102.1 The substituents are as described in the definitions section above under "first substituent," R L102.2 In an embodiment, R L102.2 If the substituent is substituted, R L102.2 The substituents are as described in the definitions section above under "first substituent," R L102.3 In the above embodiment, L is substituted with one or more third substituents represented by 102 , R L102.1 , R L102.2 , and R L102.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3 and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 102 , R L102.1 , R L102.2 , and R L102.3 Corresponds to.

[0473] In an embodiment, L 103 If is substituted, L 103is R as described in the definitions section above in the description of "first substituent" L103.1 In an embodiment, R L103.1 If the substituent is substituted, R L103.1 The substituents are as described in the definitions section above under "first substituent," R L103.2 In an embodiment, R L103.2 If the substituent is substituted, R L103.2 The substituents are as described in the definitions section above under "first substituent," R L103.3 In the above embodiment, L is substituted with one or more third substituents represented by 103 , R L103.1 , R L103.2 , and R L103.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3 and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 103 , R L103.1 , R L103.2 , and R L103.3 Corresponds to.

[0474] In an embodiment, L 104 If is replaced, L 104 is R as described in the definitions section above in the description of "first substituent" L104.1 In an embodiment, R L104.1 If the substituent is substituted, R L104.1 The substituents are as described in the definitions section above under "first substituent," R L104.2 In an embodiment, R L104.2 If the substituent is substituted, R L104.2The substituents are as described in the definitions section above under "first substituent," R L104.3 In the above embodiment, L is substituted with one or more third substituents represented by 104 , R L104.1 , R L104.2 , and R L104.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3 and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 104 , R L104.1 , R L104.2 , and R L104.3 Corresponds to.

[0475] In an embodiment, L 105 If is replaced, L 105 is R as described in the definitions section above in the description of "first substituent" L105.1 In an embodiment, R L105.1 If the substituent is substituted, R L105.1 The substituents are as described in the definitions section above under "first substituent," R L105.2 In an embodiment, R L105.2 If the substituent is substituted, R L105.2 The substituents are as described in the definitions section above under "first substituent," R L105.3 In the above embodiment, L is substituted with one or more third substituents represented by 105 , R L105.1 , R L105.2 , and R L105.3 are each L as described in the definitions section above in the description of the "first substituent." WW , R LWW.1 , R LWW.2 , and R LWW.3and L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 105 , R L105.1 , R L105.2 , and R L105.3 Corresponds to.

[0476] In embodiments, the compound has the formula:

[0477] [ka] In embodiments, the compound has the formula:

[0478] [ka] In embodiments, the compound has the formula:

[0479] [ka] In embodiments, the compound has the formula:

[0480] [ka] In embodiments, the compound has the formula:

[0481] [ka] In embodiments, the compound has the formula:

[0482] [ka] In embodiments, the compound has the formula:

[0483] [ka] It has.

[0484] In an embodiment,

[0485] [ka] is capable of forming a covalent bond with...

Claims

1. 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: 【Chemical 1】 wherein R １ is the Switch II binding pocket binding moiety, L １ is a bond or a bivalent linker; L ２ is a bond or substituted or unsubstituted alkylene; L ３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR ３０ -, -C(O)NR ３０ -, -NR ３０ C(O)-, -NR ３０ C(O)O-, -OC(O)NR ３０ -, -NR ３０ C(O)NR ３０ -, -S(O) ２ -, -NR ３０ S (O) ２ -, -S(O) ２ NR ３０ -, 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; R ３ But hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -OCX ３ ３ , -OCH ２ X ３ , -OCHX ３ ２ , -CN, -SO ｎ３ R ３Ｄ , -SO ｖ３ NR ３Ａ R ３Ｂ , -NR ３Ｃ NR ３Ａ R ３Ｂ , -ONR ３Ａ R ３Ｂ , -NR ３Ｃ C(O)NR ３Ａ R ３Ｂ , -N(O) ｍ３ , -NR ３Ａ R ３Ｂ , -C(O)R ３Ｃ , -C(O)OR ３Ｃ , -OC(O)R ３Ｃ , -OC(O)OR ３Ｃ , —C(O)NR ３Ａ R ３Ｂ , —OC(O)NR ３Ａ R ３Ｂ , -OR ３Ｄ , -SR ３Ｄ , -NR ３Ａ SO ２ R ３Ｄ , -NR ３Ａ C(O)R ３Ｃ , -NR ３Ａ C(O)OR ３Ｃ , -NR ３Ａ OR ３Ｃ , -SF ５ , -N ３ , 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; R ３０ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ３Ａ , R ３Ｂ , R ３Ｃ , and R ３Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ I, -OCH ２ F, 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, and R ３Ａ and R ３Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; each X ３ is independently —Cl, —Br, —I, or —F; n3 is an integer from 0 to 4, A compound, or a pharmaceutically acceptable salt thereof, wherein m3 and v3 are independently 1 or 2.

2. L ２ is a bond or an unsubstituted C １ ~C ４ The compound of claim 1 which is an alkylene.

3. L ３ is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O) ２ -, -NHS(O) ２ -, -S(O) ２ 2. The compound of claim 1, which is NH-, 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.

4. L ３ The compound of claim 1 , wherein is a bond.

5. L ３ The compound of claim 1, wherein is —C(O)—.

6. formula: 【Chemistry 2】 2. The compound of claim 1 having the formula:

7. formula: 【Chemistry 3】 2. The compound of claim 1 having the formula:

8. formula: 【Chemistry 4】 2. The compound of claim 1 having the formula:

9. R ３ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

10. R ３ is hydrogen or unsubstituted C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

11. R ３ The compound of claim 1 , wherein is hydrogen or unsubstituted methyl.

12. L １ But, -L １０１ -L １０２ -L １０３ -L １０４ -L １０５ - and L １０１ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０１ -, -C(O)NR １０１ -, -NR １０１ C(O)-, -NR １０１ C(O)O-, -OC(O)NR １０１ -, -NR １０１ C(O)NR １０１ -, -NR １０１ C(NH)NR １０１ -, -S(O) ２ -, -NR １０１ S (O) ２ -, -S(O) ２ NR １０１ -, 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; L １０２ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０２ -, -C(O)NR １０２ -, -NR １０２ C(O)-, -NR １０２ C(O)O-, -OC(O)NR １０２ -, -NR １０２ C(O)NR １０２ -, -NR １０２ C(NH)NR １０２ -, -S(O) ２ -, -NR １０２ S (O) ２ -, -S(O) ２ NR １０２ -, 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; L １０３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０３ -, -C(O)NR １０３ -, -NR １０３ C(O)-, -NR １０３ C(O)O-, -OC(O)NR １０３ -, -NR １０３ C(O)NR １０３ -, -NR １０３ C(NH)NR １０３ -, -S(O) ２ -, -NR １０３ S (O) ２ -, -S(O) ２ NR １０３ -, 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; L １０４ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０４ -, -C(O)NR １０４ -, -NR １０４ C(O)-, -NR １０４ C(O)O-, -OC(O)NR １０４ -, -NR １０４ C(O)NR １０４ -, -NR １０４ C(NH)NR １０４ -, -S(O) ２ -, -NR １０４ S (O) ２ -, -S(O) ２ NR １０４ -, 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; L １０５ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０５ -, -C(O)NR １０５ -, -NR １０５ C(O)-, -NR １０５ C(O)O-, -OC(O)NR １０５ -, -NR １０５ C(O)NR １０５ -, -NR １０５ C(NH)NR １０５ -, -S(O) ２ -, -NR １０５ S (O) ２ -, -S(O) ２ NR １０５ -, 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; Each R １０１ , R １０２ , R １０３ , R １０４ , and R １０５ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

13. L １ The compound of claim 1, wherein is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene.

14. L １ but, 【Chemistry 5】 2. The compound of claim 1, wherein:

15. R １ But, -L １０ -R １０ and L １０ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １００ -, -C(O)NR １００ -, -NR １００ C(O)-, -NR １００ C(O)O-, -OC(O)NR １００ -, -NR １００ C(O)NR １００ -, -NR １００ C(NH)NR １００ -, -S(O) ２ -, -NR １００ S (O) ２ -, -S(O) ２ NR １００ -, 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; R １００ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R １０ But hydrogen, halogen, -CX １０ ３ , -CHX １０ ２ , -CH ２ X １０ , -OCX １０ ３ , -OCH ２ X １０ , -OCHX １０ ２ , -CN, -SO ｎ１０ R １０Ｄ , -SO ｖ１０ NR １０Ａ R １０Ｂ , -NR １０Ｃ NR １０Ａ R １０Ｂ , -ONR １０Ａ R １０Ｂ , -NHC(O)NR １０Ｃ NR １０Ａ R １０Ｂ , -NHC(O)NR １０Ａ R １０Ｂ , -N(O) ｍ１０ , -NR １０Ａ R １０Ｂ , -C(O)R １０Ｃ , -C(O)OR １０Ｃ , —C(O)NR １０Ａ R １０Ｂ , -OR １０Ｄ , -SR １０Ｄ , -NR １０Ａ SO ２ R １０Ｄ , -NR １０Ａ C(O)R １０Ｃ , -NR １０Ａ C(O)OR １０Ｃ , -NR １０Ａ OR １０Ｃ , -SF ５ , -N ３ , 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; R １０Ａ , R １０Ｂ , R １０Ｃ , and R １０Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ I, -OCH ２ F, 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, and R １０Ａ and R １０Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; each X １０ is independently —F, —Cl, —Br, or —I; n10 is an integer from 0 to 4, The compound of claim 1, wherein m10 and v10 are independently 1 or 2.

16. R １ but, 【Chemistry 6】 and R ６ are independently oxo, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ７ are independently oxo, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ８ are independently a halogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; z6 is an integer from 0 to 7, z7 is an integer from 0 to 7, The compound according to claim 1, wherein z8 is an integer of 0 to 5.

17. R ６ are independently selected from halogen, —OH, unsubstituted C １ ~C ４ 17. The compound of claim 16, which is alkyl, substituted 2- to 6-membered heteroalkyl, or substituted 5- to 6-membered heteroaryl.

18. R ６ is independently -F, -Cl, -OH, or unsubstituted methyl.

19. R ６ 17. The compound of claim 16, wherein is independently a 2- to 6-membered heteroalkyl substituted with a substituted heterocycloalkyl or an unsubstituted fused heterocycloalkyl.

20. R ６ 17. The compound of claim 16, wherein is independently a substituted pyridyl.

21. 17. The compound of claim 16, wherein z6 is 1, 2, or 3.

22. R ７ are independently a halogen, —CF ３ , -CN, -OH, -NH ２ , unsubstituted C １ ~C ４ Alkyl, or unsubstituted C ２ ~C ４ 17. The compound of claim 16, which is alkynyl.

23. R ７ are independently —F, —Cl, —CF ３ , -CN, -OH, -NH ２ , unsubstituted methyl, or unsubstituted ethynyl.

24. 17. The compound of claim 16, wherein z7 is 1, 2, or 3.

25. R ８ are independently halogen or unsubstituted C １ ~C ４ 17. The compound of claim 16, wherein the compound is alkyl.

26. R ８ The compound of claim 16, wherein is independently -Cl or unsubstituted methyl.

27. 17. The compound of claim 16, wherein z8 is 1.

28. R １ but, 【Chemistry 7】 2. The compound of claim 1, wherein:

29. formula: 【Chemistry 8】 2. The compound of claim 1 having the formula:

30. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

31. 30. A method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

32. 32. The method of claim 31 , wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

33. 30. A method of reducing Ras protein-mediated activity in a cell, comprising contacting said cell with an effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

34. 34. The method of claim 33, wherein the Ras is a human K-Ras protein.

35. 35. The method of claim 34, wherein the human K-Ras protein comprises a G12R mutation, a G13R mutation, or a Q61R mutation.

36. 34. The method of claim 33, wherein the Ras protein is a human H-Ras protein.

37. 37. The method of claim 36, wherein the human H-Ras protein comprises a G12R mutation, a G13R mutation, or a Q61R mutation.

38. 34. The method of claim 33, wherein the Ras protein is a human N-Ras protein.

39. 39. The method of claim 38, wherein the human N-Ras protein comprises a G12R mutation, a G13R mutation, or a Q61R mutation.

40. 30. A switch II GTPase protein covalently bound to the compound of any one of claims 1 to 29, or a salt thereof, wherein the compound is covalently bound to an arginine residue of the switch II GTPase protein.

41. 41. The covalently modified Switch II GTPase protein of claim 40, wherein said compound is reversibly covalently bound to an arginine residue of said Switch II GTPase protein.

42. 41. The covalently modified Switch II GTPase protein of claim 40, wherein said compound is irreversibly covalently attached to an arginine residue of said Switch II GTPase protein.

43. 41. The covalently modified switch II GTPase protein of claim 40, wherein the switch II GTPase protein is a human K-Ras protein.

44. 44. The covalently modified Switch II GTPase protein of claim 43, wherein the human K-Ras protein comprises a G12R mutation.

45. 45. The covalently modified Switch II GTPase protein of claim 44, wherein the compound is covalently attached to arginine residue 12.

46. 41. The covalently modified Switch II GTPase protein of claim 40, wherein the Switch II GTPase protein is a human H-Ras protein.

47. 47. The covalently modified Switch II GTPase protein of claim 46, wherein the human H-Ras protein comprises a G12R mutation.

48. 48. The covalently modified Switch II GTPase protein of claim 47, wherein the compound is covalently attached to arginine residue 12.

49. 41. The covalently modified switch II GTPase protein of claim 40, wherein the switch II GTPase protein is a human N-Ras protein.

50. 50. The covalently modified Switch II GTPase protein of claim 49, wherein the human N-Ras protein comprises a G12R mutation.

51. 51. The covalently modified Switch II GTPase protein of claim 50, wherein the compound is covalently attached to arginine residue 12.

52. 1. A method of attaching a compound to an arginine residue of a protein, said method comprising contacting said compound with said arginine residue, said compound having the formula: 【Chemistry 9】 or a salt thereof, wherein: R ２ is a switch II binding pocket binding moiety, a phosphatase PTP domain binding moiety, an SH2 domain binding moiety, a pseudokinase KSR domain binding moiety, or a pseudokinase STRADα domain binding moiety; L １ is a bond or a bivalent linker; L ２ is a bond or substituted or unsubstituted alkylene; L ３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR ３０ -, -C(O)NR ３０ -, -NR ３０ C(O)-, -NR ３０ C(O)O-, -OC(O)NR ３０ -, -NR ３０ C(O)NR ３０ -, -S(O) ２ -, -NR ３０ S (O) ２ -, -S(O) ２ NR ３０ -, 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; R ３ But hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -OCX ３ ３ , -OCH ２ X ３ , -OCHX ３ ２ , -CN, -SO ｎ３ R ３Ｄ , -SO ｖ３ NR ３Ａ R ３Ｂ , -NR ３Ｃ NR ３Ａ R ３Ｂ , -ONR ３Ａ R ３Ｂ , -NR ３Ｃ C(O)NR ３Ａ R ３Ｂ , -N(O) ｍ３ , -NR ３Ａ R ３Ｂ , -C(O)R ３Ｃ , -C(O)OR ３Ｃ , -OC(O)R ３Ｃ , -OC(O)OR ３Ｃ , —C(O)NR ３Ａ R ３Ｂ , —OC(O)NR ３Ａ R ３Ｂ , -OR ３Ｄ , -SR ３Ｄ , -NR ３Ａ SO ２ R ３Ｄ , -NR ３Ａ C(O)R ３Ｃ , -NR ３Ａ C(O)OR ３Ｃ , -NR ３Ａ OR ３Ｃ , -SF ５ , -N ３ , 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; R ３０ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ３Ａ , R ３Ｂ , R ３Ｃ , and R ３Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ I, -OCH ２ F, 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, and R ３Ａ and R ３Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; each X ３ is independently —Cl, —Br, —I, or —F; n3 is an integer from 0 to 4, The method wherein m3 and v3 are independently 1 or 2.

53. 53. The method of claim 52, wherein the protein further comprises additional arginine residues, none of which react with the compound.

54. L ２ is a bond or an unsubstituted C １ ~C ４ 53. The method of claim 52, wherein the alkylene is alkylene.

55. L ３ is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O) ２ -, -NHS(O) ２ -, -S(O) ２ 53. The method of claim 52, wherein the alkylene group is NH-, 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.

56. L ３ The method of claim 52, wherein is a bond.

57. L ３ The method of claim 52, wherein is —C(O)—.

58. The compound has the formula: 【Chemistry 10】 53. The method of claim 52, comprising:

59. The compound has the formula: 【Chemistry 11】 53. The method of claim 52, comprising:

60. The compound has the formula: 【Chemistry 12】 53. The method of claim 52, comprising:

61. R ３ is hydrogen or unsubstituted C １ ~C ４ 53. The method of claim 52, wherein the alkyl is alkyl.

62. R ３ 53. The method of claim 52, wherein is hydrogen or unsubstituted methyl.

63. L １ But, -L １０１ -L １０２ -L １０３ -L １０４ -L １０５ - and L １０１ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０１ -, -C(O)NR １０１ -, -NR １０１ C(O)-, -NR １０１ C(O)O-, -OC(O)NR １０１ -, -NR １０１ C(O)NR １０１ -, -NR １０１ C(NH)NR １０１ -, -S(O) ２ -, -NR １０１ S (O) ２ -, -S(O) ２ NR １０１ -, 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; L １０２ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０２ -, -C(O)NR １０２ -, -NR １０２ C(O)-, -NR １０２ C(O)O-, -OC(O)NR １０２ -, -NR １０２ C(O)NR １０２ -, -NR １０２ C(NH)NR １０２ -, -S(O) ２ -, -NR １０２ S (O) ２ -, -S(O) ２ NR １０２ -, 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; L １０３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０３ -, -C(O)NR １０３ -, -NR １０３ C(O)-, -NR １０３ C(O)O-, -OC(O)NR １０３ -, -NR １０３ C(O)NR １０３ -, -NR １０３ C(NH)NR １０３ -, -S(O) ２ -, -NR １０３ S (O) ２ -, -S(O) ２ NR １０３ -, 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; L １０４ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０４ -, -C(O)NR １０４ -, -NR １０４ C(O)-, -NR １０４ C(O)O-, -OC(O)NR １０４ -, -NR １０４ C(O)NR １０４ -, -NR １０４ C(NH)NR １０４ -, -S(O) ２ -, -NR １０４ S (O) ２ -, -S(O) ２ NR １０４ -, 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; L １０５ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０５ -, -C(O)NR １０５ -, -NR １０５ C(O)-, -NR １０５ C(O)O-, -OC(O)NR １０５ -, -NR １０５ C(O)NR １０５ -, -NR １０５ C(NH)NR １０５ -, -S(O) ２ -, -NR １０５ S (O) ２ -, -S(O) ２ NR １０５ -, 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; Each R １０１ , R １０２ , R １０３ , R １０４ , and R １０５ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

64. L １ 53. The method of claim 52, wherein is a bond, substituted or unsubstituted 3- to 8-membered heterocycloalkylene, or substituted or unsubstituted phenylene.

65. L １ but, 【Chemistry 13】 53. The method of claim 52, wherein:

66. R ２ But, -L ２０ -R ２０ and L ２０ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR ２００ -, -C(O)NR ２００ -, -NR ２００ C(O)-, -NR ２００ C(O)O-, -OC(O)NR ２００ -, -NR ２００ C(O)NR ２００ -, -NR ２００ C(NH)NR ２００ -, -S(O) ２ -, -NR ２００ S (O) ２ -, -S(O) ２ NR ２００ -, 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; R ２００ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ２０ But hydrogen, halogen, -CX ２０ ３ , -CHX ２０ ２ , -CH ２ X ２０ , -OCX ２０ ３ , -OCH ２ X ２０ , -OCHX ２０ ２ , -CN, -SO ｎ２０ R ２０Ｄ , -SO ｖ２０ NR ２０Ａ R ２０Ｂ , -NR ２０Ｃ NR ２０Ａ R ２０Ｂ , -ONR ２０Ａ R ２０Ｂ , -NHC(O)NR ２０Ｃ NR ２０Ａ R ２０Ｂ , -NHC(O)NR ２０Ａ R ２０Ｂ , -N(O) ｍ２０ , -NR ２０Ａ R ２０Ｂ , -C(O)R ２０Ｃ , -C(O)OR ２０Ｃ , —C(O)NR ２０Ａ R ２０Ｂ , -OR ２０Ｄ , -SR ２０Ｄ , -NR ２０Ａ SO ２ R ２０Ｄ , -NR ２０Ａ C(O)R ２０Ｃ , -NR ２０Ａ C(O)OR ２０Ｃ , -NR ２０Ａ OR ２０Ｃ , -SF ５ , -N ３ , 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; R ２０Ａ , R ２０Ｂ , R ２０Ｃ , and R ２０Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ I, -OCH ２ F, 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, and R ２０Ａ and R ２０Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each X ２０ is independently —F, —Cl, —Br, or —I; n20 is an integer from 0 to 4, The method of any one of claims 52 to 65, wherein m20 and v20 are independently 1 or 2.

67. R ２ but, 【Chemistry 14】 and R ６ are independently oxo, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ７ are independently oxo, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; R ８ are independently a halogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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; z6 is an integer from 0 to 7, z7 is an integer from 0 to 7, 66. The method of any one of claims 52 to 65, wherein z8 is an integer from 0 to 5.

68. R ６ are independently selected from halogen, —OH, unsubstituted C １ ~C ４ 68. The method of claim 67, wherein the heteroaryl is alkyl, substituted 2- to 6-membered heteroalkyl, or substituted 5- to 6-membered heteroaryl.

69. R ６ is independently -F, -Cl, -OH, or unsubstituted methyl.

70. R ６ 68. The method of claim 67, wherein is independently a 2- to 6-membered heteroalkyl substituted with a substituted heterocycloalkyl or an unsubstituted fused heterocycloalkyl.

71. R ６ 68. The method of claim 67, wherein is independently substituted pyridyl.

72. 68. The method of claim 67, wherein z6 is 1, 2, or 3.

73. R ７ are independently a halogen, —CF ３ , -CN, -OH, -NH ２ , unsubstituted C １ ~C ４ Alkyl, unsubstituted C ２ ~C ４ Alkynyl, unsubstituted 2-6 membered heteroalkyl, or unsubstituted C ３ ~C ８ 68. The method of claim 67, wherein the alkyl is cycloalkyl.

74. R ７ are independently —F, —Cl, —CF ３ , -CN, -OH, -NH ２ , unsubstituted methyl, unsubstituted ethynyl, unsubstituted methoxy, or unsubstituted cyclopropyl.

75. 68. The method of claim 67, wherein z7 is 1, 2, or 3.

76. R ８ are independently halogen or unsubstituted C １ ~C ４ 68. The method of claim 67, wherein the alkyl is alkyl.

77. R ８ is independently -Cl or unsubstituted methyl.

78. 68. The method of claim 67, wherein z8 is 1.

79. R ２ but, 【Chemistry 15】 【Chemistry 16】 The method according to any one of claims 52 to 65, wherein

80. 1. A method of attaching a compound to an arginine residue, said method comprising contacting said compound with said arginine residue, said compound having the formula: 【Chemistry 17】 or a salt thereof, wherein: L １ is a bond or a bivalent linker; R ３ But hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -OCX ３ ３ , -OCH ２ X ３ , -OCHX ３ ２ , -CN, -SO ｎ３ R ３Ｄ , -SO ｖ３ NR ３Ａ R ３Ｂ , -NR ３Ｃ NR ３Ａ R ３Ｂ , -ONR ３Ａ R ３Ｂ , -NR ３Ｃ C(O)NR ３Ａ R ３Ｂ , -N(O) ｍ３ , -NR ３Ａ R ３Ｂ , -C(O)R ３Ｃ , -C(O)OR ３Ｃ , -OC(O)R ３Ｃ , -OC(O)OR ３Ｃ , —C(O)NR ３Ａ R ３Ｂ , —OC(O)NR ３Ａ R ３Ｂ , -OR ３Ｄ , -SR ３Ｄ , -NR ３Ａ SO ２ R ３Ｄ , -NR ３Ａ C(O)R ３Ｃ , -NR ３Ａ C(O)OR ３Ｃ , -NR ３Ａ OR ３Ｃ , -SF ５ , -N ３ , 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; R ４ But hydrogen, halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -OCX ４ ３ , -OCH ２ X ４ , -OCHX ４ ２ , -CN, -SO ｎ４ R ４Ｄ , -SO ｖ４ NR ４Ａ R ４Ｂ , -NR ４Ｃ NR ４Ａ R ４Ｂ , -ONR ４Ａ R ４Ｂ , -NR ４Ｃ C(O)NR ４Ａ R ４Ｂ , -N(O) ｍ４ , -NR ４Ａ R ４Ｂ , -C(O)R ４Ｃ , -C(O)OR ４Ｃ , -OC(O)R ４Ｃ , -OC(O)OR ４Ｃ , —C(O)NR ４Ａ R ４Ｂ , —OC(O)NR ４Ａ R ４Ｂ , -OR ４Ｄ , -SR ４Ｄ , -NR ４Ａ SO ２ R ４Ｄ , -NR ４Ａ C(O)R ４Ｃ , -NR ４Ａ C(O)OR ４Ｃ , -NR ４Ａ OR ４Ｃ , -SF ５ , -N ３ , 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 a biomolecule moiety; R ３Ａ , R ３Ｂ , R ３Ｃ , R ３Ｄ , R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ I, -OCH ２ F, 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, and R ３Ａ and R ３Ｂ The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ４Ａ and R ４Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each X ３ and X ４ is independently —Cl, —Br, —I, or —F; n3 and n4 are independently an integer from 0 to 4; The method wherein m3, m4, v3, and v4 are independently 1 or 2.

81. 81. The method of claim 80, wherein the arginine residue forms part of a protein.

82. L １ But, -L １０１ -L １０２ -L １０３ -L １０４ -L １０５ - and L １０１ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０１ -, -C(O)NR １０１ -, -NR １０１ C(O)-, -NR １０１ C(O)O-, -OC(O)NR １０１ -, -NR １０１ C(O)NR １０１ -, -NR １０１ C(NH)NR １０１ -, -S(O) ２ -, -NR １０１ S (O) ２ -, -S(O) ２ NR １０１ -, 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; L １０２ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０２ -, -C(O)NR １０２ -, -NR １０２ C(O)-, -NR １０２ C(O)O-, -OC(O)NR １０２ -, -NR １０２ C(O)NR １０２ -, -NR １０２ C(NH)NR １０２ -, -S(O) ２ -, -NR １０２ S (O) ２ -, -S(O) ２ NR １０２ -, 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; L １０３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０３ -, -C(O)NR １０３ -, -NR １０３ C(O)-, -NR １０３ C(O)O-, -OC(O)NR １０３ -, -NR １０３ C(O)NR １０３ -, -NR １０３ C(NH)NR １０３ -, -S(O) ２ -, -NR １０３ S (O) ２ -, -S(O) ２ NR １０３ -, 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; L １０４ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０４ -, -C(O)NR １０４ -, -NR １０４ C(O)-, -NR １０４ C(O)O-, -OC(O)NR １０４ -, -NR １０４ C(O)NR １０４ -, -NR １０４ C(NH)NR １０４ -, -S(O) ２ -, -NR １０４ S (O) ２ -, -S(O) ２ NR １０４ -, 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; L １０５ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０５ -, -C(O)NR １０５ -, -NR １０５ C(O)-, -NR １０５ C(O)O-, -OC(O)NR １０５ -, -NR １０５ C(O)NR １０５ -, -NR １０５ C(NH)NR １０５ -, -S(O) ２ -, -NR １０５ S (O) ２ -, -S(O) ２ NR １０５ -, 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; Each R １０１ , R １０２ , R １０３ , R １０４ , and R １０５ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

83. R ４ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

84. R ４ The method of any one of claims 80 to 82, wherein is a biomolecule moiety.

85. formula: 【Chemistry 18】 or a salt thereof, covalently attached to an arginine residue, wherein: L １ is a bond or a bivalent linker; R ３ But hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -OCX ３ ３ , -OCH ２ X ３ , -OCHX ３ ２ , -CN, -SO ｎ３ R ３Ｄ , -SO ｖ３ NR ３Ａ R ３Ｂ , -NR ３Ｃ NR ３Ａ R ３Ｂ , -ONR ３Ａ R ３Ｂ , -NR ３Ｃ C(O)NR ３Ａ R ３Ｂ , -N(O) ｍ３ , -NR ３Ａ R ３Ｂ , -C(O)R ３Ｃ , -C(O)OR ３Ｃ , -OC(O)R ３Ｃ , -OC(O)OR ３Ｃ , —C(O)NR ３Ａ R ３Ｂ , —OC(O)NR ３Ａ R ３Ｂ , -OR ３Ｄ , -SR ３Ｄ , -NR ３Ａ SO ２ R ３Ｄ , -NR ３Ａ C(O)R ３Ｃ , -NR ３Ａ C(O)OR ３Ｃ , -NR ３Ａ OR ３Ｃ , -SF ５ , -N ３ , 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; R ４ But hydrogen, halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -OCX ４ ３ , -OCH ２ X ４ , -OCHX ４ ２ , -CN, -SO ｎ４ R ４Ｄ , -SO ｖ４ NR ４Ａ R ４Ｂ , -NR ４Ｃ NR ４Ａ R ４Ｂ , -ONR ４Ａ R ４Ｂ , -NR ４Ｃ C(O)NR ４Ａ R ４Ｂ , -N(O) ｍ４ , -NR ４Ａ R ４Ｂ , -C(O)R ４Ｃ , -C(O)OR ４Ｃ , -OC(O)R ４Ｃ , -OC(O)OR ４Ｃ , —C(O)NR ４Ａ R ４Ｂ , —OC(O)NR ４Ａ R ４Ｂ , -OR ４Ｄ , -SR ４Ｄ , -NR ４Ａ SO ２ R ４Ｄ , -NR ４Ａ C(O)R ４Ｃ , -NR ４Ａ C(O)OR ４Ｃ , -NR ４Ａ OR ４Ｃ , -SF ５ , -N ３ , 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 a biomolecule moiety; R ３Ａ , R ３Ｂ , R ３Ｃ , R ３Ｄ , R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ I, -OCH ２ F, 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, and R ３Ａ and R ３Ｂ The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ４Ａ and R ４Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each X ３ and X ４ is independently —Cl, —Br, —I, or —F; n3 and n4 are independently an integer from 0 to 4; m3, m4, v3, and v4 are independently 1 or 2; R １１ is hydrogen, -C(O)CH ３ or a first protein moiety, R １２ is —OH or a second protein moiety.

86. 86. The covalently linked compound of claim 85, wherein said first protein moiety and said second protein moiety together form a single protein.

87. 87. The covalently linked compound of claim 86, wherein the single protein comprises an additional arginine residue that is not covalently attached to the compound, forming a reactive arginine having formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), or (VIh).

88. L １ But, -L １０１ -L １０２ -L １０３ -L １０４ -L １０５ - and L １０１ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０１ -, -C(O)NR １０１ -, -NR １０１ C(O)-, -NR １０１ C(O)O-, -OC(O)NR １０１ -, -NR １０１ C(O)NR １０１ -, -NR １０１ C(NH)NR １０１ -, -S(O) ２ -, -NR １０１ S (O) ２ -, -S(O) ２ NR １０１ -, 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; L １０２ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０２ -, -C(O)NR １０２ -, -NR １０２ C(O)-, -NR １０２ C(O)O-, -OC(O)NR １０２ -, -NR １０２ C(O)NR １０２ -, -NR １０２ C(NH)NR １０２ -, -S(O) ２ -, -NR １０２ S (O) ２ -, -S(O) ２ NR １０２ -, 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; L １０３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０３ -, -C(O)NR １０３ -, -NR １０３ C(O)-, -NR １０３ C(O)O-, -OC(O)NR １０３ -, -NR １０３ C(O)NR １０３ -, -NR １０３ C(NH)NR １０３ -, -S(O) ２ -, -NR １０３ S (O) ２ -, -S(O) ２ NR １０３ -, 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; L １０４ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０４ -, -C(O)NR １０４ -, -NR １０４ C(O)-, -NR １０４ C(O)O-, -OC(O)NR １０４ -, -NR １０４ C(O)NR １０４ -, -NR １０４ C(NH)NR １０４ -, -S(O) ２ -, -NR １０４ S (O) ２ -, -S(O) ２ NR １０４ -, 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; L １０５ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, —NR １０５ -, -C(O)NR １０５ -, -NR １０５ C(O)-, -NR １０５ C(O)O-, -OC(O)NR １０５ -, -NR １０５ C(O)NR １０５ -, -NR １０５ C(NH)NR １０５ -, -S(O) ２ -, -NR １０５ S (O) ２ -, -S(O) ２ NR １０５ -, 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; Each R １０１ , R １０２ , R １０３ , R １０４ , and R １０５ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

89. R ４ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -OSO ３ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , 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.

90. R ４ 89. The covalently linked compound of any one of claims 85 to 88, wherein is a biomolecular moiety.

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