GTP enzyme inhibitors and uses thereof

Abstract

Inhibitors of GTPase and uses thereof are described herein, inter alia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 400,620, filed on August 24, 2022, which is incorporated herein by reference in its entirety and for all purposes.

[0003] Reference to electronic sequence listing

[0004] The contents of the electronic sequence listing (048536-743001WO_Sequence_Listing_ST26.xml; size: 13,874 bytes; and creation date: August 2, 2023) are hereby incorporated by reference in their entirety.

[0005] STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0006] This invention was made with government support under Grant K00CA253758 from the National Institutes of Health. The government has certain rights in this invention. Background Art

[0007] KRAS mutations are among the most common oncogenic drivers in human cancer. While small molecule inhibitors of the G12C mutant have been successfully developed, allele-specific inhibition of other KRAS hotspot mutants remains challenging. Disclosed herein are solutions to these and other problems in the art. Summary of the Invention

[0008] In one aspect, a compound, or a pharmaceutically acceptable salt thereof, is provided, having the formula:

[0009]

[0010] R 1 It is the binding part of the switch II binding pocket.

[0011] L 1 is a bond or a divalent linker.

[0012] L 2 is a bond or a substituted or unsubstituted alkylene group.

[0013] L 3 For bonds, -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 -、-NR30 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.

[0014] R 3 For 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.

[0015] R 30 and -C13, -CBr, -CF, -CI, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl, -CHBr, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl, -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.

[0016] R 3A 、R 3B 、R 3C and R 3D R is 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, -OCHI, -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; R bonded to the same nitrogen atom 3A and R 3B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0017] Each X 3 The symbols m3 and v3 are independently 1 or 2.

[0018] In one aspect, a pharmaceutical composition is provided, comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0019] In one aspect, provided is a method of treating cancer 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, provided is a method of treating a K-Ras(G12R)-related 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.

[0021] In one aspect, provided is a method of treating an H-Ras(G12R)-related 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.

[0022] In one aspect, provided is a method of treating an N-Ras(G12R)-related 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.

[0023] In one aspect, a method for modulating the activity level of a Ras protein in a cell is provided, comprising contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0024] 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:

[0025] or its salt. 1 、L 2 、L 3 and R 3 As described herein (including in the embodiments). 2 It is a switch II binding pocket binding portion, a phosphatase PTP domain binding portion, an SH2 domain binding portion, a pseudokinase KSR domain binding portion or a pseudokinase STRADα domain binding portion.

[0026] In one aspect, a method of attaching a compound to an arginine residue is provided, the method comprising contacting the compound with the arginine residue, wherein the compound has the formula:

[0027] or its salt. 1 and R 3 As described herein (including in the embodiments).

[0028] R 4 For hydrogen, halogen, -CX 4 3. -CHX 4 2. -CH2X 4 、-OCX 4 3. -OCH2X 4 、-OCHX4 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.

[0029] R 4A 、R 4B 、R 4C and R 4DR is 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, -OCHI, -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; R bonded to the same nitrogen atom 4A and R 4B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0030] Each X 4 The symbols m4 and v4 are independently 1 or 2.

[0031] In one aspect, a switch II GTPase protein is provided that is covalently bound to a compound described herein, or a salt thereof, wherein the compound is covalently bound to an arginine residue of the switch II GTPase protein.

[0032] In one aspect, a compound covalently bound to an arginine residue is provided, the compound having the formula:

[0033] or its salt. 1 、R 3 and R 4 As described herein (including in the embodiments). 11 is hydrogen, -C(O)CH3 or the first protein moiety. 12 is -OH or a second protein moiety. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figures 1A to 1C . Figure 1A : Synthesis of α,β-diketone amide 3. Figure 1B : Scheme depicting the reaction between arginine residues and α,β-diketoamides. Figure 1C : Complete protein profiles of K-Ras(G12R)·GDP and K-Ras(G12R)·GDP·3 adducts.

[0035] Figures 2A to 2D . 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 hours). Figure 2C : Reaction of K-Ras(G12R)·GDP and compound 3 (50 μM) at various pH values. Figure 2D : Differential scanning fluorescence determination of K-Ras(G12R)·GDP and K-Ras(G12R)·GDP·3 adducts.

[0036] Figures 3A to 3D . Figure 3A : Crystal structure of K-Ras(G12R)·GDP·4 adduct. The gray network structure of compound 4 and the F of arginine 12 are depicted. o -F c Censored graph (σ=2.0). Figure 3B : Scheme depicting the reaction between compound 4 and Arg12 residue. Figure 3C : Comparison of the structures of the unliganded K-Ras(G12R)·GDP (PDB: 4QL3) and the K-Ras(G12R)·GDP·4 adduct. Figure 3D : Comparison of the structures of K-Ras(G12C)·GDP·MRTX849 (PDB: 6UT0) and K-Ras(G12R)·GDP·4 adducts.

[0037] Figures 4A to 4B . 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.

[0038] Figures 5A to 5C .Biochemical characterization of compound 4. Figure 5A : Differential scanning fluorescence determination of K-Ras(G12R)·GDP and its adduct with compound 4. Figure 5B : Reaction of K-Ras(G12R)·GDP and compound 4 (50 μM) at various pH values. Figure 5C : Whole protein profile of K-Ras(G12R)·GDP incubated with 100 μM 4 at pH 7.5 for 1 and 24 hours.

[0039] Figures 6A to 6B .Cellular activity of compound 3. Figure 6A : Immunoblot analysis of phosphorylated ERK signaling in TCC-PAN-2 cells treated with compound 3. Figure 6B : Growth inhibition of BaF3 / G12R cells (±IL-3), TCC-Pan-2 cells and A375 cells by compound 3.

[0040] Figure 7 . Growth inhibition of BaF3 / G12R cells (±IL-3) by compound 4.

[0041] Figure 8 The permeability of compound 3 was assessed in the 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.

[0042] 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.

[0043] 10A to 10C .The diketone warhead can react with arginine. Figure 10A : Chemical structure of ZZY-04-084. Figure 10B : Covalent labeling of Src protein detected by mass spectrometry. Figure 10C : Covalent labeling of Src protein detected by fluorescence.

[0044] Figure 11 Superimposed crystal structures of c-Src bound to relevant inhibitors and KSR2. The pseudokinase contains a native lysine to arginine mutation.

[0045] Figure 12 .Targeting the native arginine in the VAIR motif in KSR.

[0046] 13A to 13B The compounds react selectively with the pseudokinase KSR. Figure 13A : Chemical structures of ZZY-04-076, ZZY-04-084, ZZY-04-090 and ZZY-05-057. Figure 13B : Experimental conditions: approximately 10 ng / μL protein + 10 μM compound, 23°C, 1 hour.

[0047] Figure 14 .Targeting Arg692 in KSR.

[0048] Figure 15 STRADα has two arginines in the ATP pocket. The compound binds to both the binary and ternary complexes of STRADα, but not LKB1.

[0049] Figure 16 In the presence of 2,3-butanedione, Arg cross-links with Cys, but not Lys. The SH2 domain and the phosphatase active site contain an Arg-Cys dimer. Experimental conditions: 0.1 M NAc-Arg, 0.1 M 2,3-butanedione, 0.1 M additives, 0.5 M sodium phosphate buffer, pH 8.0, 23°C, 24 hours.

[0050] Figure 17 In the assays tested, the selected compounds modify the SHP2 PTP domain containing a coordinatable arginine. DETAILED DESCRIPTION

[0051] I. Definition

[0052] Abbreviations used herein have their conventional meanings in the chemical and biological arts.Chemical structures and formulae depicted herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0053] When substituent groups are described by their conventional chemical formula written from left to right, these substituents equally encompass the chemically identical substituents resulting from writing the structure from right to left, for example, -CH2O- is equivalent to -OCH2-.

[0054] Unless otherwise indicated, the term "alkyl", by itself or as part of another substituent, means a straight (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. An alkyl group may contain a specified number of carbon atoms (e.g., C1-C 10 Meaning one carbon to ten carbons). In an embodiment, the alkyl group is fully saturated. In an embodiment, the alkyl group is monounsaturated. In an embodiment, the alkyl group is polyunsaturated. The alkyl group is an uncyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are alkyl groups with 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 homologues and isomers. Alkoxy is an alkyl group connected to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. Alkenyl groups contain one or more double bonds. Alkynyl groups contain one or more triple bonds.

[0055] Unless otherwise stated, the term "alkylene" alone or as part of another substituent means a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene group typically having eight or fewer carbon atoms. Unless otherwise stated, the term "alkenylene" by itself or as part of another substituent means a divalent group derived from an alkene. Unless otherwise stated, the term "alkynylene" by itself or as part of another substituent means a divalent group derived from an alkyne. In an embodiment, an alkylene group is fully saturated. In an embodiment, an alkylene group is monounsaturated. In an embodiment, an alkylene group is polyunsaturated. An alkenylene group includes one or more double bonds. An alkynylene group includes one or more triple bonds.

[0056] Unless otherwise indicated, the term "heteroalkyl" alone or in combination with another term means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. One or more heteroatoms (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at a position where the alkyl group is connected to the rest of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety can contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" by itself or in combination with another term means a heteroalkyl group comprising at least one double bond. The heteroalkyl group may optionally include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. Unless otherwise stated, the term "heteroalkynyl" by itself or in combination with another term means a heteroalkyl group comprising at least one triple bond. The heteroalkynyl group may optionally include more than one triple bond and / or one or more double bonds in addition to one or more triple bonds. In an embodiment, the heteroalkyl group is fully saturated. In an embodiment, the heteroalkyl group is monounsaturated. In an embodiment, the heteroalkyl group is polyunsaturated.

[0057] Similarly, unless otherwise indicated, the term "heteroalkylene" by itself or as part of another substituent means a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene, heteroatoms may also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups that are attached to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR' and / or -S02R'. It should be understood that where "heteroalkyl" is recited after a specific heteroalkyl group such as -NR'R", the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the recitation of specific heteroalkyl groups is for added clarity. Therefore, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups such as -NR'R". Unless otherwise stated, the term "heteroalkenylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkene. Unless otherwise stated, the term "heteroalkynyl" by itself or as part of another substituent means a divalent radical derived from a heteroalkyne. In an embodiment, a heteroalkylene is fully saturated. In an embodiment, a heteroalkylene is monounsaturated. In an embodiment, a heteroalkylene is polyunsaturated. Heteroalkenylene includes one or more double bonds. Heteroalkynylene includes one or more triple bonds.

[0058] Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl" alone or in combination with other terms refer to cyclic forms of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the rest 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-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively. In an embodiment, cycloalkyl is fully saturated. In an embodiment, cycloalkyl is monounsaturated. In an embodiment, cycloalkyl is polyunsaturated. In an embodiment, heterocycloalkyl is fully saturated. In an embodiment, heterocycloalkyl is monounsaturated. In an embodiment, heterocycloalkyl is polyunsaturated.

[0059] In an embodiment, the term "cycloalkyl" means a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In an embodiment, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such groups can be saturated or unsaturated, but not aromatic. In an embodiment, the cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, wherein at least one of the fused rings is a cycloalkyl ring, and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within the cycloalkyl rings of the multiple rings.

[0060] In an embodiment, cycloalkyl is a cycloalkenyl. The term "cycloalkenyl" is used according to its ordinary general meaning. In an embodiment, cycloalkenyl is a monocyclic, bicyclic or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to a plurality of rings fused together, wherein at least one of the fused rings is a cycloalkenyl ring, and wherein the plurality of rings are connected to the parent molecular moiety through any carbon atom contained within the cycloalkenyl rings of the plurality of rings.

[0061] In an embodiment, the term "heterocycloalkyl" means a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In an embodiment, the heterocycloalkyl group is fully saturated. A bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, wherein at least one of the fused rings is a heterocycloalkyl ring, and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within the heterocycloalkyl rings of the multiple rings.

[0062] Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" are intended 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.

[0063] Unless otherwise indicated, the term "acyl" 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.

[0064] Unless otherwise indicated, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or polycyclic ring (preferably 1 to 3 rings) fused together (i.e., fused ring aryl) or covalently linked. A fused ring aryl refers to multiple rings fused together, wherein at least one fused ring is an aromatic ring, and wherein the multiple rings are connected to the parent molecular moiety through any carbon atom contained within the aromatic rings 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 atom and the sulfur atom are optionally oxidized, and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryls (i.e., multiple rings fused together, wherein at least one fused ring is a heteroaromatic ring, and wherein the multiple rings are connected to the parent molecular moiety through any atom contained within the heteroaromatic rings of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other having 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other having 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazole Substituents for each of the above noted 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 a divalent radical derived from aryl and heteroaryl, respectively. A heteroaryl group substituent can be -O- bonded to a ring heteroatom nitrogen.

[0065] Spirocycle is two or more rings in which adjacent rings are connected by a single atom. The single ring in the spirocycle can be the same or different. The single ring in the spirocycle can be substituted or unsubstituted and can have a substituent different from other single rings in the spirocycle set. The possible substituents of each ring in the spirocycle are possible substituents of the same ring (when not a part of the spirocycle) (for example, a substituent of a cycloalkyl ring or a heterocycloalkyl ring). The spirocycle can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene or a substituted or unsubstituted heterocycloalkylene, and the individual rings in the spirocyclic group can be any ring of the previous list, including all rings with one type (for example, all rings are substituted heterocycloalkylene, wherein each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocycle system, heterocycle spirocycle means that at least one ring is a heterocycle and wherein each ring can be a spirocycle of different rings. When referring to a spirocycle system, the substituted spirocycle means that at least one ring is substituted and each substituent can optionally be different.

[0066] symbol Indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0067] As used herein, the term "oxo" means an oxygen double-bonded to a carbon atom.

[0068] The term "alkylarylene" is an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In an embodiment, the alkylarylene group has the formula:

[0069]

[0070] The alkylarylene moiety can be substituted (e.g., with a substituent) on the alkylene moiety or the arylene linker (e.g., at carbon 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 C1-C5 alkyl, or substituted or unsubstituted 2- to 5-membered heteroalkyl. In an embodiment, the alkylarylene group is unsubstituted.

[0071] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0072] Substituents for alkyl and heteroalkyl groups (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", - OC(O)NR'R", -NR"C(O)R', -NR'C(O)NR"R"', -NR"C(O)2R', -NRC(NR'R"R"')=NR"", -NRC(NR'R")=N R"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN , -NO2, -NR'SO2R", -NR'C(O)R", -NR'C(O)OR", -NR'OR", the number of which ranges from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R, R', R", R'' and R"" each preferably independently represent hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy group or aralkyl group. When the compounds described herein contain more than one R group, each of the R groups is independently selected, for example, as each R' group, R" group, R"' group and R"" group is independently selected when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-membered, 5-membered, 6-membered or 7-membered ring. For example, -NR'R" includes but is not limited to 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups containing carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0073] Similar to the substituents described for alkyl, the substituents for aryl and heteroaryl are different and are selected from, for example: -OR', -NR'R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"', -CN, -NO2, -R In some embodiments, the present invention further comprises fluoro(Ci-C4)alkoxy and fluoro(Ci-C4)alkyl, -NR'S02R", -NR'C(O)R", -NR'C(O)OR", -NR'OR", and wherein R', R", R'' and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein contains more than one R group, for example, each of the R groups is independently selected as each R' group, R" group, R'' group, and R"" group is independently selected when more than one of these groups is present.

[0074] The substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylidene or heteroarylidene) can be depicted as substituents on the ring rather than on a specific atom of the ring (commonly referred to as floating substituents). In this case, the substituent can be connected to any of the ring atoms (following chemical valence rules), and in the case of a fused ring or spiro ring, the substituent depicted as being associated with a member of the fused ring or spiro ring (floating substituent on a monocycle) can be a substituent on any of the fused ring or spiro ring (floating substituent on multiple rings). When the substituent is connected to the ring rather than a specific atom (floating substituent) and the subscript of the substituent is an integer greater than one, multiple substituents can be located on the same atom, the same ring, different atoms, different fused rings, different spiro rings, and each substituent can optionally be different. In the case where the point of attachment of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the point of attachment can be any atom of the ring, and in the case of a fused ring or spiro ring, it can be any atom of any of the fused ring or spiro ring (following chemical valence rules). Where a ring, fused ring or spiro ring contains one or more ring heteroatoms and the ring, fused ring or spiro ring is shown as having a further floating substituent (including but not limited to a point of attachment to the rest of the molecule), the floating substituent may be bonded to the heteroatom. When a ring heteroatom is shown bonded to one or more hydrogens in a structure or formula having a floating substituent (e.g., a ring nitrogen with two bonds to a ring atom and a third bond to a hydrogen), the substituent will be understood to replace the hydrogen when the heteroatom is bonded to the floating substituent, while respecting chemical valence rules.

[0075] In another embodiment, the ring-forming substituent is connected to the adjacent members of the basic structure. For example, two ring-forming substituents connected with the adjacent members of the cyclic basic structure produce condensed ring structure. In another embodiment, the ring-forming substituent is connected to the single member of the basic structure. For example, two ring-forming substituents connected with the single member of the cyclic basic structure produce spirocyclic structure. In another embodiment, the ring-forming substituent is connected to the non-adjacent members of the basic structure.

[0076] Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a group of the formula -TC(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2) r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -(CRR') s -X'-(C”R”R”') d -, wherein 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.

[0077] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In an embodiment, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0078] As used herein, a "substituent group" means a group selected from the following moieties:

[0079] (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 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

[0080] (B) an alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group), a heteroalkyl group (e.g., a 2- to 8-membered heteroalkyl group, a 2- to 6-membered heteroalkyl group, or a 2- to 4-membered heteroalkyl group), a cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group), a heterocycloalkyl group (e.g., a 3- to 8-membered heterocycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a 5- to 6-membered heterocycloalkyl group), an aryl group (e.g., a C6 ... 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):

[0081] (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 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

[0082] (ii) an alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group), a heteroalkyl group (e.g., a 2- to 8-membered heteroalkyl group, a 2- to 6-membered heteroalkyl group, or a 2- to 4-membered heteroalkyl group), a cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group), a heterocycloalkyl group (e.g., a 3- to 8-membered heterocycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a 5- to 6-membered heterocycloalkyl group), an aryl group (e.g., a C6 ... 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):

[0083] (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 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

[0084] (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-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): oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCHI, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2 NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHS02H, -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).

[0085] As used herein, "a substituent of limited size" or "a substituent group of limited size" means a group selected from all substituents described above for a "substituent group", wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0086] As used herein, “lower substituent” or “lower substituent group” means a group selected from all substituents described above for “substituent group”, 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.

[0087] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one substituent group of limited size. In other embodiments, at least one or all of these groups are substituted with at least one low substituent group.

[0088] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0089] In some embodiments, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C 10 In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 2-8 membered heteroalkylene group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heterocycloalkylene group is a substituted or unsubstituted 3-7 membered heterocycloalkylene group, each substituted or unsubstituted arylene group is a substituted or unsubstituted C6-C8 alkylene group. 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a chemical substance described in the Examples section, Figures, or Tables below.

[0090] In embodiments, the 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 heteroalkylene, respectively). In embodiments, the 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).

[0091] In an embodiment, the substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In an embodiment, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0092] In an embodiment, 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-restricted substituent group, wherein if the substituted moiety is substituted with multiple size-restricted substituent groups, each size-restricted substituent group can optionally be different. In an embodiment, if the substituted moiety is substituted with multiple size-restricted substituent groups, each size-restricted substituent group is different.

[0093] In an embodiment, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with multiple lower substituent groups, each lower substituent group may optionally be different. In an embodiment, if the substituted moiety is substituted with multiple lower substituent groups, each lower substituent group is different.

[0094] In an embodiment, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted moiety is substituted with multiple groups selected from substituent groups, size-restricted substituent groups, or lower substituent groups; each substituent group, size-restricted substituent group, and / or lower substituent group may optionally be different. In an embodiment, if the substituted moiety is substituted with multiple groups selected from substituent groups, size-restricted substituent groups, or lower substituent groups; each substituent group, size-restricted substituent group, and / or lower substituent group is different.

[0095] In the claims or formula descriptions described herein, each R substituent or L linker described as "substituted," without reference to the identity of any chemical moiety comprising the "substituted" group (also referred to herein as "open substitution" on the R substituent or L linker or an "open substituted" R substituent or L linker), in embodiments, may be substituted with one or more first substituent groups as defined below.

[0096] The first substituent is represented by the corresponding first decimal point numbering system, so that, for example, R 1 You can use one or more R 1.1 The first substituent group represented by R 2 You can use one or more R 2.1 The first substituent group represented by R 3 You can use one or more R 3.1 The first substituent group represented by R 4 You can use one or more R 4.1 The first substituent group represented by R 5 You can use one or more R 5.1 The first substituent group represented by R may be substituted, and so on up to or beyond the first substituent group represented by R 100.1 The first substituent group substituted R 100 As another example, R 1A One or more R 1A.1 The first substituent group represented by R 2A One or more R 2A.1 The first substituent group represented by R 3A One or more R 3A.1 The first substituent group represented by R 4AOne or more R 4A.1 The first substituent group represented by R 5A One or more R 5A.1 The first substituent group represented by R is substituted, and so on up to or exceeding R 100A One or more R 100A.1 As another example, L 1 One or more R L1.1 The first substituent group represented by L 2 One or more R L2.1 The first substituent group represented by L 3 One or more R L3.1 The first substituent group represented by L 4 One or more R L4.1 The first substituent group represented by L 5 One or more R L5.1 The first substituent group represented by L is substituted, and so on up to or exceeding L 100 One or more R L100.1 Thus, each numbered R group or L group (or R group as referred to herein) described herein is substituted with the first substituent group represented by WW or L WW , wherein "WW" represents the superscript number of the subject R group or L group) can be respectively replaced by one or more groups generally referred to herein as R WW.1 or R LWW.1 Then, each first substituent group (e.g., R 1.1 、R 2.1 、R 3.1 、R 4.1 、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 replaced by one or more second substituent groups (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 ) is further substituted. Thus, each first substituent group, which may alternatively be represented herein as R as described above WW.1 , which may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R WW.2 .

[0097] Finally, each second substituent group (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 replaced by one or more third substituent groups (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 ;) further substituted. Thus, each second substituent group, which may alternatively be represented herein as R as described above WW.2 , may be further substituted by one or more third substituent groups, which may alternatively be represented herein as R WW.3Each of the first substituent group may optionally be different. Each of the second substituent group may optionally be different. Each of the third substituent group may optionally be different.

[0098] Therefore, as used herein, R WW = represents an open substituted substituent as described in the claims or chemical formula description herein. "WW" represents the superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Similarly, L WW is an open substituted linker as described in the claims or chemical formula description herein. Likewise, "WW" represents the superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As described above, in embodiments, each R WW may be unsubstituted or independently substituted with one or more substituted radicals referred to herein as R WW.1 The first substituent group is substituted; each first substituent group R WW.1 may be unsubstituted or independently substituted with one or more substituted radicals referred to herein as R WW.2 and each second substituent group may be unsubstituted or independently substituted with one or more substituent groups referred to herein as R WW.3 Similarly, each L WW The linker may be unsubstituted or independently substituted with one or more substituted residues referred to herein as R LWW.1 The first substituent group is substituted; each first substituent group R LWW.1 may be unsubstituted or independently substituted with one or more substituted radicals referred to herein as R LWW.2 and each second substituent group may be unsubstituted or independently substituted with one or more substituent groups referred to herein as R LWW.3 Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if R WW is phenyl, then the phenyl group is optionally replaced by one or more R as defined below WW.1 Group substitution, for example, when R WW.1 R WW.2 -substituted or unsubstituted alkyl, examples of such groups include but are not limited to itself optionally substituted with one or more R WW.2 Replace the R WW.2 Optionally, one or more R WW.3 For example, when R WW The group is R WW.1 When phenyl is substituted, the methyl group may be further substituted to form groups including but not limited to the following:

[0099]

[0100] 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.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 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- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R WW.2 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), R WW.2 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R WW.2 -substituted or unsubstituted aryl (e.g., C6-C 12 、C6-C 10 or phenyl) or R WW.2 -substituted or unsubstituted heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In one embodiment, 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, unsubstituted alkyl (e.g. C1-C8, C1-C6, C1-C4 or C1-C2), 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), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), 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), 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). X WW.1 are independently -F, -Cl, -Br or -I.

[0101] 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 or C1-C2), R WW.3 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R WW.3 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), R WW.3 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R WW.3 -substituted or unsubstituted aryl (e.g., C6-C 12 、C6-C 10or phenyl) or R WW.3 -substituted or unsubstituted heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In one embodiment, 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, unsubstituted alkyl (e.g. C1-C8, C1-C6, C1-C4 or C1-C2), 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), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), 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), 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). X WW.2 are independently -F, -Cl, -Br or -I.

[0102] 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, C1-C6, C1-C4 or C1-C2), 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), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), 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), 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). X WW.3 are independently -F, -Cl, -Br or -I.

[0103] In two different R WW Where substituents are joined together to form an open substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), in embodiments, the open substituted ring may be independently replaced by one or more substituents referred to herein as R WW.1 The first substituent group is substituted; each first substituent group R WW.1 may be unsubstituted or independently substituted with one or more substituted radicals referred to herein as R WW.2 and each second substituent group R WW.2 may be unsubstituted or independently substituted with one or more substituted radicals referred to herein as R WW.3 and each third substituent group R WW.3 is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. WW When 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 the code refers to two different R WW The specified number of one of the substituents. For example, in R 100A and R 100B In embodiments where R is optionally joined to form an open substituted ring, WW.1 R 100A.1 、R WW.2R 100A.2 , and R WW.3 R 100A.3 Alternatively, in R 100A and R 100B In embodiments where R is optionally joined to form an open substituted ring, WW.1 R 100B.1 、R WW.2 R 100B.2 , and R WW.3 R 100B.3 . R in this paragraph WW.1 、R WW.2 and R WW.3 As defined in the preceding paragraph.

[0104] 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- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R LWW.2 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), R LWW.2 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R LWW.2 -substituted or unsubstituted aryl (e.g., C6-C 12 、C6-C 10 or phenyl) or R LWW.2 -substituted or unsubstituted heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In one embodiment, R LWW.1 are independently oxo, halogen, -CX LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 、-OCXLWW.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, C1-C6, C1-C4 or C1-C2), 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), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), 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), 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). X LWW.1 are independently -F, -Cl, -Br or -I.

[0105] 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.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 LWW.3 - substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4 or C1-C2), R LWW.3 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R WW.3 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), R LWW.3 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R LWW.3-substituted or unsubstituted aryl (e.g., C6-C 12 、C6-C 10 or phenyl) or R LWW.3 -substituted or unsubstituted heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In one embodiment, 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.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, C1-C6, C1-C4 or C1-C2), 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), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), 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), 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). X LWW.2 are independently -F, -Cl, -Br or -I.

[0106] 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.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g. C1-C8, C1-C6, C1-C4 or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members or 4 to 5 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), 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), 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). X LWW.3 are independently -F, -Cl, -Br or -I.

[0107] Any R group (R WW In the case where the substituents) are not specifically defined in the present disclosure, the R group (R WW Groups) are independently defined herein as 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 or C1-C2), R WW.1 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R WW.1 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), R WW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R WW.1 -substituted or unsubstituted aryl (e.g., C6-C 12 、C6-C 10 or phenyl) or R WW.1 - substituted or unsubstituted heteroaryl (eg, 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). X WW R is independently -F, -Cl, -Br or -I. Likewise, "WW" represents the superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). WW.1 、R WW.2 and R WW.3 As defined above.

[0108] Any L linking group (i.e., L WW If the substituent) is not clearly defined, the L group (L WW Groups) are defined herein independently as 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 or C1-C2), R LWW.1 -substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R LWW.1 -substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6 or C5-C6), R LWW.1 -substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R LWW.1 - substituted or unsubstituted arylene (e.g., C6-C 12 、C6-C 10 or phenyl) or R LWW.1 - substituted or unsubstituted heteroarylene (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). Likewise, "WW" represents the superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R LWW.1 and R LWW.2 and R LWW.3 As defined above.

[0109] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; in terms of absolute stereochemistry, they can be defined as (R)- or (S)- of amino acids or as (D)- or (L)- enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and each isomer is included within the scope of the present disclosure. The compounds of the present disclosure do not include compounds that are too unstable to be synthesized and / or separated as known in the art. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that these compounds contain both E and Z geometric isomers.

[0110] 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 in the structural arrangement or configuration of the atoms.

[0111] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0112] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0113] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, 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 present disclosure.

[0114] Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, structures having a structure other than the replacement of a hydrogen by a deuterium or tritium or by a 13 C-enriched or 14 Compounds of the present structures in which a C-enriched carbon replaces a carbon other than carbon are within the scope of the present disclosure.

[0115] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14C) and other radioactive isotopes. All isotopic variations of the compounds of the present disclosure, whether radioactive or non-radioactive, are encompassed within the scope of the present disclosure.

[0116] It should be noted that throughout the application, alternatives are written in Markush groups, for example, in each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered individually, thereby comprising another embodiment, and that the Markush group should not be construed as a single unit.

[0117] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the association between atoms or molecules of a bioconjugate reactive group or a bioconjugate reactive moiety. The association can be direct or indirect. For example, the conjugation between a first bioconjugate reactive group (e.g., -NH2, -COOH, -N-hydroxysuccinimide, or -maleimide) provided herein and a second bioconjugate reactive group (e.g., a sulfhydryl, a sulfur-containing amino acid, an amine, an amine side chain containing an amino acid, or a carboxylate) can be performed directly, for example, via a covalent bond or a linker (e.g., a first linker of a second linker), or indirectly, for example, via 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 (π effect), hydrophobic interactions, etc.). In an embodiment, the bioconjugate or bioconjugate linker is 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, active esters), electrophilic substitution (e.g., enamine reaction), and addition of 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 group). 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 group). 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 group). In embodiments, a first bioconjugate reactive group (e.g., an N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). 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 group).In embodiments, a first bioconjugate reactive group (eg, a -sulfo-N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (eg, an amino group).

[0118] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry herein include, for example: (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 esters, alkenyl esters, alkynyl esters, and aromatic esters; (b) hydroxyl groups that can be converted into esters, ethers, aldehydes, etc.; (c) alkyl halides, where the halide can subsequently be displaced by a nucleophilic group such as an amine, carboxylate anion, thiol anion, carbonanion, or alkoxide ion, resulting in a new group covalently attached at the position of the halogen atom; (d) dienophilic groups capable of participating in a Diels-Alder reaction, such as a maleimido or maleimide group; (e) aldehyde or ketone groups, allowing for subsequent derivatization via formation of a carbonyl derivative such as an imine, hydrazone, semicarbazone, or oxime, or via a mechanism such as Grignard addition or alkyllithium addition; (f) Sulfonyl halide groups that subsequently react with amines, for example, to form sulfonamides; (g) thiol groups that can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or reacted with maleimides; (h) amines or sulfhydryl groups (e.g., as present in cysteine), which can be, for example, acylated, alkylated, or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylations, Michael additions, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silica bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphodiester bonds; (n) azides that can be coupled to alkynes using copper-catalyzed cycloaddition click chemistry; and (o) biotin conjugates that can react with avidin or streptavidin to form avidin-biotin complexes or streptavidin-biotin complexes.

[0119] Bioconjugate reactive groups can be selected so that they do not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups can be protected from participating in cross-linking reactions by the presence of protecting groups. In embodiments, the bioconjugate includes a molecular entity derived from the reaction of an unsaturated bond (such as maleimide) with a sulfhydryl group.

[0120] As used herein, "biomolecule" is used in its conventional sense to refer to a molecule or derivative thereof that occurs in nature, including macromolecules (such as proteins, carbohydrates, lipids, and nucleic acids) and small molecules (such as primary metabolites, secondary metabolites, and natural products). A biomolecule can exist as a moiety attached to the rest of a compound. Biomolecules include, but are not limited to, nucleic acids (e.g., DNA and RNA), peptide nucleic acids, sugars, peptides, proteins, antibodies, nucleic acid ligands, lipids, small molecule affinity ligands (e.g., inhibitors, biotin, and haptens). As used herein, "biomolecule moiety" refers to a group of a biomolecule.

[0121] "Analog," "analogue," or "derivative" are used according to their ordinary general meaning in chemistry and biology and refer to compounds that are structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound), for example, in the replacement of an atom by an atom of a different element, or in the presence or absence of a particular functional group, or in the replacement of one functional group by another functional group, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but not in structure or origin.

[0122] As used herein, the term "a / a" means one or more. In addition, as used herein, the phrase "substituted with [n]..." means that the specified group can be substituted with one or more of any or all of the named substituents. For example, in the case of a group such as an alkyl or heteroaryl group, "substituted with an unsubstituted C1-C 20 In the case of "substituted with alkyl or unsubstituted 2 to 20 membered heteroalkyl", the group may contain one or more unsubstituted C1-C 20 alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0123] Additionally, 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 specific R group is present in a description of a chemical species, such as Formula (I), a Roman letter symbol may be used to distinguish each appearance of that specific R group. For example, when multiple R 13 In the case of substituents, each R 13 Substituents can be divided into R 13.A 、R 13.B 、R 13.C 、R 13.D etc., where R 13.A 、R 13.B 、R 13.C 、R13.D Each of the above is in R 13 Where an R moiety, group or substituent as disclosed herein is indicated to be attached by a single bond and the R moiety, group or substituent is an oxo group, one of ordinary skill in the art will immediately recognize that according to normal rules of chemical valence, the oxo group is attached by a double bond.

[0124] The description of the disclosed compounds is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted by one or more of a plurality of substituents, such substitutions are selected so as to conform to the principles of chemical bonding and to yield compounds that are not inherently unstable and / or, as known to those skilled in the art, would likely be unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions). For example, heterocycloalkyl or heteroaryl groups, in accordance with the principles of chemical bonding known to those skilled in the art, are connected to the rest of the molecule via a ring heteroatom, thereby avoiding inherently unstable compounds.

[0125] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or the like. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like; and 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-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids (such as arginine salts) and salts of organic acids (such as glucuronic acid or galacturonic acid), and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow these compounds to be converted into either base or acid addition salts.

[0126] Therefore, the compounds of the present disclosure can exist in the form of salts (such as having a pharmaceutically acceptable acid). The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates or their mixtures comprising a racemic mixture), succinates, benzoates 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.

[0127] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a 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.

[0128] In addition to salt forms, the present disclosure also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that are susceptible to undergoing chemical changes under physiological conditions to provide compounds of the present disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. Additionally, prodrugs can be converted into compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment (such as, for example, when contacted with a suitable enzyme or chemical reagent).

[0129] Some compounds of the present disclosure can exist in unsolvated form and solvated form (including hydrated form). Generally, solvated form is equivalent to unsolvated form and is encompassed within the scope of the present disclosure. Some compounds of the present disclosure can exist in multiple crystallized or amorphous forms. Generally, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0130] A polypeptide or cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or non-wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, such as the genome of a recombinant organism, so that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. Proteins expressed in vitro or in vivo from a recombinant polynucleotide are examples of recombinant polypeptides. Similarly, polynucleotide sequences that do not occur in nature (e.g., variants of naturally occurring genes) are recombinant.

[0131] "Co-administration" means administering a composition described herein simultaneously with, just before, or just after the administration of one or more additional therapies. The compounds of the present invention may be administered alone or co-administered to a patient. Co-administration is intended to encompass simultaneous or sequential administration of the compounds (more than one compound), alone or in combination. Thus, the formulations may also be combined with other active substances, if desired (e.g., to reduce metabolic degradation).

[0132] As used herein, "cell" refers to a cell that performs metabolic or other functions sufficient to maintain 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 a specific dye, the ability to reproduce offspring, or, if gametes are present, the ability to combine with a second gamete to produce viable offspring. Cells can include prokaryotic cells 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 (e.g., noctuid) cells, and human cells. When cells are naturally non-adhesive or treated to not adhere to a surface, such as by trypsinization, they may be useful.

[0133] The term "treat" refers to any mark of success in the treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as alleviation; remission; lessening of symptoms or making the patient more tolerant to the injury, pathology, or condition; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; improving the patient's physical or mental health. 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 presented herein successfully treat cancer by reducing the incidence of cancer and / or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the growth or spread rate of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term "treat" and its conjugates include preventing an injury, pathology, condition, or disease. In an embodiment, treatment is prevention. In an embodiment, treatment does not include prevention. In an embodiment, treatment is not a prophylactic treatment.

[0134] "Effective amount" is an amount sufficient to enable the compound to achieve the purpose (e.g., achieve its administration effect, treat disease, reduce enzyme activity, increase enzyme activity, reduce signal transduction pathways, alleviate one or more symptoms of disease or condition) relative to the absence of the compound. When mentioned in this context, an example of an "effective amount" is an amount sufficient to facilitate the treatment, prevention or reduction of one or more symptoms of a disease, which amount may also be referred to as a "therapeutically effective amount." "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms. A "prophylactic effective amount" of a drug is an amount of the drug that, when administered to a subject, will have an expected preventive effect, such as preventing or delaying the onset (or recurrence) of damage, disease, pathology or condition or reducing the likelihood of onset (or recurrence) of damage, disease, pathology or condition or its symptoms. A complete preventive effect does not necessarily occur by administering a single dose, and may occur after only administering a series of doses. Therefore, a prophylactic effective amount may be administered in one or more administration forms. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of an antagonist. As used herein, "function-destroying amount" refers to the amount of the antagonist required for the function of an enzyme or protein relative to the absence of an antagonist. As used herein, "activity-increasing amount" refers to the amount of the agonist required for the activity of an enzyme relative to the absence of an agonist. As used herein, "function-increasing amount" refers to the amount of the agonist required for the activity of an enzyme relative to the absence of an agonist. The exact amount will depend on the therapeutic purpose, and will be determined by those skilled in the art using known technology (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 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).

[0135] "Control" or "control experiment" is used according to its ordinary general meaning and refers to an experiment in which the experimental subjects or reagents are treated as in parallel experiments, except that the experimental procedures, reagents or variables are omitted. In some cases, a control is used as a standard of comparison when evaluating the effects of an experiment. In some embodiments, a control is a measure of the activity of a protein (e.g., a signaling pathway) in the absence of a compound as described herein, including embodiments, examples, figures or tables.

[0136] "Contacting" is used according to its ordinary general meaning and refers to the process of allowing at least two different substances (e.g., compounds including biomolecules or cells) to become close enough to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product can be produced directly by a reaction between the added reagents or by an intermediate from one or more added reagents that can be produced in the reaction mixture.

[0137] The term "contacting" can include allowing two species to react, interact, or physically contact, where the two species can be a compound as described herein and a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments, contacting includes allowing a compound as 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, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) involved in a signaling pathway.

[0138] As defined herein, the term "activation" with respect to a protein refers to converting a protein from an initially inactive or inactive state into a biologically active derivative. These terms refer to activation, or activation, sensitization, or upregulation of signal transduction or enzymatic activity, or the amount of a protein that is reduced in a disease.

[0139] The terms "agonist," "activator," "up-regulator," and the like refer to substances that can detectably increase 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 some cases, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more compared to the expression or activity in the absence of the agonist.

[0140] As defined herein, the term "inhibit," or the like, with respect to a cellular component-inhibitor interaction, means negatively affecting (e.g., reducing) the activity or function of a cellular component relative to the activity or function of the cellular component in the absence of the inhibitor (e.g., reducing a signaling pathway stimulated by 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)). In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level of a cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or a symptom of a disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or a signaling pathway (e.g., a reduction in a pathway involving a cellular component). Thus, inhibition includes, at least in part, partial or complete blocking of stimulation, reduction, prevention, or delay of activation, desensitization, or downregulation of a signaling pathway or enzyme activity or the amount of a cellular component.

[0141] Interchangeably, the terms "inhibitor," "repressor," or "antagonist," or "downregulator" refer to a substance that detectably reduces 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 some cases, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more greater than the expression or activity in the absence of the antagonist.

[0142] The term "modulator" refers to a compound that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of a molecule relative to the absence of the composition (e.g., a target can be a cellular component (e.g., a protein, an ion, a lipid, a virus, a lipid droplet, a nucleic acid, a nucleotide, an amino acid, a protein, a particle, an organelle, a cellular compartment, a microorganism, a vesicle, a small molecule, a protein complex, a protein aggregate, or a macromolecule)).

[0143] The term "expression" includes any step involved in producing the polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0144] The term "modulate" is used according to its ordinary general meaning and refers to the act of changing or altering one or more properties. "Modulate" refers to the process of changing or varying one or more properties. For example, when applied to the effect of a modulator on a target protein, modulating means changing by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0145] "Patient," "person in need thereof," "subject," or "subject in need thereof" refers to a living organism having or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In embodiments, the patient is a human. In embodiments, the patient in need thereof is a human. In embodiments, the subject is a human. In embodiments, the subject in need thereof is a human.

[0146] "Disease" or "condition" refers to a state or health condition in which a patient or subject can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease associated with (caused by) a cellular component (e.g., a protein, an ion, a lipid, a nucleic acid, a nucleotide, an amino acid, a protein, a particle, an organelle, a cellular compartment, a microorganism, a vesicle, a small molecule, a protein complex, a protein aggregate, or a macromolecule). In embodiments, the disease is cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, melanoma, thyroid cancer, or urinary cancer). In embodiments, the disease is RASopathy (e.g., capillary malformation-AV malformation syndrome, autoimmune lymphoproliferative syndrome, cardiofacial syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, Noonan syndrome, Kristina's elastin deficiency, or Reye's syndrome).

[0147] As used herein, the term "cancer" refers to all types of cancers, tumors, or malignancies found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas, and sarcomas. Exemplary cancers that can 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. Additional examples include: Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, carcinoma, malignant pancreatic cancer, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0148] The term "leukemia" refers to a progressive, malignant disease of the blood-forming organs and is generally characterized by the dysregulated proliferation and development of white blood cells and their precursors in the blood and bone marrow. The clinical classification of leukemias is generally based on (1) the duration and character of the disease - acute or chronic; (2) the cell type involved - myeloid (myelocytic), lymphoid (lymphoblastic), or monocytic; and (3) the presence or absence of an increase in the number of abnormal cells in the leukemic or non-leukemic (meta-leukemic) lineages. Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, leukemia), hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia leukemia), stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0149] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphoid tissues. It begins in lymphocytes, which are blood cells found primarily in the 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 related to Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the growth rate of the cancer and the type of cells involved. There are aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHL. Exemplary B cell lymphomas that can 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, nodular (monocytoid B cell) lymphoma, splenic lymphoma, diffuse large cell B lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B lymphoblastic lymphoma. Exemplary T cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T cell lymphoma, peripheral T cell lymphoma, pleomorphic large cell lymphoma, mycosis fungoides, and precursor T lymphoblastic lymphoma.

[0150] The term "sarcoma" generally refers to tumors composed of material resembling embryonic connective tissue and usually consisting of tightly packed cells embedded in a fibrous or homogeneous mass. Sarcomas that can 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 carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, and sarcoma of the uterus. sarcoma), Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0151] The term "melanoma" is understood to refer to tumors of the melanocytic system of the skin and other organs. Melanomas that can 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, subungal melanoma, or superficial spreading melanoma.

[0152] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and give rise to metastases. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, glandular cystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell tumor, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus carcinoma, cribriform carcinoma, armored carcinoma, carcinoma cutaneum, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, carcinoma ex ulcere, fibrocarcinoma, gelatinous carcinoma, gelatinous carcinoma, carcinoma), giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanoma, soft tissue carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous cell carcinoma mucocellulare), mucoepidermoid carcinoma, carcinoma mucosum, myxoid carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthocyte carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, carcinoma scrotumscroti), signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma (carcinomaspongiosum), squamous cell carcinoma, squamous cell carcinoma, rope-shaped carcinoma, carcinoma with vasculature (carcinoma langiectaticum), carcinoma with telangiectodes (carcinoma telangiectodes), transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0153] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" are used interchangeably and refer to the spread of a proliferative disease or condition (e.g., cancer) from one organ to another non-adjacent organ or body part."Metastatic cancer" is also referred to as "stage IV cancer." Cancer arises at the site of origin (e.g., breast), which is referred to as a primary tumor, such as primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and infiltrate normal tissues surrounding the local area, and / or penetrate the lymphatic system or the walls of the vascular system through systemic circulation to other parts of the body and the ability of tissues. The second clinically detectable tumor formed by the cancer cells of the primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, it is speculated that the metastatic tumor and its cells are similar to the primary tumor. Therefore, if lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells rather than abnormal breast cells. Secondary tumors in the breast refer to metastatic lung cancer. Therefore, the phrase 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 phrases non-metastatic cancer or a subject having non-metastatic cancer refer 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 a primary lung tumor or a history of a primary lung tumor and has one or more secondary tumors in a second location or locations (e.g., in the breast).

[0154] The term "cutaneous metastasis" or "skin metastasis" refers to secondary malignant cell growth in the skin, where the malignant cells originate from the primary cancer site (e.g., breast). In cutaneous metastasis, cancer cells from the primary cancer site can migrate to the skin where they divide and cause lesions. Cutaneous metastasis can be caused by cancer cells migrating from a breast cancer tumor to the skin.

[0155] The term "visceral metastasis" refers to the growth of secondary malignant cells in an internal organ (e.g., heart, lung, liver, pancreas, intestine) or body cavity (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancer cells from the primary cancer site can migrate to an internal organ where they divide and cause lesions. Visceral metastasis can be caused by cancer cells migrating to an internal organ from a liver cancer tumor or a head and neck tumor.

[0156] As used herein, the term "RASopathy" refers to a disease caused by a germline mutation of a gene encoding a component of the RAS / MAPK signaling pathway. In embodiments, a RASopathy is a mosaic RASopathy. In embodiments, a RASopathy is a germline RASopathy. In embodiments, a RASopathy is a developmental syndrome. In embodiments, a RASopathy is Noonan syndrome. In embodiments, a RASopathy is an epidermal nevus. In embodiments, a RASopathy is Schimmelpenning syndrome. In embodiments, a RASopathy is a sebaceous nevus. In embodiments, a RASopathy is clubfoot (e.g., congenital clubfoot). In embodiments, a RASopathy is PIK3CA-associated overgrowth syndrome (PROS). In embodiments, a RASopathy is PTEN-hamartoma of soft tissue (PHOST). In embodiments, a RASopathy is fibrofatty overgrowth, hemihyperplastic multiple lipomatous hyperplasia, congenital lipomatous overgrowth, vascular malformation, epidermal nevus, spinal and skeletal syndrome, macrodactyly syndrome, macrodactyly syndrome, or congenital diffuse infiltrative lipomatous hyperplasia. 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 cardiofacial syndrome. In embodiments, the RASopathy is hereditary gingival fibromatosis type 1. In embodiments, the RASopathy is neurofibromatosis type 1. In embodiments, the RASopathy is Kristiello's elastin deficiency. In embodiments, the RASopathy is Reye's syndrome. In embodiments, 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.

[0157] As used herein, the term "switch II GTPase protein-associated disease" refers to any disease or condition caused by abnormal activity or signaling of a switch II GTPase protein. In embodiments, the switch II GTPase protein-associated disease is cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, melanoma, thyroid cancer, or urinary cancer).

[0158] As used herein, the term "K-Ras (G12R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of K-Ras (G12R). In embodiments, the K-Ras (G12R)-related disease is cancer (e.g., pancreatic cancer, lung cancer, or colorectal cancer). In embodiments, the K-Ras (G12R)-related disease is RASopathy.

[0159] As used herein, the term "H-Ras (G12R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of H-Ras (G12R). In one embodiment, the H-Ras (G12R)-related disease is cancer. In one embodiment, the H-Ras (G12R)-related disease is RASopathy.

[0160] As used herein, the term "N-Ras (G12R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of N-Ras (G12R). In embodiments, the N-Ras (G12R)-related disease is cancer. In embodiments, the N-Ras (G12R)-related disease is RASopathy.

[0161] As used herein, the term "K-Ras (G13R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of K-Ras (G13R). In one embodiment, the K-Ras (G13R)-related disease is cancer. In one embodiment, the K-Ras (G13R)-related disease is RASopathy.

[0162] As used herein, the term "H-Ras (G13R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of H-Ras (G13R). In embodiments, the H-Ras (G13R)-related disease is cancer (e.g., melanoma). In embodiments, the H-Ras (G13R)-related disease is RASopathy.

[0163] As used herein, the term "N-Ras (G13R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of N-Ras (G13R). In embodiments, the N-Ras (G13R)-related disease is cancer. In embodiments, the N-Ras (G13R)-related disease is RASopathy.

[0164] As used herein, the term "K-Ras (Q61R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of K-Ras (Q61R). In one embodiment, the K-Ras (Q61R)-related disease is cancer. In one embodiment, the K-Ras (Q61R)-related disease is RASopathy.

[0165] As used herein, the term "H-Ras (Q61R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of H-Ras (Q61R). In embodiments, the H-Ras (Q61R)-related disease is cancer (e.g., thyroid cancer or urinary cancer). In embodiments, the H-Ras (Q61R)-related disease is RASopathy.

[0166] As used herein, the term "N-Ras (Q61R)-related disease" refers to any disease or condition caused by abnormal activity or signaling of N-Ras (Q61R). In embodiments, the N-Ras (Q61R)-related disease is cancer (e.g., melanoma or thyroid cancer). In embodiments, the N-Ras (Q61R)-related disease is RASopathy.

[0167] The term "drug" is used according to its ordinary meaning and refers to a substance that has a physiological effect (e.g., a beneficial effect, useful for treating a subject) when introduced into or on a subject (e.g., into or on a subject or patient). A drug moiety is a group of a drug.

[0168] A "detectable agent," "detectable compound," "detectable label," or "detectable moiety" is a substance (e.g., an 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 Mr. 89 Zr、 94 Tc 94 Tc 99m Tc 99 For 105 pd 105 Rh、 111 Ag 111 in 123 I 124 I 125 I 131 I 142 Mr. 143 Mr. 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, fluorophores (e.g., fluorescent dyes), modified oligonucleotides (e.g., portions described in PCT / US2015 / 022063, which is incorporated herein by reference), electron dense reagents, enzymes (e.g., enzymes commonly used in ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, single crystalline iron oxide nanoparticles, single crystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing gadolinium chelate ("Gd-chelate") molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyribonucleic acid (F ... Glucose (e.g., fluorine-18 labeled), any gamma-emitting radionuclide, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., comprising a microbubble shell comprising albumin, galactose, lipids and / or polymers; a microbubble gas core comprising air, heavy gas, perfluorocarbon, nitrogen, octafluoropropane, perfluoropropane lipid microspheres, perfluoroethers, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, iopromide, diatrizoate, metrizoate, iocolic acid), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities that can be detected, for example, by incorporating a radiolabel into a peptide or antibody that specifically reacts with a target peptide.

[0169] Radioactive substances (eg, radioisotopes) that can be used as imaging agents and / or labeling agents according to embodiments of the present disclosure include, but are not limited to 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 Second, 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 225 Ac. Paramagnetic ions that can be used as additional imaging agents according to 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.

[0170] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration of an active agent to a subject and in its absorption by the subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, carboxymethyl cellulose, polyvinyl pyrrolidone, and pigments. Such preparations can be sterilized and, if desired, can be mixed with adjuvants that do not react deleteriously with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring substances, and / or aromatic substances. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0171] The term "preparation" is intended to encompass the formulation of an active compound with encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier, which in turn is in association with the active ingredient. Similarly, cachets and lozenges are encompassed. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0172] As used herein, the term "about" means a range of values ​​that includes the specified value, which one of ordinary skill in the art would consider to be reasonably similar to the specified value. In embodiments, about means within the standard deviation using measurements generally accepted in the art. In embodiments, about means a range extends to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0173] As used herein, the term "administer" is used according to its common and general meaning, and includes oral administration to a subject, administration in the form of 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). Administered 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, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusions, transdermal patches, etc. "Co-administered" means that the compositions described herein are administered while, just before, or just after, one or more other therapies (e.g., cancer therapies such as chemotherapy, hormone therapy, radiotherapy, or immunotherapy) are administered. The compounds of the present invention can be administered alone or co-administered to a patient. Co-administered means administering compounds (more than one compound) simultaneously or sequentially, either individually or in combination. Thus, the formulations may also be combined with other active substances if desired (e.g., to reduce metabolic degradation). The compositions of the invention may be delivered transdermally, topically, and may be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0174] 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 with adjunct agents that alone may not be effective but may aid in the efficacy of the active agents.

[0175] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering the two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulating, i.e., preparing a single pharmaceutical composition comprising the two active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agent and / or adjuvant can be linked or conjugated to each other.

[0176] In therapeutic applications for treating diseases, the compound used in the pharmaceutical composition of the present invention can be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg per day. The daily dose range can be 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. However, the dosage can vary according to the patient's needs, the severity of the condition being treated, and the compound or drug being used. For example, the dosage can be determined empirically based on the type and stage of the disease (e.g., cancer or RASopathy) diagnosed in a particular patient. In the context of the present invention, the dosage administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also depend on the presence, nature, and extent of any adverse side effects associated with the administration of the compound in a particular patient. It is within the practitioner's skill to determine the appropriate dosage for a specific situation. Typically, treatment is initiated with a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect is reached in most cases.For convenience, the total daily dosage may be divided and administered in portions during the day as needed.

[0177] In the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term "associated" or "associated with" means that the disease (e.g., cancer or RASopathy) is caused (in whole or in part) by the substance or substance activity or function, or that the symptoms of the disease are caused (in whole or in part) by the substance or substance activity or function, or that the disease or symptoms of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., a cellular component). As used herein, a pathogen is described as being associated with a disease if it can be a target for treating the disease.

[0178] As used herein, the term "abnormal" means different from normal. When used to describe enzymatic activity, abnormal refers to activity that is greater or less than the average of a normal control or normal non-diseased control sample. Abnormal activity can refer to an amount of activity that causes disease, wherein returning the abnormal activity to a normal or non-disease associated amount (e.g., by administering a compound or using a method as described herein) results in a reduction in the disease or one or more disease symptoms.

[0179] As used herein, the term "electrophile" refers to a chemical group that is capable of accepting electron density. An "electrophile substituent," "electrophile chemical moiety," or "electrophilic moiety" refers to an electron-deficient chemical group, substituent, or moiety (a monovalent chemical group) that can react with an electron-donating group, such as a nucleophile, to form a bond by accepting an electron pair or electron density.

[0180] As used herein, "nucleophile" refers to a chemical group that is capable of donating electron density.

[0181] The term "isolated" when applied to nucleic acids or proteins means that the nucleic acid or protein is substantially free of other cellular components with which it is associated in its native state. It can, for example, be in a homogeneous state and can be in a dry state or in aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. The major protein present in the preparation is substantially purified.

[0182] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are subsequently modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., an alpha carbon bound to a hydrogen, carboxyl, amino, and R groups), 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 naturally occurring amino acids. Amino acid mimetics refer to compounds that have a structure that differs from the general chemical structure of an amino acid but function in a manner similar to naturally occurring amino acids. The terms "non-natural amino acids" and "unnatural amino acids" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0183] 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. Likewise, nucleotides may be referred to by their commonly accepted single-letter codes.

[0184] The term "amino acid side chain" refers to the side chain on an amino acid. For example, if an amino acid has the formula Then -LR is an amino acid side chain. For example, L-arginine has the following formula And the L-arginine side chain is

[0185] As used herein, the term "arginine" refers to an amino acid having a side chain or an amino acid modified therefrom. In embodiments, the post-translational modification is methylation, citrullination, phosphorylation, ADP-ribosylation, carbonylation or saccharification. In embodiments, arginine is monomethylarginine (MMA). In embodiments, arginine is symmetrical dimethylarginine (SDMA). In embodiments, arginine is asymmetric dimethylarginine (ADMA). In embodiments, arginine is 5-hydrogen-5-methyl-4-imidazolin-2-yl)-ornithine (MG-H1). In embodiments, arginine is carboxyethylarginine (CEA). In embodiments, arginine is carboxymethylarginine (CMA). In embodiments, 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, arginine is a post-translationally modified arginine as described above. In embodiments, arginine is not post-translationally modified and has a side chain

[0186] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which polymer may, in embodiments, be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0187] The "position" of an amino acid or nucleotide base is represented by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5' end). Since deletions, insertions, truncations, fusions, etc. must be considered when determining the optimal alignment, the numbering of amino acid residues in a test sequence, as determined by counting only from the N-terminus, is not necessarily the same as the numbering of their corresponding positions in the reference sequence. For example, where a variant has a deletion relative to the aligned reference sequence, there will be no amino acid in the variant corresponding to the position at the deletion site in the reference sequence. In the case of an insertion in the aligned reference sequence, the insertion will not correspond to the numbered amino acid position in the reference sequence. In the case of truncations or fusions, there may be stretches of amino acids in the reference sequence or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0188] When used in the context of the numbering of a given amino acid or polynucleotide sequence, the term "reference number" or "corresponding to" refers to the numbering of the residues of a given reference sequence when comparing the given amino acid or polynucleotide sequence to the reference sequence.

[0189] An amino acid residue in a protein "corresponds" to a given residue when the residue occupies the same basic structural position in the protein as the given residue. For example, a selected residue in a selected protein corresponds to G12 of K-Ras when the selected residue occupies the same basic spatial or other structural relationship as G12 in K-Ras. In some embodiments in which the selected protein is aligned for maximum homology with K-Ras, the position in the selected protein that is aligned with G12 is said to correspond to G12. Instead of a primary sequence alignment, a three-dimensional structural alignment can also be used, for example, in which the structure of the selected protein is aligned for maximum correspondence with K-Ras and the overall structures are compared. In this case, the amino acid that occupies the same basic position as G12 in the structural model is considered to correspond to the G12 residue.

[0190] The term "protein complex" is used according to its ordinary general meaning and refers to a protein associated with another substance (e.g., another protein, protein subunit, or compound). A protein complex typically has a well-defined quaternary structure. The association between the protein and the other substance can be a covalent bond. In embodiments, the association between the protein and the other substance (e.g., compound) is through non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. The proteins in a protein complex are connected by non-covalent protein-protein interactions. A non-limiting example of a protein complex is a proteasome.

[0191] The term "protein aggregate" is used according to its common general meaning and refers to abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are generally associated with diseases (e.g., amyloidosis). Typically, when a protein is misfolded due to a change in the amino acid sequence or a change in the natural environment that destroys normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that can be formed: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are referred to as aggresomes.

[0192] As used herein, the term "switch II" 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 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 that is at least partially bound by (forms the boundaries or borders of) the amino acid residues that form switch II. In some embodiments, a "switch II binding pocket" is a cavity in a GDP-bound form of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras) that is at least partially bound by (forms the boundaries or borders of) the amino acid residues that form switch II. A "switch II binding pocket binding portion" is a portion of a compound (e.g., as described herein) that binds to the switch II binding pocket.

[0193] As used herein, the term "switch II GTPase protein" refers to a GTPase protein that includes switch II. In embodiments, the switch II GTPase protein includes a switch II binding pocket. In embodiments, the switch II GTPase protein is a Ras protein. In embodiments, the switch II GTPase protein is K-Ras. In embodiments, the switch II GTPase protein is H-Ras. In embodiments, the switch II GTPase protein is N-Ras. In embodiments, the switch II GTPase protein is ARF1 (e.g., UniProt P84077). In embodiments, the switch 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 Q9HOF7). 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.

[0194] As used herein, the term "switch II GTPase protein arginine residue" refers to the arginine residue of a switch II GTPase protein. In embodiments, the switch II GTPase protein arginine residue is the 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 the 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 the 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 mutated switch II GTPase protein arginine residue is arginine residue 12 of K-Ras(G12R), H-Ras(G12R), or N-Ras(G12R). In embodiments, the mutated switch II GTPase protein arginine residue is arginine residue 13 of K-Ras(G13R), H-Ras(G13R), or N-Ras(G13R). In embodiments, the mutated switch II GTPase protein arginine residue is arginine residue 61 of K-Ras(Q61R), H-Ras(Q61R), or N-Ras(Q61R).

[0195] The term "Ras" refers to one or more of the human Ras GTPase protein family (eg, K-Ras, H-Ras, N-Ras), including homologs, isoforms, and functional fragments thereof.

[0196] The term "K-Ras" refers to a protein encoded by the KRAS gene in humans. The K-Ras protein is a GTPase that converts guanosine triphosphate into guanosine diphosphate. Mutations (e.g., amino acid substitutions) in the K-Ras protein can lead to 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, RefSeqNP_004976.2, or RefSeq NP_203524.1). In an embodiment, K-Ras has the following amino acid sequence:

[0197] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM(SEQ ID NO:1).

[0198] 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 lead to a variety of malignancies (e.g., bladder cancer, thyroid cancer, salivary gland cancer, epithelial cancer, or kidney cancer). The term "H-Ras" may refer to the nucleotide sequence or protein sequence of human HRAS (e.g., Entrez 3265, UniProt P01112, RefSeq NM_001130442.2, RefSeq NM_001318054.1, RefSeq NM_005343.3, RefSeq NM_00176795.4, RefSeq NP_001123914.1, RefSeq NP_001304983.1, RefSeq NP_005334.1, or RefSeq NP_789765.1). In embodiments, H-Ras has the following amino acid sequence:

[0199] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVLVGNKCDLAARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDESGPGCMSCKCVLS(SEQ ID NO:2).

[0200] The term "N-Ras" refers to an enzyme encoded by the NRAS gene in humans. The N-Ras protein is a GTPase that converts guanosine triphosphate into guanosine diphosphate. The term "N-Ras" can refer to the nucleotide sequence or protein sequence of human NRAS (e.g., Entrez4893, UniProt P01111, RefSeq NM_002524.4, or RefSeq NP_002515.1). In an embodiment, N-Ras has the following amino acid sequence:

[0201] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDLPTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQGCMGLPCVVM(SEQ ID NO:3).

[0202] In embodiments, the switch II binding pocket is at least partially bound by one or more of V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and / or I100, or equivalent residues, of K-Ras in a homologous, related (e.g., H-Ras or N-Ras), or mutant Ras protein. Compounds as described herein (including embodiments, examples, and figures) that bind to amino acids that form or contact the amino acids that form the switch II binding pocket are "switch II binding pocket binding compounds," and portions of compounds that bind to amino acids that form or contact the amino acids that form the switch II binding pocket are "switch II binding pocket binding moieties."

[0203] In embodiments, a switch II binding pocket binding compound or a switch II binding pocket binding portion binds to or contacts one amino acid that forms the switch II binding pocket. In embodiments, a switch II binding pocket binding compound or a switch II binding pocket binding portion binds to or contacts multiple amino acids that form the switch II binding pocket. In embodiments, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts an amino acid selected from 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 an amino acid in 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 1100. In embodiments, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts a plurality of K-Ras amino acids selected from 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 an amino acid in 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 1100. In embodiments, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts two K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100.In embodiments, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts three K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In embodiments, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts four K-Ras amino acids selected from mutant K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In embodiments, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts five K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100.In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts six K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts seven K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts eight K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100.In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts nine K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts ten K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts eleven K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100.In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts twelve K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts thirteen K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100. In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts fourteen K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100.In an embodiment, a switch II binding pocket binding compound or switch II binding pocket binding portion binds to or contacts fifteen K-Ras amino acids selected from mutant K-Ras (e.g., K-Ras(G12R), K-Ras(G13R), or K-Ras(Q61R)), 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 amino acids in 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 1100.

[0204] As used herein, the term "phosphatase PTP domain" refers to a protein domain of a protein tyrosine phosphatase formed by residues corresponding to residues 1-279 of human PTP1B, including an arginine residue. In embodiments, the phosphatase PTP domain is as described in Andersen, JN et 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 portion" is a portion of a compound (e.g., as described herein) that binds to a phosphatase PTP domain.

[0205] The term "PTP1B" or "tyrosine-protein phosphatase 1B" refers to a member of the protein tyrosine phosphatase family encoded by the PTPN1 gene in humans. The term "PTP1B" may refer to the nucleotide sequence or protein sequence of human PTP1B (e.g., Entrez5770, UniProt P18031, RefSeq NM_002827.4, or RefSeq NP_002818.1). In an embodiment, PTP1B has the following amino acid sequence:

[0206] MEMEKEFEQIDKSGSWAAIYQDIRHEASDFPCRVAKLPKNKNRNRYRDVSPFDHSRIKLHQEDNDYINASLIKMEEAQRSYILTQGPLPNTCGHFWEMVWEQKSRGVVM LNRVMEKGSLKCAQYWPQKEEKEMIFEDTNLKLTLISEDIKSYYTVRQLELENLTTQETREILHFHYTTWPDFGVPESPASFLNFLFKVRESGSLSPEHGPVVVHCSAGI GRSGTFCLADCLLLMDKRKDPSSVDIKKVLLEMRKFRMGLIQTADQLRFSYLAVIEGAKFIMGDSSVQDQWKELSHEDLEPPPEHIPPPPRPPKRILEPHNGKCREFFP NHQWVKEETQEDKDCPIKEEKGSPLNAAPYGIESMSQDTEVRSRVVGGSLRGAQAASPAKGEPSLPEKDEDHALSYWKPFLVNMCVATVLTAGAYLCYRFLFNSNT(SEQ ID NO:4).

[0207] As used herein, the term "SH2 domain" refers to a protein domain of the Src oncoprotein formed by residues corresponding to residues 151-248 of the human Src oncoprotein, including an 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 herein by reference in its entirety for all purposes. An "SH2 domain binding portion" is a portion of a compound (e.g., as described herein) that binds to an SH2 domain.

[0208] The term "Src" or "proto-oncogene tyrosine-protein kinase Src" refers to a 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 an embodiment, Src has the following amino acid sequence:

[0209] (SEQ ID NO:5).

[0210] As used herein, the term "pseudokinase KSR domain" or "pseudokinase kinase inhibitor 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, DF et al., Nature 472, 366–369 (2011) and Xing, L. et al., Bioorg. Med. Chem. 23 (19), 6520–6527, which are incorporated herein by reference in their entirety for all purposes. A "pseudokinase KSR domain binding portion" is a portion of a compound (e.g., as described herein) that binds to a pseudokinase KSR domain.

[0211] The term "KSR2" or "kinase inhibitor of Ras 2" refers to a 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 an embodiment, KSR2 has the following amino acid sequence:

[0212] MDEENMTKSEEQQPLSLQKALQQCELVQNMIDLSISNLEGLRTKCATSNDLTQKEIRTLESKLVKYFSRQLSCKKKVALQERNAELDGFPQLRHWFRIVDVRKEVLEEISPGQLSLEDLLEMTDEQVCETVEKYGANREECARLNASLSCLRNVHMSGGNLSKQDWTIQWPTTETGKENNPVCPPEPTPWIRTHLSQSPRVPSKCVQHYCHTSPTPGAPVYTHVDRLTVDAYPGLCPPPPLESGHRSLPPSPRQRHAVRTPPRTPNIVTTVTPPGTPPMRKKNKLKPPGTPPPSSRKLIHLIPGFTALHRSKSHEFQLGHRVDEAHTPKAKKKSKPLNLKIHSSVGSCENIPSQQRSPLLSERSLRSFFVGHAPFLPSTPPVHTEANFSANTLSVPRWSPQIPRRDLGNSIKHRFSTKYWMSQTCTVCGKGMLFGLKCKNCKLKCHNKCTKEAPPCHLLIIHRGDPARLVRTESVPCDINNPLRKPPRYSDLHISQTLPKTNKINKDHIPVPYQPDSSSNPSSTTSSTPSSPAPPLPPSATPPSPLHPSPQCTRQQKNFNLPASHYYKYKQQFIFPDVVPVPETPTRAPQVILHPVTSNPILEGNPLLQIEVEPTSENEEVHDEAEESEDDFEEMNLSLLSARSFPRKASQTSIFLQEWDIPFEQLEIGELIGKGRFGQVYHGRWHGEVAIRLIDIERDNEDQLKAFKREVMAYRQTRHENVVLFMGACMSPPHLAIITSLCKGRTLYSVVRDAKIVLDVNKTRQIAQEIVKGMGYLHAKGILHKDLKSKNVFYDNGKVVITDFGLFSISGVLQAGRREDKLRIQNGWLCHLAPEIIRQLSPDTEEDKLPFSKHSDVFALGTIWYELHAREWPFKTQPAEAIIWQMGTGMKPNLSQIGMGKEISDILLFCWAFEQEERPTFTKLMDMLEKLPKRNRRLSHPGHFWKSAEL(SEQ ID NO:6)。

[0213] As used herein, the term "pseudokinase STRADα domain" refers to a protein domain of the STRADα protein formed by residues corresponding to residues 59-431 of the STRADα protein, including an 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 herein by reference in their entirety for all purposes. A "pseudokinase STRADα domain binding portion" is a portion of a compound (e.g., as described herein) that binds to the pseudokinase STRADα domain.

[0214] The term "STRAD alpha" or "STE20-related kinase adaptor protein alpha" refers to the protein that in humans is encoded by the STRADA gene. The term "STRADα" may refer 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 an embodiment, STRADα has the following amino acid sequence:

[0215] MSFLVSKPERIRRWVSEKFIVEGLRDLELFGEQPPGDTRRKTNDASSESIASFSKQEVMSSFLPEGGCYELLTVIGKGFEDLMTVNLARYKPTGEYVTVRRINLEACS NEMVTFLQGELHVSKLFNHPNIVPYRATFIADNELWVVTSFMAYGSAKDLICTHFMDGMNELAIAYILQGVLKALDYIHHMGYVHRSVKASHILISVDGKVYLSGLRSN LSMISHGQRQRVVHDFPKYSVKVLPWLSPEVLQQNLQGYDAKSDIYSVGITACELANGHVPFKDMPATQMLLEKLNGTVPCLLDTSTIPAEELTMSPSRSVANSGLSDS LTTSTPRPSNGDSPSHPYHRTFSPHFHHFVEQCLQRNPDARPSASTLLNHSFFKQIKRRASELPELLRPVTPITNFEGSQSQDHSGIFGLVTNLEELEVDDWEF(SEQ ID NO:7).

[0216] The terms "selective" or "selectivity" and the like with respect to a compound or agent refer to the ability of a compound or agent to increase or decrease the activity of a particular molecular target (e.g., a protein, enzyme, etc.) in preference to one or more different molecular targets (e.g., or a compound that is selective for mutant K-Ras(G12R) will inhibit K-Ras(G12R) in preference to 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).

[0217] II.Compounds

[0218] In one aspect, a compound, or a pharmaceutically acceptable salt thereof, is provided, having the formula:

[0219]

[0220] R 1 It is the binding part of the switch II binding pocket.

[0221] L 1 is a bond or a divalent linker.

[0222] L 2 is a bond or a substituted or unsubstituted alkylene group (e.g., C1-C8, C1-C6, C1-C4 or C1-C2).

[0223] L 3 For bonds, -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-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0224] R 3 For 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)OR3C 、-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-C8, C1-C6, C1-C4 or C1-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-C8, C3-C6, C4-C6 or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0225] 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, -OCH2I, -OCHCl2, -OCHBr2, -OCHF 2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0226] R 3A 、R 3B、R 3C and R 3D 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, -OCH2 I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 3A and R 3B The substituents may be optionally joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 membered), or a substituted or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0227] Each X 3 is independently -Cl, -Br, -I or -F.

[0228] The symbol n3 is an integer from 0 to 4.

[0229] The symbols m3 and v3 are independently 1 or 2.

[0230] In an embodiment, the compound has the formula:

[0231] L 1 、L 2 、L 3 、R 1 and R 3 As described herein (including in the embodiments).

[0232] In an embodiment, the compound has the formula:

[0233] L 1 、L 2 、L 3、R 1 and R 3 As described herein (including in the embodiments).

[0234] In an embodiment, the compound has the formula:

[0235] L 1 、L 2 、L 3 、R 1 and R 3 As described herein (including in the embodiments).

[0236] In an embodiment, substituted L 2 (e.g., substituted alkylene) is substituted with at least one substituent group, a substituent group of limited size, or a lower substituent group; wherein if the substituted L 2 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 2 When L is substituted, it is substituted with at least one substituent group. 2 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 2 When substituted, it is substituted with at least one lower substituent group.

[0237] In an embodiment, L 2 is a bond or an unsubstituted C1-C4 alkylene. 2 In an embodiment, L 2 is an unsubstituted C1-C4 alkylene group. 2 is an unsubstituted methylene group. In an embodiment, L 2 is unsubstituted ethylene. In the embodiment, L 2 is an unsubstituted propylene group. In the embodiment, L 2 is unsubstituted n-propylene. In the embodiment, L 2 is an unsubstituted isopropylidene group. In the embodiment, L 2 is unsubstituted butylene. In the embodiment, L 2 is unsubstituted n-butylene. In the embodiment, L 2 is an unsubstituted isobutylene group. 2 It is an unsubstituted tert-butylene group.

[0238] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 3 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 3 When L is substituted, it is substituted with at least one substituent group. 3 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 3 When substituted, it is substituted with at least one lower substituent group.

[0239] 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)2-, -NHS(O)2-, -S(O)2NH-, 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.

[0240] 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)2-, -NHS(O)2-, -S(O)2NH-, 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.

[0241] In an embodiment, L 3 In an embodiment, L 3 It is -C(O)-.

[0242] In an embodiment, substituted R 30(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 30 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 30 When substituted, it is substituted with at least one substituent group. 30 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 30 When substituted, it is substituted with at least one lower substituent group.

[0243] In an embodiment, R 30 are independently hydrogen. In an embodiment, R 30 are independently unsubstituted C1-C4 alkyl. 30 is independently unsubstituted methyl. In an embodiment, R 30 is independently unsubstituted ethyl. In an embodiment, R 30 is independently unsubstituted propyl. In an embodiment, R 30 is independently unsubstituted n-propyl. In an embodiment, R 30 is independently unsubstituted isopropyl. In an embodiment, R 30 is independently unsubstituted butyl. In an embodiment, R 30 is independently unsubstituted n-butyl. In an embodiment, R 30 is independently unsubstituted isobutyl. In an embodiment, R 30 is independently unsubstituted tert-butyl.

[0244] In an embodiment, the compound has the formula:

[0245] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0246] In an embodiment, the compound has the formula:

[0247] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0248] In an embodiment, the compound has the formula:

[0249] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0250] In an embodiment, the compound has the formula:

[0251] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0252] In an embodiment, the compound has the formula:

[0253] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0254] In an embodiment, the compound has the formula:

[0255] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0256] In an embodiment, the compound has the formula:

[0257] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0258] In an embodiment, the compound has the formula:

[0259] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0260] In an embodiment, the compound has the formula:

[0261] L 1 、R 1 and R 3 As described herein (including in the embodiments).

[0262] In an embodiment, substituted R3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 3 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 3 When substituted, it is substituted with at least one substituent group. 3 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 3 When substituted, it is substituted with at least one lower substituent group.

[0263] In an embodiment, substituted R 3A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 3A is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 3A When substituted, it is substituted with at least one substituent group. 3A When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 3A When substituted, it is substituted with at least one lower substituent group.

[0264] In an embodiment, substituted R 3B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 3B is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 3B When substituted, it is substituted with at least one substituent group. 3B When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R3B When substituted, it is substituted with at least one lower substituent group.

[0265] In an embodiment, when R bonded to the same nitrogen atom 3A and R 3B The substituted ring formed when the substituents are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, a substituent group of limited size, or a lower substituent group; wherein if R 3A and R 3B The substituted ring formed when the substituents are joined is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, a substituent group of limited size, and / or a lower substituent group may optionally be different. In an embodiment, when R 3A and R 3B When the substituted ring formed when the substituents are joined is substituted, it is substituted with at least one substituent group. In an embodiment, when R 3A and R 3B When the substituted ring formed when the substituents are joined is substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 3A and R 3B When the substituted ring formed when the substituents are attached is substituted, it is substituted with at least one lower substituent group.

[0266] In an embodiment, substituted R 3C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 3C is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, or a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 3C When substituted, it is substituted with at least one substituent group. 3C When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 3C When substituted, it is substituted with at least one lower substituent group.

[0267] In an embodiment, substituted R 3D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 3D is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, or a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 3D When substituted, it is substituted with at least one substituent group. 3D When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 3D When substituted, it is substituted with at least one lower substituent group.

[0268] In an embodiment, R 3 For 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-C8, C1-C6, C1-C4, or C1-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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0269] In an embodiment, R 3 is hydrogen or unsubstituted C1-C4 alkyl. 3 is hydrogen or unsubstituted methyl. In an embodiment, R 3 is hydrogen. In an embodiment, R3 is an unsubstituted C1-C4 alkyl. 3 is an unsubstituted methyl group. In an embodiment, R 3 is an unsubstituted ethyl group. In an embodiment, R 3 is unsubstituted propyl. In the embodiment, R 3 is unsubstituted n-propyl. In an embodiment, R 3 is unsubstituted isopropyl. In the embodiment, R 3 is an unsubstituted butyl group. In an embodiment, R 3 is unsubstituted n-butyl. In an embodiment, R 3 is an unsubstituted isobutyl group. In an embodiment, R 3 is an unsubstituted tert-butyl group.

[0270] In an embodiment, R 3 is halogen. In an embodiment, R 3 In an embodiment, R 3 In the embodiment, R 3 is -Br. In an embodiment, R 3 In an embodiment, R 3 In the embodiment, R 3 is -CBr3. In an embodiment, R 3 In the embodiment, R 3 In the embodiment, R 3 is -CH2Cl. In an embodiment, R 3 is -CH2Br. In an embodiment, R 3 is -CH2F. In an embodiment, R 3 In an embodiment, R 3 is -CHCl2. In an embodiment, R 3 is -CHBr2. In an embodiment, R 3 is -CHF2. In an embodiment, R 3 In an embodiment, R 3 In an embodiment, R 3 In the embodiment, R 3 is -NH2. In an embodiment, R 3 In an embodiment, R 3 In an embodiment, R 3 In the embodiment, R 3 In the embodiment, R 3In the embodiment, R 3 is -OSO3H. In an embodiment, R 3 In the embodiment, R 3 is -NHNH2. In an embodiment, R 3 In the embodiment, R 3 is -NHC(O)NHNH2. In an embodiment, R 3 is -NHC(O)NH2. In an embodiment, R 3 is -NHSO2H. In an embodiment, R 3 is -NHC(O)H. In an embodiment, R 3 is -NHC(O)OH. In an embodiment, R 3 is independently -NHOH. In an embodiment, R 3 In the embodiment, R 3 In an embodiment, R 3 In the embodiment, R 3 In the embodiment, R 3 In an embodiment, R 3 is -OCH2Br. In an embodiment, R 3 is -OCH2F. In an embodiment, R 3 In an embodiment, R 3 In an embodiment, R 3 is -OCHBr2. In an embodiment, R 3 is -OCHF2. In an embodiment, R 3 In the embodiment, R 3 is an unsubstituted C3-C8 cycloalkyl. 3 is unsubstituted cyclopropyl. In an embodiment, R 3 is unsubstituted cyclobutyl. In an embodiment, R 3 is an unsubstituted cyclopentyl. In an embodiment, R 3 is an unsubstituted cyclohexyl group. In an embodiment, R 3 is unsubstituted cycloheptyl. In an embodiment, R 3 is an unsubstituted cyclooctyl group. In an embodiment, R 3 is an unsubstituted phenyl group.

[0271] In an embodiment, R 3A is hydrogen. In an embodiment, R 3A is an unsubstituted C1-C4 alkyl.3A is an unsubstituted methyl group. In an embodiment, R 3A is an unsubstituted ethyl group. In an embodiment, R 3A is unsubstituted propyl. In the embodiment, R 3A is unsubstituted n-propyl. In an embodiment, R 3A is unsubstituted isopropyl. In the embodiment, R 3A is an unsubstituted butyl group. In an embodiment, R 3A is unsubstituted n-butyl. In an embodiment, R 3A is an unsubstituted isobutyl group. In an embodiment, R 3A is an unsubstituted tert-butyl group.

[0272] In an embodiment, R 3B is hydrogen. In an embodiment, R 3B is an unsubstituted C1-C4 alkyl. 3B is an unsubstituted methyl group. In an embodiment, R 3B is an unsubstituted ethyl group. In an embodiment, R 3B is unsubstituted propyl. In the embodiment, R 3B is unsubstituted n-propyl. In an embodiment, R 3B is unsubstituted isopropyl. In the embodiment, R 3B is an unsubstituted butyl group. In an embodiment, R 3B is unsubstituted n-butyl. In an embodiment, R 3B is an unsubstituted isobutyl group. In an embodiment, R 3B is an unsubstituted tert-butyl group.

[0273] In an embodiment, R 3C is hydrogen. In an embodiment, R 3C is an unsubstituted C1-C4 alkyl. 3C is an unsubstituted methyl group. In an embodiment, R 3C is an unsubstituted ethyl group. In an embodiment, R 3C is unsubstituted propyl. In the embodiment, R 3C is unsubstituted n-propyl. In an embodiment, R 3C is unsubstituted isopropyl. In the embodiment, R 3C is an unsubstituted butyl group. In an embodiment, R 3C is unsubstituted n-butyl. In an embodiment, R 3C is an unsubstituted isobutyl group. In an embodiment, R 3C is an unsubstituted tert-butyl group.

[0274] In an embodiment, R 3Dis hydrogen. In an embodiment, R 3D is an unsubstituted C1-C4 alkyl. 3D is an unsubstituted methyl group. In an embodiment, R 3D is an unsubstituted ethyl group. In an embodiment, R 3D is unsubstituted propyl. In the embodiment, R 3D is unsubstituted n-propyl. In an embodiment, R 3D is unsubstituted isopropyl. In the embodiment, R 3D is an unsubstituted butyl group. In an embodiment, R 3D is unsubstituted n-butyl. In an embodiment, R 3D is an unsubstituted isobutyl group. In an embodiment, R 3D is an unsubstituted tert-butyl group.

[0275] In an embodiment, L 1 -L 101 -L 102 -L 103 -L 104 -L 105 -.

[0276] In an embodiment, L 101 Direct connection to R 1 .

[0277] L 101 For bonds, -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-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0278] L 102 For bonds, -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-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0279] L 103 For bonds, -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-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0280] L 104 For bonds, -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-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0281] L 105 For bonds, -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 -、-NR105 C(NH)NR 105 -、-S(O)2-、-NR 105 S(O)2-、-S(O)2NR 105 -, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0282] Each R 101 、R 102 、R 103 、R 104 and R 105 are 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, -OCHI2, -OCHCl2, -OCHBr, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0283] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 101 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 101 When L is substituted, it is substituted with at least one substituent group. 101 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 101 When substituted, it is substituted with at least one lower substituent group.

[0284] 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), substituted or unsubstituted heteroalkylene (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0285] In an embodiment, L 101 In an embodiment, L 101 is -C(O)-. In an embodiment, L 101 is -C(O)O-. In an embodiment, L 101 is -OC(O)-. In an embodiment, L 101 In the embodiment, L 101 In the embodiment, L 101 -NR 101 -. In an embodiment, L 101 In the embodiment, L 101-C(O)NR 101 -. In an embodiment, L 101 is -C(O)NH-. In an embodiment, L 101 -NR 101 C(O)-. In an embodiment, L 101 is -NHC(O)-. In an embodiment, L 101 -NR 101 C(O)O-. In an embodiment, L 101 is -NHC(O)O-. In an embodiment, L 101 -OC(O)NR 101 -.

[0286] In an embodiment, L 101 is -OC(O)NH-. In an embodiment, L 101 -NR 101 C(O)NR 101 -. In an embodiment, L 101 is -NHC(O)NH-. In an embodiment, L 101 -NR 101 C(NH)NR 101 -. In an embodiment, L 101 is -NHC(NH)NH-. In an embodiment, L 101 is -S(O)2-. In the embodiment, L 101 -NR 101 S(O)2-. In an embodiment, L 101 is -NHS(O)2-. In an embodiment, L 101 -S(O)2NR 101 -. In an embodiment, L 101 is -S(O)2NH-. In the embodiment, L 101 is a substituted or unsubstituted C1-C6 alkylene group. 101 is a substituted or unsubstituted methylene group. 101 is substituted or unsubstituted ethylene. In the embodiment, L 101 is a substituted or unsubstituted propylene group. In the embodiment, L 101 is a substituted or unsubstituted n-propylene group. In the embodiment, L 101 is a substituted or unsubstituted isopropylidene group. 101 is a substituted or unsubstituted butylene group. In the embodiment, L 101 is substituted or unsubstituted n-butylene. In the embodiment, L 101 is a substituted or unsubstituted isobutylene group.101 is a substituted or unsubstituted tert-butylene group. 101 is a substituted or unsubstituted pentylene. In the embodiment, L 101 is a substituted or unsubstituted hexamethylene group. 101 is a substituted or unsubstituted 2 to 6 membered heteroalkylene group. 101 is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene group. 101 is a substituted or unsubstituted azetidinyl group. In an embodiment, L 101 is substituted or unsubstituted piperazinyl. In an embodiment, L 101 for In an embodiment, L 101 for In an embodiment, L 101 for

[0287] In an embodiment, substituted R 101 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 101 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 101 When substituted, it is substituted with at least one substituent group. 101 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 101 When substituted, it is substituted with at least one lower substituent group.

[0288] In an embodiment, R 101 are independently hydrogen. In an embodiment, R 101 are independently unsubstituted C1-C4 alkyl. 101 is independently unsubstituted methyl. In an embodiment, R 101 is independently unsubstituted ethyl. In an embodiment, R 101 is independently unsubstituted propyl. In an embodiment, R 101 is independently unsubstituted n-propyl. In an embodiment, R 101 is independently unsubstituted isopropyl. In an embodiment, R 101 is independently unsubstituted butyl. In an embodiment, R101 is independently unsubstituted n-butyl. In an embodiment, R 101 is independently unsubstituted isobutyl. In an embodiment, R 101 is independently unsubstituted tert-butyl.

[0289] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 102 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 102 When L is substituted, it is substituted with at least one substituent group. 102 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 102 When substituted, it is substituted with at least one lower substituent group.

[0290] In an embodiment, L 102 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), substituted or unsubstituted heteroalkylene (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0291] In an embodiment, L 102 In an embodiment, L 102 is -C(O)-. In an embodiment, L 102 is -C(O)O-. In an embodiment, L 102is -OC(O)-. In an embodiment, L 102 In the embodiment, L 102 In the embodiment, L 102 -NR 102 -. In an embodiment, L 102 In the embodiment, L 102 -C(O)NR 102 -. In an embodiment, L 102 is -C(O)NH-. In an embodiment, L 102 -NR 102 C(O)-. In an embodiment, L 102 is -NHC(O)-. In an embodiment, L 102 -NR 102 C(O)O-. In an embodiment, L 102 is -NHC(O)O-. In an embodiment, L 102 -OC(O)NR 102 -. In an embodiment, L 102 is -OC(O)NH-. In an embodiment, L 102 -NR 102 C(O)NR 102 -. In an embodiment, L 102 is -NHC(O)NH-. In an embodiment, L 102 -NR 102 C(NH)NR 102 -. In an embodiment, L 102 is -NHC(NH)NH-. In an embodiment, L 102 is -S(O)2-. In the embodiment, L 102 -NR 102 S(O)2-. In an embodiment, L 102 is -NHS(O)2-. In an embodiment, L 102 -S(O)2NR 102 -. In an embodiment, L 102 is -S(O)2NH-. In the embodiment, L 102 is a substituted or unsubstituted C1-C6 alkylene group. 102 is a substituted or unsubstituted methylene group. 102 is substituted or unsubstituted ethylene. In the embodiment, L 102 is a substituted or unsubstituted propylene group. In the embodiment, L 102 is a substituted or unsubstituted n-propylene group. In the embodiment, L 102is a substituted or unsubstituted isopropylidene group. 102 is a substituted or unsubstituted butylene group. In the embodiment, L 102 is substituted or unsubstituted n-butylene. In the embodiment, L 102 is a substituted or unsubstituted isobutylene group. 102 is a substituted or unsubstituted tert-butylene group. 102 is a substituted or unsubstituted pentylene. In the embodiment, L 102 is a substituted or unsubstituted hexamethylene group. 102 is a substituted or unsubstituted 2 to 6 membered heteroalkylene group. 102 is a substituted or unsubstituted phenylene group.

[0292] In an embodiment, substituted R 102 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 102 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 102 When substituted, it is substituted with at least one substituent group. 102 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 102 When substituted, it is substituted with at least one lower substituent group.

[0293] In an embodiment, R 102 are independently hydrogen. In an embodiment, R 102 are independently unsubstituted C1-C4 alkyl. 102 is independently unsubstituted methyl. In an embodiment, R 102 is independently unsubstituted ethyl. In an embodiment, R 102 is independently unsubstituted propyl. In an embodiment, R 102 is independently unsubstituted n-propyl. In an embodiment, R 102 is independently unsubstituted isopropyl. In an embodiment, R 102 is independently unsubstituted butyl. In an embodiment, R 102 is independently unsubstituted n-butyl. In an embodiment, R 102 is independently unsubstituted isobutyl. In an embodiment, R102 is independently unsubstituted tert-butyl.

[0294] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 103 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 103 When L is substituted, it is substituted with at least one substituent group. 103 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 103 When substituted, it is substituted with at least one lower substituent group.

[0295] In an embodiment, L 103 In an embodiment, L 103 is -C(O)-. In an embodiment, L 103 is -C(O)O-. In an embodiment, L 103 is -OC(O)-. In an embodiment, L 103 In the embodiment, L 103 In the embodiment, L 103 -NR 103 -. In an embodiment, L 103 In the embodiment, L 103 -C(O)NR 103 -. In an embodiment, L 103 is -C(O)NH-. In an embodiment, L 103 -NR 103 C(O)-. In an embodiment, L 103 is -NHC(O)-. In an embodiment, L 103 -NR 103 C(O)O-. In an embodiment, L 103 is -NHC(O)O-. In an embodiment, L 103 -OC(O)NR 103 -. In an embodiment, L 103 is -OC(O)NH-. In an embodiment, L 103 -NR 103 C(O)NR103 -. In an embodiment, L 103 is -NHC(O)NH-. In an embodiment, L 103 -NR 103 C(NH)NR 103 -. In an embodiment, L 103 is -NHC(NH)NH-. In an embodiment, L 103 is -S(O)2-. In the embodiment, L 103 -NR 103 S(O)2-. In an embodiment, L 103 is -NHS(O)2-. In an embodiment, L 103 -S(O)2NR 103 -. In an embodiment, L 103 is -S(O)2NH-. In the embodiment, L 103 is a substituted or unsubstituted C1-C6 alkylene group. 103 is a substituted or unsubstituted methylene group. 103 is substituted or unsubstituted ethylene. In the embodiment, L 103 is a substituted or unsubstituted propylene group. In the embodiment, L 103 is a substituted or unsubstituted n-propylene group. In the embodiment, L 103 is a substituted or unsubstituted isopropylidene group. 103 is a substituted or unsubstituted butylene group. In the embodiment, L 103 is substituted or unsubstituted n-butylene. In the embodiment, L 103 is a substituted or unsubstituted isobutylene group. 103 is a substituted or unsubstituted tert-butylene group. 103 is a substituted or unsubstituted pentylene. In the embodiment, L 103 is a substituted or unsubstituted hexamethylene group. 103 is a substituted or unsubstituted 2 to 6 membered heteroalkylene group. 103 is a substituted or unsubstituted phenylene group.

[0296] In an embodiment, substituted R 103 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 103is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 103 When substituted, it is substituted with at least one substituent group. 103 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 103 When substituted, it is substituted with at least one lower substituent group.

[0297] In an embodiment, R 103 are independently hydrogen. In an embodiment, R 103 are independently unsubstituted C1-C4 alkyl. 103 is independently unsubstituted methyl. In an embodiment, R 103 is independently unsubstituted ethyl. In an embodiment, R 103 is independently unsubstituted propyl. In an embodiment, R 103 is independently unsubstituted n-propyl. In an embodiment, R 103 is independently unsubstituted isopropyl. In an embodiment, R 103 is independently unsubstituted butyl. In an embodiment, R 103 is independently unsubstituted n-butyl. In an embodiment, R 103 is independently unsubstituted isobutyl. In an embodiment, R 103 is independently unsubstituted tert-butyl.

[0298] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 104 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 104 When L is substituted, it is substituted with at least one substituent group. 104 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 104 When substituted, it is substituted with at least one lower substituent group.

[0299] In an embodiment, L 104In an embodiment, L 104 is -C(O)-. In an embodiment, L 104 is -C(O)O-. In an embodiment, L 104 is -OC(O)-. In an embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 -NR 104 -. In an embodiment, L 104 In the embodiment, L 104 -C(O)NR 104 -. In an embodiment, L 104 is -C(O)NH-. In an embodiment, L 104 -NR 104 C(O)-. In an embodiment, L 104 is -NHC(O)-. In an embodiment, L 104 -NR 104 C(O)O-. In an embodiment, L 104 is -NHC(O)O-. In an embodiment, L 104 -OC(O)NR 104 -. In an embodiment, L 104 is -OC(O)NH-. In an embodiment, L 104 -NR 104 C(O)NR 104 -. In an embodiment, L 104 is -NHC(O)NH-. In an embodiment, L 104 -NR 104 C(NH)NR 104 -. In an embodiment, L 104 is -NHC(NH)NH-. In an embodiment, L 104 is -S(O)2-. In the embodiment, L 104 -NR 104 S(O)2-. In an embodiment, L 104 is -NHS(O)2-. In an embodiment, L 104 -S(O)2NR 104 -. In an embodiment, L 104 is -S(O)2NH-. In the embodiment, L 104 is a substituted or unsubstituted C1-C6 alkylene group. 104 is a substituted or unsubstituted methylene group. 104 is substituted or unsubstituted ethylene. In the embodiment, L104 is a substituted or unsubstituted propylene group. In the embodiment, L 104 is a substituted or unsubstituted n-propylene group. In the embodiment, L 104 is a substituted or unsubstituted isopropylidene group. 104 is a substituted or unsubstituted butylene group. In the embodiment, L 104 is substituted or unsubstituted n-butylene. In the embodiment, L 104 is a substituted or unsubstituted isobutylene group. 104 is a substituted or unsubstituted tert-butylene group. 104 is a substituted or unsubstituted pentylene. In the embodiment, L 104 is a substituted or unsubstituted hexamethylene group. 104 is a substituted or unsubstituted 2 to 6 membered heteroalkylene group. 104 is a substituted or unsubstituted phenylene group.

[0300] In an embodiment, substituted R 104 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 104 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 104 When substituted, it is substituted with at least one substituent group. 104 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 104 When substituted, it is substituted with at least one lower substituent group.

[0301] In an embodiment, R 104 are independently hydrogen. In an embodiment, R 104 are independently unsubstituted C1-C4 alkyl. 104 is independently unsubstituted methyl. In an embodiment, R 104 is independently unsubstituted ethyl. In an embodiment, R 104 is independently unsubstituted propyl. In an embodiment, R 104 is independently unsubstituted n-propyl. In an embodiment, R 104 is independently unsubstituted isopropyl. In an embodiment, R 104is independently unsubstituted butyl. In an embodiment, R 104 is independently unsubstituted n-butyl. In an embodiment, R 104 is independently unsubstituted isobutyl. In an embodiment, R 104 is independently unsubstituted tert-butyl.

[0302] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 105 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 105 When L is substituted, it is substituted with at least one substituent group. 105 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 105 When substituted, it is substituted with at least one lower substituent group.

[0303] In an embodiment, L 105 In an embodiment, L 105 is -C(O)-. In an embodiment, L 105 is -C(O)O-. In an embodiment, L 105 is -OC(O)-. In an embodiment, L 105 In the embodiment, L 105 In the embodiment, L 105 -NR 105 -. In an embodiment, L 105 In the embodiment, L 105 -C(O)NR 105 -. In an embodiment, L 105 is -C(O)NH-. In an embodiment, L 105 -NR 105 C(O)-. In an embodiment, L 105 is -NHC(O)-. In an embodiment, L 105 -NR 105 C(O)O-. In an embodiment, L 105 is -NHC(O)O-. In an embodiment, L 105 -OC(O)NR 105-. In an embodiment, L 105 is -OC(O)NH-. In an embodiment, L 105 -NR 105 C(O)NR 105 -. In an embodiment, L 105 is -NHC(O)NH-. In an embodiment, L 105 -NR 105 C(NH)NR 105 -. In an embodiment, L 105 is -NHC(NH)NH-. In an embodiment, L 105 is -S(O)2-. In the embodiment, L 105 -NR 105 S(O)2-. In an embodiment, L 105 is -NHS(O)2-. In an embodiment, L 105 -S(O)2NR 105 -. In an embodiment, L 105 is -S(O)2NH-. In the embodiment, L 105 is a substituted or unsubstituted C1-C6 alkylene group. 105 is a substituted or unsubstituted methylene group. 105 is substituted or unsubstituted ethylene. In the embodiment, L 105 is a substituted or unsubstituted propylene group. In the embodiment, L 105 is a substituted or unsubstituted n-propylene group. In the embodiment, L 105 is a substituted or unsubstituted isopropylidene group. 105 is a substituted or unsubstituted butylene group. In the embodiment, L 105 is substituted or unsubstituted n-butylene. In the embodiment, L 105 is a substituted or unsubstituted isobutylene group. 105 is a substituted or unsubstituted tert-butylene group. 105 is a substituted or unsubstituted pentylene. In the embodiment, L 105 is a substituted or unsubstituted hexamethylene group. 105 is a substituted or unsubstituted 2 to 6 membered heteroalkylene group. 105 is a substituted or unsubstituted phenylene group.

[0304] In an embodiment, substituted R 105(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 105 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 105 When substituted, it is substituted with at least one substituent group. 105 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 105 When substituted, it is substituted with at least one lower substituent group.

[0305] In an embodiment, R 105 are independently hydrogen. In an embodiment, R 105 are independently unsubstituted C1-C4 alkyl. 105 is independently unsubstituted methyl. In an embodiment, R 105 is independently unsubstituted ethyl. In an embodiment, R 105 is independently unsubstituted propyl. In an embodiment, R 105 is independently unsubstituted n-propyl. In an embodiment, R 105 is independently unsubstituted isopropyl. In an embodiment, R 105 is independently unsubstituted butyl. In an embodiment, R 105 is independently unsubstituted n-butyl. In an embodiment, R 105 is independently unsubstituted isobutyl. In an embodiment, R 105 is independently unsubstituted tert-butyl.

[0306] In an embodiment, L 1 is 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 group. 1 is substituted or unsubstituted piperazinylene. In an embodiment, L 1 for In an embodiment, L 1 for In an embodiment, L 1 for In an embodiment, L 1 for In an embodiment, L 1 for In an embodiment, L 1 for In an embodiment, L 1 for In an embodiment, L 1 for

[0307] In an embodiment, R 1 -L 10 -R 10 .

[0308] L 10 For bonds, -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-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (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 cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (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 arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0309] 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, -OCHI2, -OCHCl2, -OCHBr, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0310] R 10 For 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)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 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-C8, C1-C6, C1-C4 or C1-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-C8, C3-C6, C4-C6 or C5-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-C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0311] R 10A 、R 10B 、R 10C and R 10D 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, -OCH2 I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 10A and R 10BThe substituents may be optionally joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 membered), or a substituted or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0312] Each X 10 are independently -F, -Cl, -Br or -I.

[0313] The symbol n10 is an integer from 0 to 4.

[0314] The symbols m10 and v10 are independently 1 or 2.

[0315] In an embodiment, substituted 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 group, size-restricted substituent group, or lower substituent group; wherein if the substituted L 10 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when L 10 When L is substituted, it is substituted with at least one substituent group. 10 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when L 10 When substituted, it is substituted with at least one lower substituent group.

[0316] 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), substituted or unsubstituted heteroalkylene (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0317] In an embodiment, L 10 In an embodiment, L 10 is -C(O)-. In an embodiment, L 10 is -C(O)O-. In an embodiment, L 10 is -OC(O)-. In an embodiment, L 10 In the embodiment, L 10 In the embodiment, L 10 -NR 100 -. In an embodiment, L 10 In the embodiment, L 10 -C(O)NR 100 -. In an embodiment, L 10 is -C(O)NH-. In an embodiment, L 10 -NR 100 C(O)-. In an embodiment, L 10 is -NHC(O)-. In an embodiment, L 10 -NR 100 C(O)O-. In an embodiment, L 10 is -NHC(O)O-. In an embodiment, L 10 -OC(O)NR 100 -. In an embodiment, L 10 is -OC(O)NH-. In an embodiment, L 10 -NR 100 C(O)NR 100 -. In an embodiment, L 10 is -NHC(O)NH-. In an embodiment, L 10 -NR 100 C(NH)NR 100 -. In an embodiment, L 10 is -NHC(NH)NH-. In an embodiment, L 10 is -S(O)2-. In the embodiment, L 10 -NR 100 S(O)2-. In an embodiment, L 10 is -NHS(O)2-. In an embodiment, L 10 -S(O)2NR 100 -. In an embodiment, L 10 is -S(O)2NH-. In the embodiment, L 10 is a substituted or unsubstituted C1-C6 alkylene group. 10is a substituted or unsubstituted methylene group. 10 is substituted or unsubstituted ethylene. In the embodiment, L 10 is a substituted or unsubstituted propylene group. In the embodiment, L 10 is a substituted or unsubstituted n-propylene group. In the embodiment, L 10 is a substituted or unsubstituted isopropylidene group. 10 is a substituted or unsubstituted butylene group. In the embodiment, L 10 is substituted or unsubstituted n-butylene. In the embodiment, L 10 is a substituted or unsubstituted isobutylene group. 10 is a substituted or unsubstituted tert-butylene group. 10 is a substituted or unsubstituted pentylene. In the embodiment, L 10 is a substituted or unsubstituted hexamethylene group. 10 is a substituted or unsubstituted 2- to 6-membered heteroalkylene group.

[0318] In an embodiment, substituted R 100 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 100 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 100 When substituted, it is substituted with at least one substituent group. 100 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 100 When substituted, it is substituted with at least one lower substituent group.

[0319] In an embodiment, R 100 are independently hydrogen. In an embodiment, R 100 are independently unsubstituted C1-C4 alkyl. 100 is independently unsubstituted methyl. In an embodiment, R 100 is independently unsubstituted ethyl. In an embodiment, R 100 is independently unsubstituted propyl. In an embodiment, R 100 is independently unsubstituted n-propyl. In an embodiment, R 100is independently unsubstituted isopropyl. In an embodiment, R 100 is independently unsubstituted butyl. In an embodiment, R 100 is independently unsubstituted n-butyl. In an embodiment, R 100 is independently unsubstituted isobutyl. In an embodiment, R 100 is independently unsubstituted tert-butyl.

[0320] In an embodiment, substituted R 10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 10 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 10 When substituted, it is substituted with at least one substituent group. 10 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 10 When substituted, it is substituted with at least one lower substituent group.

[0321] In an embodiment, substituted R 10A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 10A is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 10A When substituted, it is substituted with at least one substituent group. 10A When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 10A When substituted, it is substituted with at least one lower substituent group.

[0322] In an embodiment, substituted R 10B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R10B is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 10B When substituted, it is substituted with at least one substituent group. 10B When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 10B When substituted, it is substituted with at least one lower substituent group.

[0323] In an embodiment, when R bonded to the same nitrogen atom 10A and R 10B The substituted ring formed when the substituents are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, a substituent group of limited size, or a lower substituent group; wherein if R 10A and R 10B The substituted ring formed when the substituents are joined is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, a substituent group of limited size, and / or a lower substituent group may optionally be different. In an embodiment, when R 10A and R 10B When the substituted ring formed when the substituents are joined is substituted, it is substituted with at least one substituent group. In an embodiment, when R 10A and R 10B When the substituted ring formed when the substituents are joined is substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 10A and R 10B When the substituted ring formed when the substituents are attached is substituted, it is substituted with at least one lower substituent group.

[0324] In an embodiment, substituted R 10C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 10C is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, or a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 10CWhen substituted, it is substituted with at least one substituent group. 10C When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 10C When substituted, it is substituted with at least one lower substituent group.

[0325] In an embodiment, substituted R 10D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 10D is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, or a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 10D When substituted, it is substituted with at least one substituent group. 10D When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 10D When substituted, it is substituted with at least one lower substituent group.

[0326] In an embodiment, R 10 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 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- to 10-membered heteroaryl. In an embodiment, R 10 is a substituted C3-C8 cycloalkyl. 10 is a substituted 3 to 8 membered heterocycloalkyl. 10 For the replacement of C6-C 10 In an embodiment, R 10 is substituted phenyl. In an embodiment, R 10 is a substituted 5- to 10-membered heteroaryl. In one embodiment, R 10 is a substituted pyrimidinyl. In an embodiment, R 10 is a substituted tetrahydropyridopyrimidine. In an embodiment, R 10 is a substituted pyridopyrimidine. In an embodiment, R 10 is a substituted quinazolinyl. In an embodiment, R 10 is substituted pyrazolyl. In an embodiment, R10 is a substituted piperazinyl.

[0327] In an embodiment, R 10A is hydrogen. In an embodiment, R 10A is an unsubstituted C1-C4 alkyl. 10A is an unsubstituted methyl group. In an embodiment, R 10A is an unsubstituted ethyl group. In an embodiment, R 10A is unsubstituted propyl. In the embodiment, R 10A is unsubstituted n-propyl. In an embodiment, R 10A is unsubstituted isopropyl. In the embodiment, R 10A is an unsubstituted butyl group. In an embodiment, R 10A is unsubstituted n-butyl. In an embodiment, R 10A is an unsubstituted isobutyl group. In an embodiment, R 10A is an unsubstituted tert-butyl group.

[0328] In an embodiment, R 10B is hydrogen. In an embodiment, R 10B is an unsubstituted C1-C4 alkyl. 10B is an unsubstituted methyl group. In an embodiment, R 10B is an unsubstituted ethyl group. In an embodiment, R 10B is unsubstituted propyl. In the embodiment, R 10B is unsubstituted n-propyl. In an embodiment, R 10B is unsubstituted isopropyl. In the embodiment, R 10B is an unsubstituted butyl group. In an embodiment, R 10B is unsubstituted n-butyl. In an embodiment, R 10B is an unsubstituted isobutyl group. In an embodiment, R 10B is an unsubstituted tert-butyl group.

[0329] In an embodiment, R 10C is hydrogen. In an embodiment, R 10C is an unsubstituted C1-C4 alkyl. 10C is an unsubstituted methyl group. In an embodiment, R 10C is an unsubstituted ethyl group. In an embodiment, R 10C is unsubstituted propyl. In the embodiment, R 10C is unsubstituted n-propyl. In an embodiment, R 10C is unsubstituted isopropyl. In the embodiment, R 10C is an unsubstituted butyl group. In an embodiment, R 10Cis unsubstituted n-butyl. In an embodiment, R 10C is an unsubstituted isobutyl group. In an embodiment, R 10C is an unsubstituted tert-butyl group.

[0330] In an embodiment, R 10D is hydrogen. In an embodiment, R 10D is an unsubstituted C1-C4 alkyl. 10D is an unsubstituted methyl group. In an embodiment, R 10D is an unsubstituted ethyl group. In an embodiment, R 10D is unsubstituted propyl. In the embodiment, R 10D is unsubstituted n-propyl. In an embodiment, R 10D is unsubstituted isopropyl. In the embodiment, R 10D is an unsubstituted butyl group. In an embodiment, R 10D is unsubstituted n-butyl. In an embodiment, R 10D is an unsubstituted isobutyl group. In an embodiment, R 10D is an unsubstituted tert-butyl group.

[0331] In an embodiment, R 1 for

[0332]

[0333]

[0334] In an embodiment, R 1 for

[0335] In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for

[0336] 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, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0337] R 7are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3 , -OCH2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0338] R 8are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, - OCH2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0339] Symbol z6 is an integer from 0 to 7.

[0340] Symbol z7 is an integer from 0 to 7.

[0341] Symbol z8 is an integer from 0 to 5.

[0342] In an embodiment, substituted R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 6 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 6 When substituted, it is substituted with at least one substituent group. 6 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 6 When substituted, it is substituted with at least one lower substituent group.

[0343] In an embodiment, R 6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, - OCH2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0344] In an embodiment, R 6 is independently oxo. In an embodiment, R 6 are 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 -CCl3. In an embodiment, R 6 is independently -CBr3. In an embodiment, R 6 is independently -CF3. In an embodiment, R 6 is independently -CI3. In an embodiment, R 6 is independently -CH2Cl. In an embodiment, R 6 is independently -CH2Br. In an embodiment, R 6 is independently -CH2F. In an embodiment, R 6is independently -CH2I. In an embodiment, R 6 is independently -CHCl2. In an embodiment, R 6 is independently -CHBr2. In an embodiment, R 6 is independently -CHF2. In an embodiment, R 6 is independently -CHI2. In an embodiment, R 6 is independently -CN. In an embodiment, R 6 is independently -OH. In an embodiment, R 6 is independently -NH2. In an embodiment, R 6 is independently -COOH. In an embodiment, R 6 is independently -CONH2. In an embodiment, R 6 is independently -NO2. In an embodiment, R 6 are independently -SH. In an embodiment, R 6 is independently -SO3H. In an embodiment, R 6 is independently -OSO3H. In an embodiment, R 6 is independently -SO2NH2. In an embodiment, R 6 is independently -NHNH2. In an embodiment, R 6 is independently -ONH2. In an embodiment, R 6 is independently -NHC(O)NHNH2. In an embodiment, R 6 is independently -NHC(O)NH2. In an embodiment, 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 an embodiment, R 6 is independently -NHOH. In an embodiment, R 6 is independently -OCCl3. In an embodiment, R 6 is independently -OCBr3. In an embodiment, R 6 is independently -OCF3. In an embodiment, R 6 is independently -OCI3. In an embodiment, R 6 is independently -OCH2Cl. In an embodiment, R 6 is independently -OCH2Br. In an embodiment, R 6 is independently -OCH2F. In an embodiment, R 6 is independently -OCH2I. In an embodiment, R 6is independently -OCHCl2. In an embodiment, R 6 is independently -OCHBr2. In an embodiment, R 6 is independently -OCHF2. In an embodiment, R 6 is independently -OCHI2. In an embodiment, R 6 are independently unsubstituted C1-C4 alkyl. 6 is independently unsubstituted methyl. In an embodiment, R 6 is independently unsubstituted ethyl. In an embodiment, R 6 is independently unsubstituted propyl. In an embodiment, R 6 is independently unsubstituted n-propyl. In an embodiment, R 6 is independently unsubstituted isopropyl. In an embodiment, R 6 is independently unsubstituted butyl. In an embodiment, R 6 is independently unsubstituted n-butyl. In an embodiment, R 6 is independently unsubstituted isobutyl. In an embodiment, R 6 is independently unsubstituted tert-butyl. 6 is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. 6 is independently substituted 2 to 6 membered heteroalkyl. 6 is independently unsubstituted methoxy. In an embodiment, R 6 is independently unsubstituted ethoxy. In an embodiment, R 6 is independently unsubstituted propoxy. In an embodiment, R 6 is independently unsubstituted n-propoxy. In an embodiment, R 6 is independently unsubstituted isopropoxy. 6 is independently unsubstituted butoxy. 6 is independently unsubstituted n-butoxy. In an embodiment, R 6 is independently unsubstituted isobutyloxy. 6 is independently unsubstituted tert-butoxy. 6 and independently substituted or unsubstituted 5- to 6-membered heteroaryl.

[0345] In an embodiment, R 6 is independently halogen, -OH, unsubstituted C1-C4 alkyl, substituted 2- to 6-membered heteroalkyl, or substituted 5- to 6-membered heteroaryl. 6 is independently -F, -Cl, -OH or unsubstituted methyl. In an embodiment, R6 is independently a 2 to 6 membered heteroalkyl substituted with a substituted heterocycloalkyl or an unsubstituted fused heterocycloalkyl. 6 is independently substituted pyridinyl.

[0346] 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.

[0347] In an embodiment, substituted R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 7 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 7 When substituted, it is substituted with at least one substituent group. 7 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 7 When substituted, it is substituted with at least one lower substituent group.

[0348] In an embodiment, R 7are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, - OCH2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 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-C8, C3-C6, C4-C6, or C5-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-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0349] In an embodiment, R 7 is independently oxo. In an embodiment, R 7 are 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 -CCl3. In an embodiment, R 7 is independently -CBr3. In an embodiment, R 7 is independently -CF3. In an embodiment, R 7 is independently -CI3. In an embodiment, R 7 is independently -CH2Cl. In an embodiment, R 7 is independently -CH2Br. In an embodiment, R 7 is independently -CH2F. In an embodiment, R 7 is independently -CH2I. In an embodiment, R 7is independently -CHCl2. In an embodiment, R 7 is independently -CHBr2. In an embodiment, R 7 is independently -CHF2. In an embodiment, R 7 is independently -CHI2. In an embodiment, R 7 is independently -CN. In an embodiment, R 7 is independently -OH. In an embodiment, R 7 is independently -NH2. In an embodiment, R 7 is independently -COOH. In an embodiment, R 7 is independently -CONH2. In an embodiment, R 7 is independently -NO2. In an embodiment, R 7 are independently -SH. In an embodiment, R 7 is independently -SO3H. In an embodiment, R 7 is independently -OSO3H. In an embodiment, R 7 is independently -SO2NH2. In an embodiment, R 7 is independently -NHNH2. In an embodiment, R 7 is independently -ONH2. In an embodiment, R 7 is independently -NHC(O)NHNH2. In an embodiment, R 7 is independently -NHC(O)NH2. In an embodiment, 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 an embodiment, R 7 is independently -NHOH. In an embodiment, R 7 is independently -OCCl3. In an embodiment, R 7 is independently -OCBr3. In an embodiment, R 7 is independently -OCF3. In an embodiment, R 7 is independently -OCI3. In an embodiment, R 7 is independently -OCH2Cl. In an embodiment, R 7 is independently -OCH2Br. In an embodiment, R 7 is independently -OCH2F. In an embodiment, R 7 is independently -OCH2I. In an embodiment, R 7 is independently -OCHCl2. In an embodiment, R 7is independently -OCHBr2. In an embodiment, R 7 is independently -OCHF2. In an embodiment, R 7 is independently -OCHI2. In an embodiment, R 7 are independently unsubstituted C1-C4 alkyl. 7 is independently unsubstituted methyl. In an embodiment, R 7 is independently unsubstituted ethyl. In an embodiment, R 7 is independently unsubstituted propyl. In an embodiment, R 7 is independently unsubstituted n-propyl. In an embodiment, R 7 is independently unsubstituted isopropyl. In an embodiment, R 7 is independently unsubstituted butyl. In an embodiment, R 7 is independently unsubstituted n-butyl. In an embodiment, R 7 is independently unsubstituted isobutyl. In an embodiment, R 7 is independently unsubstituted tert-butyl. 7 is independently unsubstituted C2-C4 alkynyl. 7 is independently unsubstituted ethynyl. 7 is independently unsubstituted propynyl. In an embodiment, R 7 is independently unsubstituted butynyl. In an embodiment, R 7 and independently substituted or unsubstituted 2- to 6-membered heteroalkyl.

[0350] In an embodiment, R 7 is independently unsubstituted methoxy. In an embodiment, R 7 is independently unsubstituted ethoxy. In an embodiment, R 7 is independently unsubstituted propoxy. In an embodiment, R 7 is independently unsubstituted n-propoxy. In an embodiment, R 7 is independently unsubstituted isopropoxy. 7 is independently unsubstituted butoxy. 7 is independently unsubstituted n-butoxy. In an embodiment, R 7 is independently unsubstituted isobutyloxy. 7 and independently unsubstituted tert-butoxy.

[0351] In an embodiment, R 7is independently halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkynyl, unsubstituted 2 to 6 membered heteroalkyl, or unsubstituted C3-C8 cycloalkyl. 7 independently -F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, unsubstituted ethynyl, unsubstituted methoxy or unsubstituted cyclopropyl.

[0352] In an embodiment, R 7 is independently halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkynyl, or unsubstituted C3-C8 cycloalkyl. 7 is independently -F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, unsubstituted ethynyl, or unsubstituted cyclopropyl.

[0353] 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.

[0354] In an embodiment, substituted R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-restricted substituent group, or lower substituent group; wherein if the substituted R 8 is substituted with a plurality of groups selected from a substituent group, a substituent group of limited size, and a lower substituent group; each substituent group, substituent group of limited size, and / or lower substituent group may optionally be different. In an embodiment, when R 8 When substituted, it is substituted with at least one substituent group. 8 When substituted, it is substituted with at least one substituent group of limited size. In an embodiment, when R 8 When substituted, it is substituted with at least one lower substituent group.

[0355] In an embodiment, R 8 are 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, R8 is independently -CCl3. In an embodiment, R 8 is independently -CBr3. In an embodiment, R 8 is independently -CF3. In an embodiment, R 8 is independently -CI3. In an embodiment, R 8 is independently -CH2Cl. In an embodiment, R 8 is independently -CH2Br. In an embodiment, R 8 is independently -CH2F. In an embodiment, R 8 is independently -CH2I. In an embodiment, R 8 is independently -CHCl2. In an embodiment, R 8 is independently -CHBr2. In an embodiment, R 8 is independently -CHF2. In an embodiment, R 8 is independently -CHI2. In an embodiment, R 8 is independently -CN. In an embodiment, R 8 is independently -OH. In an embodiment, R 8 is independently -NH2. In an embodiment, R 8 is independently -COOH. In an embodiment, R 8 is independently -CONH2. In an embodiment, R 8 is independently -NO2. In an embodiment, R 8 are independently -SH. In an embodiment, R 8 is independently -SO3H. In an embodiment, R 8 is independently -OSO3H. In an embodiment, R 8 is independently -SO2NH2. In an embodiment, R 8 is independently -NHNH2. In an embodiment, R 8 is independently -ONH2. In an embodiment, R 8 is independently -NHC(O)NHNH2. In an embodiment, R 8 is independently -NHC(O)NH2. In an embodiment, 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 an embodiment, R 8 is independently -NHOH. In an embodiment, R 8 is independently -OCCl3. In an embodiment, R 8is independently -OCBr3. In an embodiment, R 8 is independently -OCF3. In an embodiment, R 8 is independently -OCI3. In an embodiment, R 8 is independently -OCH2Cl. In an embodiment, R 8 is independently -OCH2Br. In an embodiment, R 8 is independently -OCH2F. In an embodiment, R 8 is independently -OCH2I. In an embodiment, R 8 is independently -OCHCl2. In an embodiment, R 8 is independently -OCHBr2. In an embodiment, R 8 is independently -OCHF2. In an embodiment, R 8 is independently -OCHI2. In an embodiment, R 8 are independently unsubstituted C1-C4 alkyl. 8 is independently unsubstituted methyl. In an embodiment, R 8 is independently unsubstituted ethyl. In an embodiment, R 8 is independently unsubstituted propyl. In an embodiment, R 8 is independently unsubstituted n-propyl. In an embodiment, R 8 is independently unsubstituted isopropyl. In an embodiment, R 8 is independently unsubstituted butyl. In an embodiment, R 8 is independently unsubstituted n-butyl. In an embodiment, R 8 is independently unsubstituted isobutyl. In an embodiment, R 8 is independently unsubstituted tert-butyl. 8 is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. 8 is independently unsubstituted methoxy. In an embodiment, R 8 is independently unsubstituted ethoxy. In an embodiment, R 8 is independently unsubstituted propoxy. In an embodiment, R 8 is independently unsubstituted n-propoxy. In an embodiment, R 8 is independently unsubstituted isopropoxy. 8 is independently unsubstituted butoxy. 8 and independently unsubstituted n-butoxy.

[0356] In an embodiment, R 8is independently unsubstituted isobutyloxy. 8 and independently unsubstituted tert-butoxy.

[0357] In an embodiment, R 8 are independently halogen or unsubstituted C1-C4 alkyl. 8 is independently -Cl or unsubstituted methyl.

[0358] 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.

[0359] In an embodiment, R 1 for

[0360]

[0361] In an embodiment, R 1 for

[0362] In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for

[0363] In an embodiment, R 1 is a monovalent form of ARS-1620. In an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 A monovalent form of a portion of ARS-1620, wherein R 1 Substituted piperazinyl moieties are not included.

[0364] In an embodiment, R 1 is a monovalent form of AMG-510. In an embodiment, R 1 is a monovalent form of the 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. 1 for In the embodiment, R 1 for In an embodiment, R 1 AMG-510 is a unit price form of part of which R 1 Substituted piperazinyl moieties of the compounds described by Canon et al. or equivalents are not included.

[0365] In an embodiment, R 1 is a monovalent form of MRTX-849. In an embodiment, R 1is a monovalent form of the 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 an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 It is a monovalent form of a portion of MRTX-849, where R 1 Substituted piperazinyl moieties of the compounds described by Fell et al. or equivalents are not included.

[0366] In an embodiment, R 1 is a monovalent form of GDC-6036. In an embodiment, 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 an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 It is a monovalent form of a portion of GDC-6036, where R 1 Substituted piperazinyl moieties or equivalents of the compounds described in WO2020097537 are not included.

[0367] In an embodiment, R 1 is a monovalent form of MRTX1133. In an embodiment, R 1 is a monovalent form of the 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 an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 It is a monovalent form of a part of MRTX1133, where R 1The diazabicyclooctanyl moiety of the compounds described by Wang et al. or equivalents are not included.

[0368] In an embodiment, R 1 is a monovalent form of BBO-8520. In an embodiment, R 1 is the putative monovalent form of BBO-8520. In an embodiment, R 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 an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 The unit price form of a part of BBO-8520, where R 1 Excluding compounds described in WO2023004102 or equivalent.

[0369] In an embodiment, R 1 is a monovalent form of JDQ-443. In an embodiment, 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 an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 It is a unit price form of a part of JDQ-443, where R 1 The azaspiroheptyl moiety or equivalents of the compounds described in WO2021120890 are not included.

[0370] In an embodiment, R 1 is a monovalent form of BI-0474. In an embodiment, R 1 is the monovalent form of the compound, such as J. et al., J. Med. Chem. 65, 14614–14629 (2022), which is incorporated herein by reference in its entirety for all purposes. In an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 It is a monovalent form of a portion of BI-0474, where R 1 Not included et al. or an equivalent of the piperazinyl moiety of the compounds described in .

[0371] In an embodiment, 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 an embodiment, R 1 for In an embodiment, R 1 is a monovalent form of a portion of the compound described in WO2021118877, wherein R 1 The acryloyl moiety of the compounds described in WO2021118877 or equivalents are not included.

[0372] In an embodiment, 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 an embodiment, R 1 for In an embodiment, R 1 is a monovalent form of a portion of the compound described in WO2021120045, wherein R 1 Substituted piperazinyl moieties or equivalents of the compounds described in WO2021120045 are not included.

[0373] In an embodiment, R 1 is a monovalent form of sotolacib. In an embodiment, R 1 is a monovalent form of a compound as described in US 10,519,146, US 11,236,091 and US 11,426,404, which are incorporated herein by reference in their entirety for all purposes. In an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 is a monovalent form of a portion of Sotolacib, where R 1 Substituted piperazinyl moieties or equivalents of compounds described in US 10,519,146, US 11,236,091 and US 11,426,404 are excluded.

[0374] In an embodiment, R 1is a monovalent form of adagrasib. In an embodiment, 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. In an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 is the monovalent form of a part of Adagrasib, where R 1 Substituted piperazinyl moieties or equivalents of the compounds described in WO 2021 / 037018 are not included.

[0375] In an embodiment, R 1 is a monovalent form of MRTX1257. In an embodiment, R 1 is a monovalent form of a compound as described in US2018 / 0072723, which is incorporated herein by reference in its entirety for all purposes. In an embodiment, R 1 for In the embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 for In an embodiment, R 1 It is a monovalent form of a component of MRTX1257, where R 1 Substituted piperazinyl moieties or equivalents of the compounds described in US2018 / 0072723 are not included.

[0376] In an embodiment, when R 3 When replaced, R 3 By one or more R 3.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3.1 When the substituent group is substituted, R 3.1 The substituent is composed of one or more R 3.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3.2 When the substituent group is substituted, R 3.2 The substituent group is composed of one or more R3.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3 、R 3.1 、R 3.2 and R 3.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 3 、R 3.1 、R 3.2 and R 3.3 .

[0377] In an embodiment, when R 3A When replaced, R 3A By one or more R 3A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3A.1 When the substituent group is substituted, R 3A.1 The substituent group is composed of one or more R 3A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3A.2 When the substituent group is substituted, R 3A.2 The substituent group is composed of one or more R 3A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3A 、R 3A.1 、R 3A.2 and R 3A.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 3A 、R 3A.1 、R 3A.2 and R 3A.3 .

[0378] In an embodiment, when R 3B When replaced, R 3B By one or more R 3B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3B.1 When the substituent group is substituted, R 3B.1 The substituent group is composed of one or more R 3B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3B.2 When the substituent group is substituted, R 3B.2 The substituent group is composed of one or more R 3B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3B 、R 3B.1 、R 3B.2 and R 3B.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 3B 、R 3B.1 、R 3B.2 and R 3B.3 .

[0379] In an embodiment, when R bonded to the same nitrogen atom 3A and R 3B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 3A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3A.1 When the substituent group is substituted, R 3A.1 The substituent group is composed of one or more R 3A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3A.2 When the substituent group is substituted, R 3A.2 The substituent group is composed of one or more R 3A.3The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3A.1 、R 3A.2 and R 3A.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 3A.1 、R 3A.2 and R 3A.3 .

[0380] In an embodiment, when R bonded to the same nitrogen atom 3A and R 3B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 3B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3B.1 When the substituent group is substituted, R 3B.1 The substituent group is composed of one or more R 3B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3B.2 When the substituent group is substituted, R 3B.2 The substituent group is composed of one or more R 3B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3B.1 、R 3B.2 and R 3B.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 3B.1 、R 3B.2 and R 3B.3 .

[0381] In an embodiment, when R 3C When replaced, R 3C By one or more R 3C.1The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3C.1 When the substituent group is substituted, R 3C.1 The substituent group is composed of one or more R 3C.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3C.2 When the substituent group is substituted, R 3C.2 The substituent group is composed of one or more R 3C.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3C 、R 3C.1 、R 3C.2 and R 3C.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 3C 、R 3C.1 、R 3C.2 and R 3C.3 .

[0382] In an embodiment, when R 3D When replaced, R 3D By one or more R 3D.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3D.1 When the substituent group is substituted, R 3D.1 The substituent group is composed of one or more R 3D.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 3D.2 When the substituent group is substituted, R 3D.2 The substituent group is composed of one or more R 3D.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 3D 、R 3D.1 、R 3D.2 and R 3D.3 The values ​​corresponding to R WW 、RWW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 3D 、R 3D.1 、R 3D.2 and R 3D.3 .

[0383] In an embodiment, when R 4 When replaced, R 4 By one or more R 4.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4.1 When the substituent group is substituted, R 4.1 The substituent is composed of one or more R 4.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4.2 When the substituent group is substituted, R 4.2 The substituent group is composed of one or more R 4.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4 、R 4.1 、R 4.2 and R 4.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 4 、R 4.1 、R 4.2 and R 4.3 .

[0384] In an embodiment, when R 4A When replaced, R 4A By one or more R 4A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4A.1 When the substituent group is substituted, R4A.1 The substituent group is composed of one or more R 4A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4A.2 When the substituent group is substituted, R 4A.2 The substituent group is composed of one or more R 4A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4A 、R 4A.1 、R 4A.2 and R 4A.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 4A 、R 4A.1 、R 4A.2 and R 4A.3 .

[0385] In an embodiment, when R 4B When replaced, R 4B By one or more R 4B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4B.1 When the substituent group is substituted, R 4B.1 The substituent group is composed of one or more R 4B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4B.2 When the substituent group is substituted, R 4B.2 The substituent group is composed of one or more R 4B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4B 、R 4B.1 、R 4B.2 and R 4B.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein RWW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 4B 、R 4B.1 、R 4B.2 and R 4B.3 .

[0386] In an embodiment, when R bonded to the same nitrogen atom 4A and R 4B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 4A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4A.1 When the substituent group is substituted, R 4A.1 The substituent group is composed of one or more R 4A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4A.2 When the substituent group is substituted, R 4A.2 The substituent group is composed of one or more R 4A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4A.1 、R 4A.2 and R 4A.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 4A.1 、R 4A.2 and R 4A.3 .

[0387] In an embodiment, when R bonded to the same nitrogen atom 4A and R 4B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 4B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4B.1 When the substituent group is substituted, R 4B.1 The substituent group is composed of one or more R 4B.2The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4B.2 When the substituent group is substituted, R 4B.2 The substituent group is composed of one or more R 4B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4B.1 、R 4B.2 and R 4B.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 4B.1 、R 4B.2 and R 4B.3 .

[0388] In an embodiment, when R 4C When replaced, R 4C By one or more R 4C.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4C.1 When the substituent group is substituted, R 4C.1 The substituent group is composed of one or more R 4C.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4C.2 When the substituent group is substituted, R 4C.2 The substituent group is composed of one or more R 4C.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4C 、R 4C.1 、R 4C.2 and R 4C.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 4C 、R 4C.1 、R4C.2 and R 4C.3 .

[0389] In an embodiment, when R 4D When replaced, R 4D By one or more R 4D.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4D.1 When the substituent group is substituted, R 4D.1 The substituent group is composed of one or more R 4D.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 4D.2 When the substituent group is substituted, R 4D.2 The substituent group is composed of one or more R 4D.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 4D 、R 4D.1 、R 4D.2 and R 4D.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 4D 、R 4D.1 、R 4D.2 and R 4D.3 .

[0390] In an embodiment, when R 6 When replaced, R 6 By one or more R 6.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 6.1 When the substituent group is substituted, R 6.1 The substituent is composed of one or more R 6.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 6.2 When the substituent group is substituted, R 6.2 The substituent group is composed of one or more R 6.3The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 6 、R 6.1 、R 6.2 and R 6.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 6 、R 6.1 、R 6.2 and R 6.3 .

[0391] In an embodiment, when R 7 When replaced, R 7 By one or more R 7.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 7.1 When the substituent group is substituted, R 7.1 The substituent is composed of one or more R 7.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 7.2 When the substituent group is substituted, R 7.2 The substituent group is composed of one or more R 7.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 7 、R 7.1 、R 7.2 and R 7.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 7 、R 7.1 、R 7.2 and R 7.3 .

[0392] In an embodiment, when R 8 When replaced, R 8 By one or more R 8.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 8.1 When the substituent group is substituted, R 8.1 The substituent is composed of one or more R 8.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 8.2 When the substituent group is substituted, R 8.2 The substituent group is composed of one or more R 8.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 8 、R 8.1 、R 8.2 and R 8.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 8 、R 8.1 、R 8.2 and R 8.3 .

[0393] In an embodiment, when R 10 When replaced, R 10 By one or more R 10.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10.1 When the substituent group is substituted, R 10.1 The substituent is composed of one or more R 10.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10.2 When the substituent group is substituted, R 10.2 The substituent group is composed of one or more R 10.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10 、R 10.1、R 10.2 and R 10.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 10 、R 10.1 、R 10.2 and R 10.3 .

[0394] In an embodiment, when R 10A When replaced, R 10A By one or more R 10A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10A.1 When the substituent group is substituted, R 10A.1 The substituent group is composed of one or more R 10A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10A.2 When the substituent group is substituted, R 10A.2 The substituent group is composed of one or more R 10A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10A 、R 10A.1 、R 10A.2 and R 10A.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 10A 、R 10A.1 、R 10A.2 and R 10A.3 .

[0395] In an embodiment, when R 10B When replaced, R 10B By one or more R 10B.1The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10B.1 When the substituent group is substituted, R 10B.1 The substituent group is composed of one or more R 10B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10B.2 When the substituent group is substituted, R 10B.2 The substituent group is composed of one or more R 10B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10B 、R 10B.1 、R 10B.2 and R 10B.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 10B 、R 10B.1 、R 10B.2 and R 10B.3 .

[0396] In an embodiment, when R bonded to the same nitrogen atom 10A and R 10B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 10A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10A.1 When the substituent group is substituted, R 10A.1 The substituent group is composed of one or more R 10A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10A.2 When the substituent group is substituted, R 10A.2 The substituent group is composed of one or more R 10A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10A.1 、R 10A.2 and R 10A.3The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 10A.1 、R 10A.2 and R 10A.3 .

[0397] In an embodiment, when R bonded to the same nitrogen atom 10A and R 10B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 10B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10B.1 When the substituent group is substituted, R 10B.1 The substituent group is composed of one or more R 10B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10B.2 When the substituent group is substituted, R 10B.2 The substituent group is composed of one or more R 10B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10B.1 、R 10B.2 and R 10B.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 10B.1 、R 10B.2 and R 10B.3 .

[0398] In an embodiment, when R 10C When replaced, R 10C By one or more R 10C.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10C.1 When the substituent group is substituted, R 10C.1 The substituent group is composed of one or more R10C.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10C.2 When the substituent group is substituted, R 10C.2 The substituent group is composed of one or more R 10C.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10C 、R 10C.1 、R 10C.2 and R 10C.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 10C 、R 10C.1 、R 10C.2 and R 10C.3 .

[0399] In an embodiment, when R 10D When replaced, R 10D By one or more R 10D.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10D.1 When the substituent group is substituted, R 10D.1 The substituent group is composed of one or more R 10D.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 10D.2 When the substituent group is substituted, R 10D.2 The substituent group is composed of one or more R 10D.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 10D 、R 10D.1 、R 10D.2 and R 10D.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1、R WW.2 and R WW.3 Corresponding to R 10D 、R 10D.1 、R 10D.2 and R 10D.3 .

[0400] In an embodiment, when R 20 When replaced, R 20 By one or more R 20.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20.1 When the substituent group is substituted, R 20.1 The substituent is composed of one or more R 20.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20.2 When the substituent group is substituted, R 20.2 The substituent group is composed of one or more R 20.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20 、R 20.1 、R 20.2 and R 20.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 20 、R 20.1 、R 20.2 and R 20.3 .

[0401] In an embodiment, when R 20A When replaced, R 20A By one or more R 20A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20A.1 When the substituent group is substituted, R 20A.1 The substituent group is composed of one or more R 20A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20A.2When the substituent group is substituted, R 20A.2 The substituent group is composed of one or more R 20A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20A 、R 20A.1 、R 20A.2 and R 20A.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 20A 、R 20A.1 、R 20A.2 and R 20A.3 .

[0402] In an embodiment, when R 20B When replaced, R 20B By one or more R 20B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20B.1 When the substituent group is substituted, R 20B.1 The substituent group is composed of one or more R 20B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20B.2 When the substituent group is substituted, R 20B.2 The substituent group is composed of one or more R 20B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20B 、R 20B.1 、R 20B.2 and R 20B.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 20B 、R 20B.1 、R20B.2 and R 20B.3 .

[0403] In an embodiment, when R bonded to the same nitrogen atom 20A and R 20B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 20A.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20A.1 When the substituent group is substituted, R 20A.1 The substituent group is composed of one or more R 20A.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20A.2 When the substituent group is substituted, R 20A.2 The substituent group is composed of one or more R 20A.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20A.1 、R 20A.2 and R 20A.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 20A.1 、R 20A.2 and R 20A.3 .

[0404] In an embodiment, when R bonded to the same nitrogen atom 20A and R 20B When substituents are optionally joined to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety is replaced by one or more R 20B.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20B.1 When the substituent group is substituted, R 20B.1 The substituent group is composed of one or more R 20B.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20B.2 When the substituent group is substituted, R 20B.2 The substituent group is composed of one or more R20B.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20B.1 、R 20B.2 and R 20B.3 The values ​​corresponding to R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW.1 、R WW.2 and R WW.3 Corresponding to R 20B.1 、R 20B.2 and R 20B.3 .

[0405] In an embodiment, when R 20C When replaced, R 20C By one or more R 20C.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20C.1 When the substituent group is substituted, R 20C.1 The substituent group is composed of one or more R 20C.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20C.2 When the substituent group is substituted, R 20C.2 The substituent group is composed of one or more R 20C.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20C 、R 20C.1 、R 20C.2 and R 20C.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 20C 、R 20C.1 、R 20C.2 and R 20C.3 .

[0406] In an embodiment, when R 20D When replaced, R 20D By one or more R20D.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20D.1 When the substituent group is substituted, R 20D.1 The substituent group is composed of one or more R 20D.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 20D.2 When the substituent group is substituted, R 20D.2 The substituent group is composed of one or more R 20D.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 20D 、R 20D.1 、R 20D.2 and R 20D.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 20D 、R 20D.1 、R 20D.2 and R 20D.3 .

[0407] In an embodiment, when R 30 When replaced, R 30 By one or more R 30.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 30.1 When the substituent group is substituted, R 30.1 The substituent is composed of one or more R 30.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 30.2 When the substituent group is substituted, R 30.2 The substituent group is composed of one or more R 30.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 30 、R 30.1 、R 30.2 and R 30.3 The values ​​corresponding to RWW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 30 、R 30.1 、R 30.2 and R 30.3 .

[0408] In an embodiment, when R 100 When replaced, R 100 By one or more R 100.1 The first substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 100.1 When the substituent group is substituted, R 100.1 The substituent is composed of one or more R 100.2 The second substituent group represented by is substituted as explained in the definition section above in the description of the "first substituent group". In an embodiment, when R 100.2 When the substituent group is substituted, R 100.2 The substituent group is composed of one or more R 100.3 The third substituent group represented by is substituted as explained in the definition section of the description of the "first substituent group" above. In the above embodiment, R 100 、R 100.1 、R 100.2 and R 100.3 The values ​​corresponding to R WW 、R WW.1 、R WW.2 and R WW.3 The value of is as explained in the definition section in the description of the “first substituent group” above, wherein R WW 、R WW.1 、R WW.2 and R WW.3 Corresponding to R 100 、R 100.1 、R 100.2 and R 100.3 .

[0409] In an embodiment, when R 101 When replaced, R 101 By one or more...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: in R 1 It is the binding part of the switch II binding pocket; L 1 is a bond or a divalent linker; L 2 is a bond or a substituted or unsubstituted alkylene group; 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; R 3 For 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 S02R 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; 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; R 3A , R 3B , R 3C and R 3D R is 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, -OCHI, -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; R bonded to the same nitrogen atom 3A and R 3B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; Each X 3 are independently -Cl, -Br, -I or -F; n3 is an integer from 0 to 4; and m3 and v3 are independently 1 or 2.

2. The compound according to claim 1, wherein L 2 is a bond or an unsubstituted C1-C4 alkylene group.

3. The compound according to claim 1, wherein 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)2NH-, 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. The compound according to claim 1, wherein L 3 is the key.

5. The compound according to claim 1, wherein L 3 It is -C(O)-.

6. The compound according to claim 1, which has the formula:

7. The compound according to claim 1, which has the formula:

8. The compound according to claim 1, which has the formula:

9. The compound according to claim 1, wherein R 3 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, -NHSO2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

10. The compound according to claim 1, wherein R 3 is hydrogen or unsubstituted C1-C4 alkyl.

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

12. The compound according to claim 1, wherein L 1 For -L 101 -L 102 -L 103 -L 104 -L 105 -; 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, 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)2NR 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)2NR 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)2NR 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)2NR 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; and Each R 101 , R 102 , R 103 , R 104 and R 105 are 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, -NHS O2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

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

14. The compound according to claim 1, wherein L 1 for 15. The compound according to claim 1, wherein R 1 For -L 10 -R 10 ; 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, 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, -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, -NHS OH, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl, -OCBr, -OCF, -OCI, -OCHCl, -OCHBr, -OCHF, -OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, 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 For 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)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 S02R 10D 、-NR 10A C(O)R 10C 、-NR 10A C(O)OR 10C 、-NR 10A OR 10C , -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; R 10A , R 10B , R 10C and R 10D R is 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, -OCHI, -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; R bonded to the same nitrogen atom 10A and R 10B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; Each X 10 are independently -F, -Cl, -Br or -I; n10 is an integer from 0 to 4; and m10 and v10 are independently 1 or 2.

16. The compound according to claim 1, wherein R 1 for 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, -NH SO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; 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, -NH SO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; R 8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; z6 is an integer from 0 to 7; z7 is an integer from 0 to 7; and z8 is an integer from 0 to 5.

17. The compound according to claim 16, wherein R 6 and -4-(2- to 6-membered) heteroaryl.

18. The compound according to claim 16, wherein R 6 are independently -F, -Cl, -OH or unsubstituted methyl.

19. The compound according to claim 16, wherein R 6 and independently 2 to 6-membered heteroalkyl substituted with substituted heterocycloalkyl or unsubstituted fused heterocycloalkyl.

20. The compound according to claim 16, wherein R 6 is independently substituted pyridinyl.

21. The compound according to claim 16, wherein z6 is 1, 2 or 3.

22. The compound according to claim 16, wherein R 7 Independently, they are halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4 alkyl or unsubstituted C2-C4 alkynyl.

23. The compound according to claim 16, wherein R 7 Independently, -F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl or unsubstituted ethynyl.

24. The compound according to claim 16, wherein z7 is 1, 2 or 3.

25. The compound according to claim 16, wherein R 8 are independently halogen or unsubstituted C1-C4 alkyl.

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

27. The compound according to claim 16, wherein z8 is 1.

28. The compound according to claim 1, wherein R 1 for 29. The compound of claim 1, which has the formula:

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

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

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

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

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

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

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

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

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

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

40. A switch II GTPase protein covalently bound to a compound according to 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. The covalently modified switch II GTPase protein of claim 40, wherein the compound reversibly covalently binds to an arginine residue of the switch II GTPase protein.

42. The covalently modified switch II GTPase protein of claim 40, wherein the compound is irreversibly covalently bound to an arginine residue of the switch II GTPase protein.

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

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

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

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

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

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

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

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

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

52. A method of attaching a compound to an arginine residue of a protein, the method comprising contacting the compound with the arginine residue, wherein the compound has the formula: or a salt thereof, wherein R 2 is a switch II binding pocket binding portion, a phosphatase PTP domain binding portion, an SH2 domain binding portion, a pseudokinase KSR domain binding portion, or a pseudokinase STRADα domain binding portion; L 1 is a bond or a divalent linker; and L 2 is a bond or a substituted or unsubstituted alkylene group; 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; R 3 For 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 S02R 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; 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; R 3A , R 3B , R 3C and R 3D R is 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, -OCHI, -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; R bonded to the same nitrogen atom 3A and R 3B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; Each X 3 are independently -Cl, -Br, -I or -F; n3 is an integer from 0 to 4; and m3 and v3 are independently 1 or 2.

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

54. The method of claim 52, wherein L 2 is a bond or an unsubstituted C1-C4 alkylene group.

55. The method of claim 52, wherein 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)2NH-, 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. The method of claim 52, wherein L 3 is the key.

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

58. The method of claim 52, wherein the compound has the formula:

59. The method of claim 52, wherein the compound has the formula:

60. The method of claim 52, wherein the compound has the formula:

61. The method of claim 52, wherein R 3 is hydrogen or unsubstituted C1-C4 alkyl.

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

63. The method of claim 52, wherein L 1 For -L 101 -L 102 -L 103 -L 104 -L 105 -; 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, 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)2NR 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)2NR 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; and 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, 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)2NR 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, -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, -NHS O2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

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

65. The method of claim 52, wherein L 1 for 66. The method according to one of claims 52 to 65, wherein R 2 For -L 20 -R 20 ; 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)2NR 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, -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, -NHS OH, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl, -OCBr, -OCF, -OCI, -OCHCl, -OCHBr, -OCHF, -OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, 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 For hydrogen, halogen, -CX 20 3. -CHX 20 2. -CH2X 20 、-OCX 20 3. -OCH2X 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 S02R 20D 、-NR 20A C(O)R 20C 、-NR 20A C(O)OR 20C 、-NR 20A OR 20C , -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; R 20A , R 20B , R 20C and R 20D R is 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, -OCHI, -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; R bonded to the same nitrogen atom 20A and R 20B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; Each X 20 are independently -F, -Cl, -Br or -I; n20 is an integer from 0 to 4; and m20 and v20 are independently 1 or 2.

67. The method according to one of claims 52 to 65, wherein R 2 for 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, -NH SO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; 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, -NH SO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; R 8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; z6 is an integer from 0 to 7; z7 is an integer from 0 to 7; and z8 is an integer from 0 to 5.

68. The method of claim 67, wherein R 6 and -4-(2- to 6-membered) heteroaryl.

69. The method of claim 67, wherein R 6 are independently -F, -Cl, -OH or unsubstituted methyl.

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

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

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

73. The method of claim 67, wherein R 7 Independently, it is halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkynyl, unsubstituted 2 to 6 membered heteroalkyl, or unsubstituted C3-C8 cycloalkyl.

74. The method of claim 67, wherein R 7 independently -F, -Cl, -CF3, -CN, -OH, -NH2, unsubstituted methyl, unsubstituted ethynyl, unsubstituted methoxy or unsubstituted cyclopropyl.

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

76. The method of claim 67, wherein R 8 are independently halogen or unsubstituted C1-C4 alkyl.

77. The method of claim 67, wherein R 8 is independently -Cl or unsubstituted methyl.

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

79. The method according to one of claims 52 to 65, wherein R 2 for 80. A method of attaching a compound to an arginine residue, the method comprising contacting the compound with the arginine residue, wherein the compound has the formula: or its salt; wherein L 1 is a bond or a divalent linker; R 3 For 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 S02R 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; R 4 For 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 S02R 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, 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 R is 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, -OCHI, -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; R bonded to the same nitrogen atom 3A and R 3B Substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 4A and R 4B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; Each X 3 and X 4 are independently -Cl, -Br, -I or -F; n3 and n4 are independently integers from 0 to 4; and m3, m4, v3 and v4 are independently 1 or 2.

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

82. The method of claim 80, wherein L 1 For -L 101 -L 102 -L 103 -L 104 -L 105 -; 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, 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)2NR 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)2NR 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; and 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, 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)2NR 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, -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, -NHS O2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

83. The method according to one of claims 80 to 82, wherein R 4 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, -NHSO2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

84. The method according to one of claims 80 to 82, wherein R 4 For the biomolecule part.

85. A compound covalently bound to an arginine residue, said compound having the formula: or its salt; wherein L 1 is a bond or a divalent linker; R 3 For 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 S02R 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; R 4 For 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 S02R 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, 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 R is 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, -OCHI, -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; R bonded to the same nitrogen atom 3A and R 3B Substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 4A and R 4B Substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; Each X 3 and X 4 are independently -Cl, -Br, -I or -F; n3 and n4 are independently integers from 0 to 4; m3, m4, v3 and v4 are independently 1 or 2; R 11 is hydrogen, -C(O)CH3, or a first protein moiety; and R 12 is -OH or a second protein moiety.

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

87. The covalently bound compound of claim 86, wherein the single protein comprises an additional arginine residue that is not covalently bound to the compound to form a reacted arginine having Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg) or (VIh).

88. The covalently bound compound of claim 85, wherein L 1 For -L 101 -L 102 -L 103 -L 104 -L 105 -; 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, 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)2NR 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)2NR 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; and 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, 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)2NR 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, -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, -NHS O2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

89. according to the compound of one of claims 85 to 88 described covalent bonding, wherein R 4 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, -NHSO2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

90. A covalently bound compound according to one of claims 85 to 88, wherein R 4 For the biomolecule part.

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