ITK inhibitors and uses thereof

Abstract

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

Description

PATENT Attorney Docket No.: 048517-557001WO ITK INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 550,378 filed February 6, 2024, which is incorporated herein by reference in its entirety and for all purposes. BACKGROUND

[0002] Interleukin-2-inducible T-cell kinase (ITK) plays an important role in T-cell development, differentiation, signalling and the production of pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL-17. The modulation of Interleukin-2-inducible T-cell kinase (ITK) activity has been a target for the treatment of inflammation (e.g., inflammatory skin conditions), autoimmune, allergic disease conditions, and cancers (e.g., T- cell cancers such as T-cell lymphoma and lymphblastic T-cell leukemia). For example, ITK inhibition has been studied for the treatment of diseases such as allergic asthma, atopic dermatitis, allergic dermatitis, and psoriasis. Thus, there is a need in the art for ITK modulators. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY

[0003] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: ., , (O)NH-, or -NHC(O)O-.

[0005] L2is a bond or unsubstituted alkylene.

[0006] R1is 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.

[0007] R2is -NR2AR2Bor unsubstituted alkyl.

[0008] R2Aand R2Bare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, R2C-substituted or unsubstituted alkyl, or R2C-substituted or unsubstituted heteroalkyl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form an R2C-substituted or unsubstituted heterocycloalkyl or R2C-substituted or unsubstituted heteroaryl.

[0009] R2Cis independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, or unsubstituted alkyl.

[0010] R3is hydrogen, halogen, -CX33, -CHX32, -CH3X3, -OCX33, -OCH2X3, -OCHX33, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO3R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0011] R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0012] The symbol z4 is an integer from 0 to 4.

[0013] R5is independently oxo, halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, alkyl,or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two R5substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0014] The symbol z5 is an integer from 0 to 8.

[0015] R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0016] Each X3, X4, and X5is independently –F, -Cl, -Br, or –I. The symbols n3, n4, and n5 are independently an integer from 0 to 4. The symbols m3, m4, m5, v3, v4, and v5 are independently 1 or 2.

[0017] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0019] In an aspect is provided a method of treating an autoimmune disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0020] In an aspect is provided a method of treating an allergy in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0021] In an aspect is provided a method of treating an inflammatory disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0022] In an aspect is provided a method of treating a subject having deficient Th1 activity, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity.

[0023] In an aspect is provided a method of treating a Th2 / ITK-mediated disease in a subject in need thereof, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. DETAILED DESCRIPTION I. Definitions

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

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

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

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

[0028] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionallydifferent heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0053] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20alkylene, each substituted orunsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0075] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0076] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0077] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0078] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0079] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0080] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0081] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups)including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0082] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted todisulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex.

[0083] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0084] “Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0085] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0086] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substitutedwith at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[0087] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0088] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric,sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0089] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0090] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0091] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0092] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0093] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0094] The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0095] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0096] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

[0097] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directlyfrom a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0098] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0099] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0100] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0101] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of thecellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0102] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0103] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0104] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0105] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0106] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0107] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a cancer. In embodiments, the disease is an autoimmune disease. In embodiments, the disease is an allergy. In embodiments, the disease is an inflammatory disease.

[0108] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0109] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development ofleukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0110] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0111] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0112] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

[0113] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse,carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0114] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormallung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0115] The terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignantcell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0116] The term “visceral metastasis” refer to secondary malignant cell growths in theinteral organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0117] As used herein, the term “autoimmune disease” refers to a disease or condition in which a subject’s immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria,Axonal or neuronal neuropathies, Balo disease, Behcet’s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid / benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia , Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener’s Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic’s), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitonealfibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia, Takayasu’s arteritis, Temporal arteritis / Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener’s granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA).

[0118] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by aberrant inflammation (e.g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0119] The term “Th2 / ITK-mediated disease” as used herein refers to a disease in which there is an increased expression of ITK and / or an increased Th2 cell response, resulting in the secretion or increased secretion of pro-inflammatory cytokines. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, an eosinophilic disease, a mast cell disease, or human immunodeficiency viral disease.

[0120] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating asubject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug.

[0121] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra,225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu,32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT / US2015 / 022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0122] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0123] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0124] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0125] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0126] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0127] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0128] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0129] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer, autoimmune disease, allergy, or inflammatory disease) diagnosed in a particular patient. The dose administered to a patient, in the context of the presently disclosed methods of therapeutic treatment, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0130] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer, autoimmune disease, allergy, or inflammatory disease) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0131] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using amethod as described herein), results in reduction of the disease or one or more disease symptoms.

[0132] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0133] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0134] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0135] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0136] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of acorresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0137] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0138] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0139] An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected protein corresponds to Cys442 of human ITK protein when the selected residue occupies the same essential spatial or other structural relationship as Cys442 of human ITK protein. In some embodiments, where a selected protein is aligned for maximum homology with the human ITK protein, the position in the aligned selected protein aligning with Cys442 is said to correspond to Cys442. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human ITK protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as Cys442 in the structural model is said to correspond to the Cys442 residue.

[0140] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.

[0141] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). In embodiments, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates (also referred to herein as amorphous protein aggregates), oligomers (also referred to herein as protein oligomers), and amyloid fibrils.

[0142] The terms “Tec kinase” and “Tec kinase family” refer to a protein family (including homologs, isoforms, and functional fragments thereof) of non-receptor protein tyrosine kinases including the proteins TEC, BTK (Bruton’s Tyrosine Kinase), ITK / EMT / TSK, BMX, and TXK / RLK. The term includes any recombinant or naturally-occurring form of a Tec family kinase or variant thereof that maintains Tec family kinase activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Tec family kinase).

[0143] The terms “Interleukin-2-inducible T-cell kinase” and “ITK” refer to a protein (including homologs, isoforms, and functional fragments thereof) with Interleukin-2- inducible T-cell kinase activity. The term includes any recombinant or naturally-occurring form of Interleukin-2-inducible T-cell kinase or variants thereof that maintain Interleukin-2- inducible T-cell kinase activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Interleukin-2-inducible T-cell kinase). In embodiments, the Interleukin-2-inducible T-cell kinase protein encoded by the ITK gene hasthe amino acid sequence set forth in or corresponding to Entrez 3702, UniProt Q08881, or RefSeq (protein) NP_005537. In embodiments, the ITK gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_005546. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

[0144] The terms “tyrosine-protein kinase” and “TXK” refer to a protein (including homologs, isoforms, and functional fragments thereof) encoded by the TXK gene. The term includes any recombinant or naturally-occurring form of tyrosine-protein kinase or variants thereof that maintain tyrosine-protein kinase activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype tyrosine-protein kinase). In embodiments, the tyrosine-protein kinase protein encoded by the TXK gene has the amino acid sequence set forth in or corresponding to Entrez 7294, UniProt P42681, or RefSeq (protein) NP_003319. In embodiments, the TXK gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_003328. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

[0145] The terms “Bruton’s tyrosine kinase” and “BTK” refer to a protein (including homologs, isoforms, and functional fragments thereof) encoded by the BTK gene. The term includes any recombinant or naturally-occurring form of Bruton’s tyrosine kinase or variants thereof that maintain Bruton’s tyrosine kinase activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Bruton’s tyrosine kinase). In embodiments, the Bruton’s tyrosine kinase protein encoded by the BTK gene has the amino acid sequence set forth in or corresponding to Entrez 695, UniProt Q06187, RefSeq (protein) NP_000052, RefSeq (protein) NP_001274273, or RefSeq (protein) NP_001274274. In embodiments, the BTK gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_00001287345, RefSeq (mRNA) NM_000061, or RefSeq (mRNA) NM_001287344. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

[0146] The term “selective” or “selectivity” or the like in reference to a compound or agent refers to the compound’s or agent’s ability to cause an increase or decrease in activity of a particular molecular target (e.g., protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity toward ITK would preferentially inhibit ITK over other kinases (e.g., TXK or BTK)). In embodiments, an “ITK-selective compound” refers to a compound (e.g., compound described herein) havingselectivity towards ITK. In embodiments, the compound (e.g., compound described herein) is about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or about 100-fold more selective for ITK over one or more of TXK or BTK. In embodiments, the compound (e.g., compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or at least 100- fold more selective for ITK over one or more of TXK or BTK. II. Compounds

[0147] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: .(O)NH-, or -NHC(O)O-.

[0149] L2is a bond or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4).

[0150] R1is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0151] R2is -NR2AR2Bor unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4).

[0152] R2Aand R2Bare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, R2C-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), or R2C- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered); R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form an R2C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or R2C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0153] R2Cis independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4).

[0154] R3is hydrogen, halogen, -CX33, -CHX32, -CH3X3, -OCX33, -OCH2X3, -OCHX33, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO3R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0155] R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0156] The symbol z4 is an integer from 0 to 4.

[0157] R5is independently oxo, halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -C(NR5C)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8,C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R5substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0158] The symbol z5 is an integer from 0 to 8.

[0159] R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCH Br2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0160] Each X3, X4, and X5is independently –F, -Cl, -Br, or –I.

[0161] The symbols n3, n4, and n5 are independently an integer from 0 to 4.

[0162] The symbols m3, m4, m5, v3, v4, and v5 are independently 1 or 2.

[0163] In embodiments, R2is not an electrophilic moiety. In embodiments, R2is not capable of covalently binding cysteine. In embodiments, R2is not a covalent cysteine modifier moiety. In embodiments, R2is not capable of covalently binding cysteine under physiological conditions. In embodiments, R2is not capable of covalently binding cysteine, wherein the cysteine forms part of an ITK protein. In embodiments, R2is not capable of reacting with the sulfhydryl functional group of a cysteine amino acid (e.g., cysteine 442 of the Interleukin-2-inducible T-cell kinase (ITK, TSK) (e.g., human Interleukin-2-inducible T- cell kinase (ITK, TSK)), or amino acid corresponding to cysteine 442 of the Interleukin-2- inducible T-cell kinase) to form a covalent bond.

[0164] In embodiments, R2is . In embodiments, R2is Inembodiments, R2isR2is not . In embodiments, R2is . In embodiments, R2is not. In embodiments, R2is notis herein incorporated by reference in its entirety and for all purposes.

[0165] In embodiments, the compound has the formula:I). L1, L2, R1, R2, R3, R5, and z5 are as described R4.2are independently hydrogen or any value of R as described herein, including in embodiments.

[0166] R4.1and R4.2are independently hydrogen, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl(e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0167] In embodiments, the compound has the formula:

[0168] In embodiments, the compound has the formula:z5

[0169] In embodiments, the compound has the formula: z5 are as described

[0170] In embodiments, L1is a bond. In embodiments, L1is -NH-. In embodiments, L1is -NHC(O)-. In embodiments, L1is -NHC(O)NH-. In embodiments, L1is -NHC(O)O-.

[0171] In embodiments, L2is a bond or unsubstituted C1-C4alkylene. In embodiments, L2is a bond. In embodiments, L2is unsubstituted C1-C4 alkylene. In embodiments, L2is unsubstituted methylene. In embodiments, L2is unsubstituted ethylene. In embodiments, L2is unsubstituted propylene. In embodiments, L2is unsubstituted n-propylene. In embodiments, L2is unsubstituted isopropylene. In embodiments, L2is unsubstituted butylene. In embodiments, R2is unsubstituted n-butylene. In embodiments, L2is unsubstituted isobutylene. In embodiments, L2is unsubstituted tert-butylene.

[0172] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1is substituted, it is substituted with at least one substituent group. In embodiments, when R1is substituted, it is substituted with atleast one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0173] In embodiments, R1is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R1is substituted or unsubstituted C1-C6 alkyl. In embodiments, R1is substituted or unsubstituted methyl. In embodiments, R1is substituted or unsubstituted ethyl. In embodiments, R1is substituted or unsubstituted propyl. In embodiments, R1is substituted or unsubstituted n-propyl. In embodiments, R1is unsubstituted isopropyl. In embodiments, R1is unsubstituted butyl. In embodiments, R1is unsubstituted n-butyl. In embodiments, R1is unsubstituted isobutyl. In embodiments, R1is unsubstituted tert-butyl. In embodiments, R1is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1is substituted or unsubstituted C3-C8cycloalkyl. In embodiments, R1is substituted or unsubstituted cyclopropyl. In embodiments, R1is substituted or unsubstituted cyclobutyl. In embodiments, R1is substituted or unsubstituted cyclopentyl. In embodiments, R1is substituted or unsubstituted cyclohexyl. In embodiments, R1is substituted or unsubstituted adamantyl. In embodiments, R1is substituted or unsubstituted C6-C10aryl. In embodiments, R1is substituted or unsubstituted phenyl. In embodiments, R1is substituted or unsubstituted naphthyl.

[0174] In embodiments, R1is substituted or unsubstituted 3 to 8 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R1is substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrazinyl.

[0175] In embodiments, R1is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R1is substituted or unsubstituted azetidinyl. In embodiments, R1is substituted or unsubstituted pyrrolidinyl. In embodiments, R1is substituted or unsubstituted tetrahydrofuranyl. In embodiments, R1is substituted or unsubstituted imidazolidinyl. In embodiments, R1is substituted or unsubstituted pyrazolidinyl. In embodiments, R1is substituted or unsubstituted oxazolidinyl. In embodiments, R1is substituted or unsubstituted isoxazolidinyl. In embodiments, R1is substituted or unsubstituted thiazolidinyl. In embodiments, R1is substituted or unsubstitutedisothiazolidinyl. In embodiments, R1is substituted or unsubstituted dioxolanyl. In embodiments, R1is substituted or unsubstituted dithiolanyl. In embodiments, R1is substituted or unsubstituted piperidinyl. In embodiments, R1is substituted or unsubstituted oxanyl. In embodiments, R1is substituted or unsubstituted piperazinyl. In embodiments, R1is substituted or unsubstituted morpholinyl. In embodiments, R1is substituted or unsubstituted tetrahydropyranyl. In embodiments, R1is substituted or unsubstituted tetrahydrothiopyranyl.

[0176] In embodiments, R1is substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R1is substituted or unsubstituted pyridyl. In embodiments, R1is substituted or unsubstituted pyrazinyl. In embodiments, R1is substituted or unsubstituted pyrimidinyl. In embodiments, R1is substituted or unsubstituted pyridazinyl. In embodiments, R1is substituted or unsubstituted imidazolyl. In embodiments, R1is substituted or unsubstituted pyrrolyl. In embodiments, R1is substituted or unsubstituted pyrazolyl. In embodiments, R1is substituted or unsubstituted triazolyl. In embodiments, R1is substituted or unsubstituted tetrazolyl. In embodiments, R1is substituted or unsubstituted furanyl. In embodiments, R1is substituted or unsubstituted oxazolyl. In embodiments, R1is substituted or unsubstituted isoxazolyl. In embodiments, R1is substituted or unsubstituted oxadiazolyl. In embodiments, R1is substituted or unsubstituted oxatriazolyl. In embodiments, R1is substituted or unsubstituted thienyl. In embodiments, R1is substituted or unsubstituted thiazolyl. In embodiments, R1is substituted or unsubstituted isothiazolyl. In embodiments, R1is substituted or unsubstituted triazinyl. In embodiments, R1is substituted or unsubstituted quinolinyl. In embodiments, R1is substituted or unsubstituted isoquinolinyl. In embodiments, R1is substituted or unsubstituted indolyl. In embodiments, R1is substituted or unsubstituted benzimidazolyl. In embodiments, R1is substituted or unsubstituted indazolyl. In embodiments, R1is substituted or unsubstituted isoindolyl. In embodiments, R1is substituted or unsubstituted benzofuranyl. In embodiments, R1is substituted or unsubstituted benzo[c]thienyl. In embodiments, R1is substituted or unsubstituted 2,3-dihydro-1H-indenyl. In embodiments, R1is substituted or unsubstituted 1,2,3,4-tetrahydronaphthyl. In embodiments, R1is substituted or unsubstituted triazolyl. In embodiments, R1is substituted or unsubstituted quinoxalinyl. In embodiments, R1is substituted or unsubstituted quinazolinyl. In embodiments, R1is substituted or unsubstituted triazinyl. In embodiments, R1is substituted or unsubstituted cinnolinyl. In embodiments, R1is substituted or unsubstituted phthalazinyl. In embodiments, R1is substituted or unsubstituted benzoxazolyl.In embodiments, R1is substituted or unsubstituted benzisoxazolyl. In embodiments, R1is substituted or unsubstituted benzothiazolyl. In embodiments, R1is substituted or unsubstituted benzisothiazolyl. In embodiments, R1is substituted or unsubstituted benzo[d][1,2,3]triazolyl.

[0177] In embodiments, R1is or, wherein R10 and z10 are as described herein, including in embodiments.In embodiments, R1. In embodiments, R1. InIn.

[0178] R10-CX103, -CHX102, -CH2X10, -OCX103, -OCH2X10, -OCHX102, -CN, -SOn10R10D, -SOv10NR10AR10B, ^NR10CNR10AR10B, ^ONR10AR10B, -NR10CC(O)NR10AR10B, -N(O)m10, -NR10AR10B, -C(O)R10C, -C(O)OR10C, -OC(O)R10C, -OC(O)OR10C, -C(O)NR10AR10B, -C(NR10C)NR10AR10B, -OC(O)NR10AR10B, -OR10D, -SR10D, -NR10ASO2R10D, -NR10AC(O)R10C, -NR10AC(O)OR10C, -NR10AOR10C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R10substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0179] The symbol z10 is an integer from 0 to 10.

[0180] R10A, R10B, R10C, and R10Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl(e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0181] Each X10is independently –F, -Cl, -Br, or –I.

[0182] The symbol n10 is an integer from 0 to 4.

[0183] The symbols m10 and v10 are independently 1 or 2.

[0184] In embodiments, a substituted R10(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10is substituted, it is substituted with at least one substituent group. In embodiments, when R10is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10is substituted, it is substituted with at least one lower substituent group.

[0185] In embodiments, a substituted ring formed when two R10substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R10substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R10substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R10substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R10substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0186] In embodiments, a substituted R10A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one lower substituent group.

[0187] In embodiments, a substituted R10B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Bis substituted, it is substituted with at least one substituent group. In embodiments, when R10Bis substituted, itis substituted with at least one size-limited substituent group. In embodiments, when R10Bis substituted, it is substituted with at least one lower substituent group.

[0188] In embodiments, a substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0189] In embodiments, a substituted R10C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Cis substituted, it is substituted with at least one substituent group. In embodiments, when R10Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Cis substituted, it is substituted with at least one lower substituent group.

[0190] In embodiments, a substituted R10D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10Dis substituted, it is substituted with at least one substituent group. In embodiments, when R10Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Dis substituted, it is substituted with at least one lower substituent group.

[0191] In embodiments, R10Ais independently hydrogen. In embodiments, R10Ais independently unsubstituted C1-C4 alkyl. In embodiments, R10Ais independently unsubstituted methyl. In embodiments, R10Ais independently unsubstituted ethyl. In embodiments, R10Ais independently unsubstituted propyl. In embodiments, R10Ais independently unsubstituted n-propyl. In embodiments, R10Ais independently unsubstituted isopropyl. In embodiments, R10Ais independently unsubstituted butyl. In embodiments, R10Ais independently unsubstituted n-butyl. In embodiments, R10Ais independently unsubstituted isobutyl. In embodiments, R10Ais independently unsubstituted tert-butyl.

[0192] In embodiments, R10Bis independently hydrogen. In embodiments, R10Bis independently unsubstituted C1-C4alkyl. In embodiments, R10Bis independently unsubstituted methyl. In embodiments, R10Bis independently unsubstituted ethyl. In embodiments, R10Bis independently unsubstituted propyl. In embodiments, R10Bis independently unsubstituted n-propyl. In embodiments, R10Bis independently unsubstituted isopropyl. In embodiments, R10Bis independently unsubstituted butyl. In embodiments, R10Bis independently unsubstituted n-butyl. In embodiments, R10Bis independently unsubstituted isobutyl. In embodiments, R10Bis independently unsubstituted tert-butyl.

[0193] In embodiments, R10Cis independently hydrogen. In embodiments, R10Cis independently unsubstituted C1-C4 alkyl. In embodiments, R10Cis independently unsubstituted methyl. In embodiments, R10Cis independently unsubstituted ethyl. In embodiments, R10Cis independently unsubstituted propyl. In embodiments, R10Cis independently unsubstituted n-propyl. In embodiments, R10Cis independently unsubstituted isopropyl. In embodiments, R10Cis independently unsubstituted butyl. In embodiments, R10Cis independently unsubstituted n-butyl. In embodiments, R10Cis independently unsubstituted isobutyl. In embodiments, R10Cis independently unsubstituted tert-butyl.

[0194] In embodiments, R10Dis independently hydrogen. In embodiments, R10Dis independently unsubstituted C1-C4alkyl. In embodiments, R10Dis independently unsubstituted methyl. In embodiments, R10Dis independently unsubstituted ethyl. Inembodiments, R10Dis independently unsubstituted propyl. In embodiments, R10Dis independently unsubstituted n-propyl. In embodiments, R10Dis independently unsubstituted isopropyl. In embodiments, R10Dis independently unsubstituted butyl. In embodiments, R10Dis independently unsubstituted n-butyl. In embodiments, R10Dis independently unsubstituted isobutyl. In embodiments, R10Dis independently unsubstituted tert-butyl.

[0195] In embodiments, R10is 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)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0196] In embodiments, R10is independently substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0197] In embodiments, R10is independently oxo. In embodiments, R10is independently halogen. In embodiments, R10is independently –F. In embodiments, R10is independently –Cl. In embodiments, R10is independently –Br. In embodiments, R10is independently –I. In embodiments, R10is independently -CCl3. In embodiments, R10is independently -CBr3. In embodiments, R10is independently -CF3. In embodiments, R10is independently -CI3. In embodiments, R10is independently -CH2Cl. In embodiments, R10is independently -CH2Br. In embodiments, R10is independently -CH2F. In embodiments, R10is independently -CH2I. In embodiments, R10is independently -CHCl2. In embodiments, R10is independently -CHBr2. In embodiments, R10is independently -CHF2. In embodiments, R10is independently -CHI2. In embodiments, R10is independently –CN. In embodiments, R10is independently –OH. In embodiments, R10is independently -NH2. In embodiments, R10is independently –COOH. In embodiments, R10is independently -CONH2. In embodiments, R10is independently -NO2. In embodiments, R10is independently –SH. In embodiments, R10is independently -SO3H. In embodiments, R10is independently -OSO3H. In embodiments, R10is independently -SO2NH2. In embodiments, R10is independently ^NHNH2. Inembodiments, R10is independently ^ONH2. In embodiments, R10is independently ^NHC(O)NH2. In embodiments, R10is independently -NHSO2H. In embodiments, R10is independently -NHC(O)H. In embodiments, R10is independently -NHC(O)OH. In embodiments, R10is independently –NHOH. In embodiments, R10is independently -OCCl3. In embodiments, R10is independently -OCBr3. In embodiments, R10is independently -OCF3. In embodiments, R10is independently -OCI3. In embodiments, R10is independently -OCH2Cl. In embodiments, R10is independently -OCH2Br. In embodiments, R10is independently -OCH2F. In embodiments, R10is independently -OCH2I. In embodiments, R10is independently -OCHCl2. In embodiments, R10is independently -OCHBr2. In embodiments, R10is independently -OCHF2. In embodiments, R10is independently -OCHI2. In embodiments, R10is independently -SF5. In embodiments, R10is independently -N3. In embodiments, R10is independently unsubstituted C1-C4alkyl. In embodiments, R10is independently unsubstituted methyl. In embodiments, R10is independently unsubstituted ethyl. In embodiments, R10is independently unsubstituted propyl. In embodiments, R10is independently unsubstituted n-propyl. In embodiments, R10is independently unsubstituted isopropyl. In embodiments, R10is independently unsubstituted butyl. In embodiments, R10is independently unsubstituted n-butyl. In embodiments, R10is independently unsubstituted isobutyl. In embodiments, R10is independently unsubstituted tert-butyl. In embodiments, R10is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R10is independently unsubstituted methoxy. In embodiments, R10is independently unsubstituted ethoxy. In embodiments, R10is independently unsubstituted propoxy. In embodiments, R10is independently unsubstituted n-propoxy. In embodiments, R10is independently unsubstituted isopropoxy. In embodiments, R10is independently unsubstituted butoxy.

[0198] In embodiments, two R10substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R10substituents are joined to form an unsubstituted C3-C8 cycloalkyl. In embodiments, two R10substituents are joined to form an unsubstituted cyclopropyl. In embodiments, two R10substituents are joined to form an unsubstituted cyclobutyl. In embodiments, two R10substituents are joined to form an unsubstituted cyclopentyl. In embodiments, two R10substituents are joined to form anunsubstituted cyclohexyl. In embodiments, two R10substituents are joined to form .In embodiments, z10 is 0. In embodiments, z10 is 1. In embodiments, z10 is 2. In embodiments, z10 is 3. In embodiments, z10 is 4. In embodiments, z10 is 5. In embodiments, z10 is 6. In embodiments, z10 is 7. In embodiments, z10 is 8. In embodiments, z10 is 9. In embodiments, z10 is 10.

[0200] In embodiments, R1is .including in embodiments. In embodiments, R2is unsubstituted alkyl. In embodiments, R2is a saturated unsubstituted alkyl. In embodiments, R2is a saturated unsubstituted C1-C4alkyl. In embodiments, R2is unsubstituted methyl. In embodiments, R2is unsubstituted ethyl. In embodiments, R2is unsubstituted propyl. In embodiments, R2is unsubstituted n-propyl. In embodiments, R2is unsubstituted isopropyl. In embodiments, R2is unsubstituted butyl. In embodiments, R2is unsubstituted n-butyl. In embodiments, R2is unsubstituted isobutyl. In embodiments, R2is unsubstituted tert-butyl.

[0202] In embodiments, R2Ais hydrogen. In embodiments, R2Ais -CCl3. In embodiments, R2Ais -CBr3. In embodiments, R2Ais -CF3. In embodiments, R2Ais -CI3. In embodiments, R2Ais -CH2Cl. In embodiments, R2Ais -CH2Br. In embodiments, R2Ais -CH2F. In embodiments, R2Ais -CH2I. In embodiments, R2Ais -CHCl2. In embodiments, R2Ais -CHBr2. In embodiments, R2Ais -CHF2. In embodiments, R2Ais -CHI2. In embodiments, R2Ais –CN. In embodiments, R2Ais –OH. In embodiments, R2Ais -NH2. In embodiments, R2Ais –COOH. In embodiments, R2Ais -CONH2. In embodiments, R2Ais -OCCl3. In embodiments, R2Ais -OCBr3. In embodiments, R2Ais -OCF3. In embodiments, R2Ais -OCI3. In embodiments, R2Ais -OCH2Cl. In embodiments, R2Ais -OCH2Br. In embodiments, R2Ais -OCH2F. In embodiments, R2Ais -OCH2I. In embodiments, R2Ais -OCHCl2. In embodiments, R2Ais -OCHBr2. In embodiments, R2Ais -OCHF2. In embodiments, R2Ais -OCHI2. In embodiments, R2Ais R2C-substituted C1-C4 alkyl. In embodiments, R2Ais unsubstituted C1-C4alkyl. In embodiments, R2Ais unsubstituted methyl. In embodiments, R2Ais unsubstituted ethyl. In embodiments, R2Ais unsubstituted propyl. In embodiments, R2Ais unsubstituted n-propyl. In embodiments, R2Ais unsubstituted isopropyl. In embodiments, R2Ais unsubstituted butyl. In embodiments, R2Ais unsubstituted n-butyl. In embodiments, R2Ais unsubstituted isobutyl. In embodiments, R2Ais unsubstituted tert-butyl. In embodiments, R2Ais R2C-substituted 2 to 6 membered heteroalkyl. In embodiments, R2Ais unsubstituted 2 to 6 membered heteroalkyl.

[0203] In embodiments, R2Bis hydrogen. In embodiments, R2Bis -CCl3. In embodiments, R2Bis -CBr3. In embodiments, R2Bis -CF3. In embodiments, R2Bis -CI3. In embodiments, R2Bis -CH2Cl. In embodiments, R2Bis -CH2Br. In embodiments, R2Bis -CH2F. In embodiments, R2Bis -CH2I. In embodiments, R2Bis -CHCl2. In embodiments, R2Bis -CHBr2. In embodiments, R2Bis -CHF2. In embodiments, R2Bis -CHI2. In embodiments, R2Bis –CN. In embodiments, R2Bis –OH. In embodiments, R2Bis -NH2. In embodiments, R2Bis –COOH. In embodiments, R2Bis -CONH2. In embodiments, R2Bis -OCCl3. In embodiments, R2Bis -OCBr3. In embodiments, R2Bis -OCF3. In embodiments, R2Bis -OCI3. In embodiments, R2Bis -OCH2Cl. In embodiments, R2Bis -OCH2Br. In embodiments, R2Bis -OCH2F. In embodiments, R2Bis -OCH2I. In embodiments, R2Bis -OCHCl2. In embodiments, R2Bis -OCHBr2. In embodiments, R2Bis -OCHF2. In embodiments, R2Bis -OCHI2. In embodiments, R2Bis R2C-substituted C1-C4alkyl. In embodiments, R2Bis unsubstituted C1-C4 alkyl. In embodiments, R2Bis unsubstituted methyl. In embodiments, R2Bis unsubstituted ethyl. In embodiments, R2Bis unsubstituted propyl. In embodiments,R2Bis unsubstituted n-propyl. In embodiments, R2Bis unsubstituted isopropyl. In embodiments, R2Bis unsubstituted butyl. In embodiments, R2Bis unsubstituted n-butyl. In embodiments, R2Bis unsubstituted isobutyl. In embodiments, R2Bis unsubstituted tert-butyl. In embodiments, R2Bis R2C-substituted 2 to 6 membered heteroalkyl. In embodiments, R2Bis unsubstituted 2 to 6 membered heteroalkyl.

[0204] In embodiments, R2Aand R2Bsubstituents are joined to form an R2C-substituted or unsubstituted 3 to 8 membered heterocycloalkyl or R2C-substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R2Aand R2Bsubstituents are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl or unsubstituted 5 to 6 membered heteroaryl.

[0205] In embodiments, R2Cis independently halogen. In embodiments, R2Cis independently –F. In embodiments, R2Cis independently –Cl. In embodiments, R2Cis independently –Br. In embodiments, R2Cis independently –I. In embodiments, R2Cis independently -CCl3. In embodiments, R2Cis independently -CBr3. In embodiments, R2Cis independently -CF3. In embodiments, R2Cis independently -CI3. In embodiments, R2Cis independently -CH2Cl. In embodiments, R2Cis independently -CH2Br. In embodiments, R2Cis independently -CH2F. In embodiments, R2Cis independently -CH2I. In embodiments, R2Cis independently -CHCl2. In embodiments, R2Cis independently -CHBr2. In embodiments, R2Cis independently -CHF2. In embodiments, R2Cis independently -CHI2. In embodiments, R2Cis independently –CN. In embodiments, R2Cis independently –OH. In embodiments, R2Cis independently -NH2. In embodiments, R2Cis independently unsubstituted C1-C4 alkyl. In embodiments, R2Cis independently unsubstituted methyl. In embodiments, R2Cis independently unsubstituted ethyl. In embodiments, R2Cis independently unsubstituted propyl. In embodiments, R2Cis independently unsubstituted n-propyl. In embodiments, R2Cis independently unsubstituted isopropyl. In embodiments, R2Cis independently unsubstituted butyl. In embodiments, R2Cis independently unsubstituted n-butyl. In embodiments, R2Cis independently unsubstituted isobutyl. In embodiments, R2Cis independently unsubstituted tert-butyl.

[0206] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituentgroups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0207] In embodiments, a substituted R3A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3Ais substituted, it is substituted with at least one substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one lower substituent group.

[0208] In embodiments, a substituted R3B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3Bis substituted, it is substituted with at least one substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one lower substituent group.

[0209] In embodiments, a substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group mayoptionally be different. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0210] In embodiments, a substituted R3C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3Cis substituted, it is substituted with at least one substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one lower substituent group.

[0211] In embodiments, a substituted R3D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3Dis substituted, it is substituted with at least one substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one lower substituent group.

[0212] In embodiments, R3Ais hydrogen. In embodiments, R3Ais unsubstituted C1-C4alkyl. In embodiments, R3Ais unsubstituted methyl. In embodiments, R3Ais unsubstituted ethyl. In embodiments, R3Ais unsubstituted propyl. In embodiments, R3Ais unsubstituted n- propyl. In embodiments, R3Ais unsubstituted isopropyl. In embodiments, R3Aisunsubstituted butyl. In embodiments, R3Ais unsubstituted n-butyl. In embodiments, R3Ais unsubstituted isobutyl. In embodiments, R3Ais unsubstituted tert-butyl.

[0213] In embodiments, R3Bis hydrogen. In embodiments, R3Bis unsubstituted C1-C4 alkyl. In embodiments, R3Bis unsubstituted methyl. In embodiments, R3Bis unsubstituted ethyl. In embodiments, R3Bis unsubstituted propyl. In embodiments, R3Bis unsubstituted n- propyl. In embodiments, R3Bis unsubstituted isopropyl. In embodiments, R3Bis unsubstituted butyl. In embodiments, R3Bis unsubstituted n-butyl. In embodiments, R3Bis unsubstituted isobutyl. In embodiments, R3Bis unsubstituted tert-butyl.

[0214] In embodiments, R3Cis hydrogen. In embodiments, R3Cis unsubstituted C1-C4alkyl. In embodiments, R3Cis unsubstituted methyl. In embodiments, R3Cis unsubstituted ethyl. In embodiments, R3Cis unsubstituted propyl. In embodiments, R3Cis unsubstituted n- propyl. In embodiments, R3Cis unsubstituted isopropyl. In embodiments, R3Cis unsubstituted butyl. In embodiments, R3Cis unsubstituted n-butyl. In embodiments, R3Cis unsubstituted isobutyl. In embodiments, R3Cis unsubstituted tert-butyl.

[0215] In embodiments, R3Dis hydrogen. In embodiments, R3Dis unsubstituted C1-C4 alkyl. In embodiments, R3Dis unsubstituted methyl. In embodiments, R3Dis unsubstituted ethyl. In embodiments, R3Dis unsubstituted propyl. In embodiments, R3Dis unsubstituted n- propyl. In embodiments, R3Dis unsubstituted isopropyl. In embodiments, R3Dis unsubstituted butyl. In embodiments, R3Dis unsubstituted n-butyl. In embodiments, R3Dis unsubstituted isobutyl. In embodiments, R3Dis unsubstituted tert-butyl.

[0216] In embodiments, R3is 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)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0217] In embodiments, R3is hydrogen. In embodiments, R3is halogen. In embodiments, R3is –F. In embodiments, R3is –Cl. In embodiments, R3is –Br. In embodiments, R3is –I. In embodiments, R3is -CCl3. In embodiments, R3is -CBr3. In embodiments, R3is -CF3. Inembodiments, R3is -CI3. In embodiments, R3is -CH2Cl. In embodiments, R3is -CH2Br. In embodiments, R3is -CH2F. In embodiments, R3is -CH2I. In embodiments, R3is -CHCl2. In embodiments, R3is -CHBr2. In embodiments, R3is -CHF2. In embodiments, R3is -CHI2. In embodiments, R3is –CN. In embodiments, R3is –OH. In embodiments, R3is -NH2. In embodiments, R3is –COOH. In embodiments, R3is -CONH2. In embodiments, R3is -NO2. In embodiments, R3is –SH. In embodiments, R3is -SO3H. In embodiments, R3is -OSO3H. In embodiments, R3is -SO2NH2. In embodiments, R3is ^NHNH2. In embodiments, R3is ^ONH2. In embodiments, R3is ^NHC(O)NH2. In embodiments, R3is -NHSO2H. In embodiments, R3is -NHC(O)H. In embodiments, R3is -NHC(O)OH. In embodiments, R3is –NHOH. In embodiments, R3is -OCCl3. In embodiments, R3is -OCBr3. In embodiments, R3is -OCF3. In embodiments, R3is -OCI3. In embodiments, R3is -OCH2Cl. In embodiments, R3is -OCH2Br. In embodiments, R3is -OCH2F. In embodiments, R3is -OCH2I. In embodiments, R3is -OCHCl2. In embodiments, R3is -OCHBr2. In embodiments, R3is -OCHF2. In embodiments, R3is -OCHI2. In embodiments, R3is -SF5. In embodiments, R3is -N3. In embodiments, R3is unsubstituted C1-C4 alkyl. In embodiments, R3is unsubstituted methyl. In embodiments, R3is unsubstituted ethyl. In embodiments, R3is unsubstituted propyl. In embodiments, R3is unsubstituted n-propyl. In embodiments, R3is unsubstituted isopropyl. In embodiments, R3is unsubstituted butyl. In embodiments, R3is unsubstituted n-butyl. In embodiments, R3is unsubstituted isobutyl. In embodiments, R3is unsubstituted tert-butyl. In embodiments, R3is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is unsubstituted methoxy. In embodiments, R3is unsubstituted ethoxy. In embodiments, R3is unsubstituted propoxy. In embodiments, R3is unsubstituted n-propoxy. In embodiments, R3is unsubstituted isopropoxy. In embodiments, R3is unsubstituted butoxy.

[0218] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4is substituted, it is substituted with at least one substituent group. In embodiments, when R4is substituted, it is substituted with atleast one size-limited substituent group. In embodiments, when R4is substituted, it is substituted with at least one lower substituent group.

[0219] In embodiments, a substituted R4A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Ais substituted, it is substituted with at least one substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one lower substituent group.

[0220] In embodiments, a substituted R4B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Bis substituted, it is substituted with at least one substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one lower substituent group.

[0221] In embodiments, a substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0222] In embodiments, a substituted R4C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Cis substituted, it is substituted with at least one substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one lower substituent group.

[0223] In embodiments, a substituted R4D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Dis substituted, it is substituted with at least one substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one lower substituent group.

[0224] In embodiments, R4Ais hydrogen. In embodiments, R4Ais unsubstituted C1-C4 alkyl. In embodiments, R4Ais unsubstituted methyl. In embodiments, R4Ais unsubstituted ethyl. In embodiments, R4Ais unsubstituted propyl. In embodiments, R4Ais unsubstituted n- propyl. In embodiments, R4Ais unsubstituted isopropyl. In embodiments, R4Ais unsubstituted butyl. In embodiments, R4Ais unsubstituted n-butyl. In embodiments, R4Ais unsubstituted isobutyl. In embodiments, R4Ais unsubstituted tert-butyl.

[0225] In embodiments, R4Bis hydrogen. In embodiments, R4Bis unsubstituted C1-C4alkyl. In embodiments, R4Bis unsubstituted methyl. In embodiments, R4Bis unsubstitutedethyl. In embodiments, R4Bis unsubstituted propyl. In embodiments, R4Bis unsubstituted n- propyl. In embodiments, R4Bis unsubstituted isopropyl. In embodiments, R4Bis unsubstituted butyl. In embodiments, R4Bis unsubstituted n-butyl. In embodiments, R4Bis unsubstituted isobutyl. In embodiments, R4Bis unsubstituted tert-butyl.

[0226] In embodiments, R4Cis hydrogen. In embodiments, R4Cis unsubstituted C1-C4 alkyl. In embodiments, R4Cis unsubstituted methyl. In embodiments, R4Cis unsubstituted ethyl. In embodiments, R4Cis unsubstituted propyl. In embodiments, R4Cis unsubstituted n- propyl. In embodiments, R4Cis unsubstituted isopropyl. In embodiments, R4Cis unsubstituted butyl. In embodiments, R4Cis unsubstituted n-butyl. In embodiments, R4Cis unsubstituted isobutyl. In embodiments, R4Cis unsubstituted tert-butyl.

[0227] In embodiments, R4Dis hydrogen. In embodiments, R4Dis unsubstituted C1-C4alkyl. In embodiments, R4Dis unsubstituted methyl. In embodiments, R4Dis unsubstituted ethyl. In embodiments, R4Dis unsubstituted propyl. In embodiments, R4Dis unsubstituted n- propyl. In embodiments, R4Dis unsubstituted isopropyl. In embodiments, R4Dis unsubstituted butyl. In embodiments, R4Dis unsubstituted n-butyl. In embodiments, R4Dis unsubstituted isobutyl. In embodiments, R4Dis unsubstituted tert-butyl.

[0228] In embodiments, R4is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0229] In embodiments, R4is independently halogen. In embodiments, R4is independently –F. In embodiments, R4is independently –Cl. In embodiments, R4is independently –Br. In embodiments, R4is independently –I. In embodiments, R4is independently -CCl3. In embodiments, R4is independently -CBr3. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2Cl. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHCl2. In embodiments, R4is independently -CHBr2. In embodiments, R4is independently -CHF2. Inembodiments, R4is independently -CHI2. In embodiments, R4is independently –CN. In embodiments, R4is independently –OH. In embodiments, R4is independently -NH2. In embodiments, R4is independently –COOH. In embodiments, R4is independently -CONH2. In embodiments, R4is independently -NO2. In embodiments, R4is independently –SH. In embodiments, R4is independently -SO3H. In embodiments, R4is independently -OSO3H. In embodiments, R4is independently -SO2NH2. In embodiments, R4is independently ^NHNH2. In embodiments, R4is independently ^ONH2. In embodiments, R4is independently ^NHC(O)NH2. In embodiments, R4is independently -NHSO2H. In embodiments, R4is independently -NHC(O)H. In embodiments, R4is independently -NHC(O)OH. In embodiments, R4is independently –NHOH. In embodiments, R4is independently -OCCl3. In embodiments, R4is independently -OCBr3. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2Cl. In embodiments, R4is independently -OCH2Br. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCl2. In embodiments, R4is independently -OCHBr2. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently -SF5. In embodiments, R4is independently -N3. In embodiments, R4is independently unsubstituted C1-C4alkyl. In embodiments, R4is independently unsubstituted methyl. In embodiments, R4is independently unsubstituted ethyl. In embodiments, R4is independently unsubstituted propyl. In embodiments, R4is independently unsubstituted n-propyl. In embodiments, R4is independently unsubstituted isopropyl. In embodiments, R4is independently unsubstituted butyl. In embodiments, R4is independently unsubstituted n-butyl. In embodiments, R4is independently unsubstituted isobutyl. In embodiments, R4is independently unsubstituted tert-butyl. In embodiments, R4is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is independently unsubstituted methoxy. In embodiments, R4is independently unsubstituted ethoxy. In embodiments, R4is independently unsubstituted propoxy. In embodiments, R4is independently unsubstituted n-propoxy. In embodiments, R4is independently unsubstituted isopropoxy. In embodiments, R4is independently unsubstituted butoxy.

[0230] In embodiments, R4is independently -OR4D, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is independently -OR4D, wherein R4Dis as described herein, including in embodiments.

[0231] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4.

[0232] In embodiments, a substituted R4.1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.1is substituted, it is substituted with at least one substituent group. In embodiments, when R4.1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.1is substituted, it is substituted with at least one lower substituent group.

[0233] In embodiments, R4.1hydrogen, 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)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0234] In embodiments, R4.1is hydrogen. In embodiments, R4.1is halogen. In embodiments, R4.1is –F. In embodiments, R4.1is –Cl. In embodiments, R4.1is –Br. In embodiments, R4.1is –I. In embodiments, R4.1is -CCl3. In embodiments, R4.1is -CBr3. In embodiments, R4.1is -CF3. In embodiments, R4.1is -CI3. In embodiments, R4.1is -CH2Cl. In embodiments, R4.1is -CH2Br. In embodiments, R4.1is -CH2F. In embodiments, R4.1is -CH2I. In embodiments, R4.1is -CHCl2. In embodiments, R4.1is -CHBr2. In embodiments, R4.1is -CHF2. In embodiments, R4.1is -CHI2. In embodiments, R4.1is –CN. In embodiments, R4.1is –OH. In embodiments, R4.1is -NH2. In embodiments, R4.1is –COOH. In embodiments, R4.1is -CONH2. In embodiments, R4.1is -NO2. In embodiments, R4.1is –SH. In embodiments, R4.1is -SO3H. In embodiments, R4.1is -OSO3H. In embodiments, R4.1is -SO2NH2. In embodiments, R4.1is ^NHNH2. In embodiments, R4.1is ^ONH2. In embodiments, R4.1is ^NHC(O)NH2. In embodiments, R4.1is -NHSO2H. In embodiments,R4.1is -NHC(O)H. In embodiments, R4.1is -NHC(O)OH. In embodiments, R4.1is –NHOH. In embodiments, R4.1is -OCCl3. In embodiments, R4.1is -OCBr3. In embodiments, R4.1is -OCF3. In embodiments, R4.1is -OCI3. In embodiments, R4.1is -OCH2Cl. In embodiments, R4.1is -OCH2Br. In embodiments, R4.1is -OCH2F. In embodiments, R4.1is -OCH2I. In embodiments, R4.1is -OCHCl2. In embodiments, R4.1is -OCHBr2. In embodiments, R4.1is -OCHF2. In embodiments, R4.1is -OCHI2. In embodiments, R4.1is -SF5. In embodiments, R4.1is -N3. In embodiments, R4.1is unsubstituted C1-C4alkyl. In embodiments, R4.1is unsubstituted methyl. In embodiments, R4.1is unsubstituted ethyl. In embodiments, R4.1is unsubstituted propyl. In embodiments, R4.1is unsubstituted n-propyl. In embodiments, R4.1is unsubstituted isopropyl. In embodiments, R4.1is unsubstituted butyl. In embodiments, R4.1is unsubstituted n-butyl. In embodiments, R4.1is unsubstituted isobutyl. In embodiments, R4.1is unsubstituted tert-butyl. In embodiments, R4.1is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4.1is unsubstituted methoxy. In embodiments, R4.1is unsubstituted ethoxy. In embodiments, R4.1is unsubstituted propoxy. In embodiments, R4.1is unsubstituted n-propoxy. In embodiments, R4.1is unsubstituted isopropoxy. In embodiments, R4.1is unsubstituted butoxy.

[0235] In embodiments, R4.1is -OR4D, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4.1is -OR4D, wherein R4Dis as described herein, including in embodiments.

[0236] In embodiments, a substituted R4.2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.2is substituted, it is substituted with at least one substituent group. In embodiments, when R4.2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.2is substituted, it is substituted with at least one lower substituent group.

[0237] In embodiments, R4.2hydrogen, 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)NH2, -NHSO2H, -NHC(O)H,-NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0238] In embodiments, R4.2is hydrogen. In embodiments, R4.2is halogen. In embodiments, R4.2is –F. In embodiments, R4.2is –Cl. In embodiments, R4.2is –Br. In embodiments, R4.2is –I. In embodiments, R4.2is -CCl3. In embodiments, R4.2is -CBr3. In embodiments, R4.2is -CF3. In embodiments, R4.2is -CI3. In embodiments, R4.2is -CH2Cl. In embodiments, R4.2is -CH2Br. In embodiments, R4.2is -CH2F. In embodiments, R4.2is -CH2I. In embodiments, R4.2is -CHCl2. In embodiments, R4.2is -CHBr2. In embodiments, R4.2is -CHF2. In embodiments, R4.2is -CHI2. In embodiments, R4.2is –CN. In embodiments, R4.2is –OH. In embodiments, R4.2is -NH2. In embodiments, R4.2is –COOH. In embodiments, R4.2is -CONH2. In embodiments, R4.2is -NO2. In embodiments, R4.2is –SH. In embodiments, R4.2is -SO3H. In embodiments, R4.2is -OSO3H. In embodiments, R4.2is -SO2NH2. In embodiments, R4.2is ^NHNH2. In embodiments, R4.2is ^ONH2. In embodiments, R4.2is ^NHC(O)NH2. In embodiments, R4.2is -NHSO2H. In embodiments, R4.2is -NHC(O)H. In embodiments, R4.2is -NHC(O)OH. In embodiments, R4.2is –NHOH. In embodiments, R4.2is -OCCl3. In embodiments, R4.2is -OCBr3. In embodiments, R4.2is -OCF3. In embodiments, R4.2is -OCI3. In embodiments, R4.2is -OCH2Cl. In embodiments, R4.2is -OCH2Br. In embodiments, R4.2is -OCH2F. In embodiments, R4.2is -OCH2I. In embodiments, R4.2is -OCHCl2. In embodiments, R4.2is -OCHBr2. In embodiments, R4.2is -OCHF2. In embodiments, R4.2is -OCHI2. In embodiments, R4.2is -SF5. In embodiments, R4.2is -N3. In embodiments, R4.2is unsubstituted C1-C4 alkyl. In embodiments, R4.2is unsubstituted methyl. In embodiments, R4.2is unsubstituted ethyl. In embodiments, R4.2is unsubstituted propyl. In embodiments, R4.2is unsubstituted n-propyl. In embodiments, R4.2is unsubstituted isopropyl. In embodiments, R4.2is unsubstituted butyl. In embodiments, R4.2is unsubstituted n-butyl. In embodiments, R4.2is unsubstituted isobutyl. In embodiments, R4.2is unsubstituted tert-butyl. In embodiments, R4.2is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4.2is unsubstituted methoxy. In embodiments, R4.2is unsubstituted ethoxy. In embodiments, R4.2is unsubstituted propoxy. In embodiments, R4.2is unsubstituted n-propoxy. In embodiments, R4.2is unsubstituted isopropoxy. In embodiments, R4.2is unsubstituted butoxy.

[0239] In embodiments, R4.2is -OR4D, unsubstituted C1-C4alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4.2is -OR4D, wherein R4Dis as described herein, including in embodiments.

[0240] In embodiments, R4.1is unsubstituted methyl and R4.2is unsubstituted methoxy.

[0241] In embodiments, a substituted R5(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5is substituted, it is substituted with at least one substituent group. In embodiments, when R5is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5is substituted, it is substituted with at least one lower substituent group.

[0242] In embodiments, a substituted ring formed when two R5substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R5substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R5substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R5substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R5substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0243] In embodiments, a substituted R5A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Ais substituted, it is substituted with at least one substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one lower substituent group.

[0244] In embodiments, a substituted R5B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Bis substituted, it is substituted with at least one substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one lower substituent group.

[0245] In embodiments, a substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0246] In embodiments, a substituted R5C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R5Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Cis substituted, it is substituted with at least one substituent group. In embodiments, when R5Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Cis substituted, it is substituted with at least one lower substituent group.

[0247] In embodiments, a substituted R5D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Dis substituted, it is substituted with at least one substituent group. In embodiments, when R5Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Dis substituted, it is substituted with at least one lower substituent group.

[0248] In embodiments, R5Ais hydrogen. In embodiments, R5Ais unsubstituted C1-C4 alkyl. In embodiments, R5Ais unsubstituted methyl. In embodiments, R5Ais unsubstituted ethyl. In embodiments, R5Ais unsubstituted propyl. In embodiments, R5Ais unsubstituted n- propyl. In embodiments, R5Ais unsubstituted isopropyl. In embodiments, R5Ais unsubstituted butyl. In embodiments, R5Ais unsubstituted n-butyl. In embodiments, R5Ais unsubstituted isobutyl. In embodiments, R5Ais unsubstituted tert-butyl.

[0249] In embodiments, R5Bis hydrogen. In embodiments, R5Bis unsubstituted C1-C4alkyl. In embodiments, R5Bis unsubstituted methyl. In embodiments, R5Bis unsubstituted ethyl. In embodiments, R5Bis unsubstituted propyl. In embodiments, R5Bis unsubstituted n- propyl. In embodiments, R5Bis unsubstituted isopropyl. In embodiments, R5Bis unsubstituted butyl. In embodiments, R5Bis unsubstituted n-butyl. In embodiments, R5Bis unsubstituted isobutyl. In embodiments, R5Bis unsubstituted tert-butyl.

[0250] In embodiments, R5Cis hydrogen. In embodiments, R5Cis unsubstituted C1-C4 alkyl. In embodiments, R5Cis unsubstituted methyl. In embodiments, R5Cis unsubstituted ethyl. In embodiments, R5Cis unsubstituted propyl. In embodiments, R5Cis unsubstituted n-propyl. In embodiments, R5Cis unsubstituted isopropyl. In embodiments, R5Cis unsubstituted butyl. In embodiments, R5Cis unsubstituted n-butyl. In embodiments, R5Cis unsubstituted isobutyl. In embodiments, R5Cis unsubstituted tert-butyl.

[0251] In embodiments, R5Dis hydrogen. In embodiments, R5Dis unsubstituted C1-C4alkyl. In embodiments, R5Dis unsubstituted methyl. In embodiments, R5Dis unsubstituted ethyl. In embodiments, R5Dis unsubstituted propyl. In embodiments, R5Dis unsubstituted n- propyl. In embodiments, R5Dis unsubstituted isopropyl. In embodiments, R5Dis unsubstituted butyl. In embodiments, R5Dis unsubstituted n-butyl. In embodiments, R5Dis unsubstituted isobutyl. In embodiments, R5Dis unsubstituted tert-butyl.

[0252] In embodiments, R5is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0253] In embodiments, R5is independently oxo. In embodiments, R5is independently halogen. In embodiments, R5is independently –F. In embodiments, R5is independently –Cl. In embodiments, R5is independently –Br. In embodiments, R5is independently –I. In embodiments, R5is independently -CCl3. In embodiments, R5is independently -CBr3. In embodiments, R5is independently -CF3. In embodiments, R5is independently -CI3. In embodiments, R5is independently -CH2Cl. In embodiments, R5is independently -CH2Br. In embodiments, R5is independently -CH2F. In embodiments, R5is independently -CH2I. In embodiments, R5is independently -CHCl2. In embodiments, R5is independently -CHBr2. In embodiments, R5is independently -CHF2. In embodiments, R5is independently -CHI2. In embodiments, R5is independently –CN. In embodiments, R5is independently –OH. In embodiments, R5is independently -NH2. In embodiments, R5is independently –COOH. In embodiments, R5is independently -CONH2. In embodiments, R5is independently -NO2. In embodiments, R5is independently –SH. In embodiments, R5is independently -SO3H. In embodiments, R5is independently -OSO3H. In embodiments, R5is independently -SO2NH2. In embodiments, R5is independently ^NHNH2. In embodiments, R5is independently^ONH2. In embodiments, R5is independently ^NHC(O)NH2. In embodiments, R5is independently -NHSO2H. In embodiments, R5is independently -NHC(O)H. In embodiments, R5is independently -NHC(O)OH. In embodiments, R5is independently –NHOH. In embodiments, R5is independently -OCCl3. In embodiments, R5is independently -OCBr3. In embodiments, R5is independently -OCF3. In embodiments, R5is independently -OCI3. In embodiments, R5is independently -OCH2Cl. In embodiments, R5is independently -OCH2Br. In embodiments, R5is independently -OCH2F. In embodiments, R5is independently -OCH2I. In embodiments, R5is independently -OCHCl2. In embodiments, R5is independently -OCHBr2. In embodiments, R5is independently -OCHF2. In embodiments, R5is independently -OCHI2. In embodiments, R5is independently -SF5. In embodiments, R5is independently -N3. In embodiments, R5is independently unsubstituted C1-C4 alkyl. In embodiments, R5is independently unsubstituted methyl. In embodiments, R5is independently unsubstituted ethyl. In embodiments, R5is independently unsubstituted propyl. In embodiments, R5is independently unsubstituted n-propyl. In embodiments, R5is independently unsubstituted isopropyl. In embodiments, R5is independently unsubstituted butyl. In embodiments, R5is independently unsubstituted n-butyl. In embodiments, R5is independently unsubstituted isobutyl. In embodiments, R5is independently unsubstituted tert-butyl. In embodiments, R5is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5is independently unsubstituted methoxy. In embodiments, R5is independently unsubstituted ethoxy. In embodiments, R5is independently unsubstituted propoxy. In embodiments, R5is independently unsubstituted n-propoxy. In embodiments, R5is independently unsubstituted isopropoxy. In embodiments, R5is independently unsubstituted butoxy.

[0254] In embodiments, two R5substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R5substituents are joined to form an unsubstituted C3-C8cycloalkyl. In embodiments, two R5substituents are joined to form an unsubstituted cyclopropyl. In embodiments, two R5substituents are joined to form an unsubstituted cyclobutyl. In embodiments, two R5substituents are joined to form anunsubstituted cyclopentyl. In embodiments, two R5substituents are joined to form an unsubstituted cyclohexyl. In embodiments, two R5substituents are joined to .

[0255] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments,embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. In embodiments, z5 is 6. In embodiments, z5 is 7. In embodiments, z5 is 8.

[0256] In embodiments, when R1is substituted, R1is substituted with one or more first substituent groups denoted by R1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1substituent group is substituted, the R1.1substituent group is substituted with one or more second substituent groups denoted by R1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2substituent group is substituted, the R1.2substituent group is substituted with one or more third substituent groups denoted by R1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

[0257] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above ingroup(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0258] In embodiments, when R3Ais substituted, R3Ais substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3A, R3A.1, R3A.2, and R3A.3, respectively.

[0259] In embodiments, when R3Bis substituted, R3Bis substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.1substituent group is substituted with one or more second substituent groups denoted by R3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3B, R3B.1, R3B.2, and R3B.3, respectively.

[0260] In embodiments, when R3Aand R3Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted,the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3A, R3A.1, R3A.2, and R3A.3, respectively.

[0261] In embodiments, when R3Aand R3Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.1substituent group is substituted with one or more second substituent groups denoted by R3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3B, R3B.1, R3B.2, and R3B.3, respectively.

[0262] In embodiments, when R3Cis substituted, R3Cis substituted with one or more first substituent groups denoted by R3C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.1substituent group is substituted, the R3C.1substituent group is substituted with one or more second substituent groups denoted by R3C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.2substituent group is substituted, the R3C.2substituent group is substituted with one or more third substituent groups denoted by R3C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3C, R3C.1, R3C.2, and R3C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3C, R3C.1, R3C.2, and R3C.3, respectively.

[0263] In embodiments, when R3Dis substituted, R3Dis substituted with one or more first substituent groups denoted by R3D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D.1substituent group is substituted, the R3D.1substituent group is substituted with one or more second substituent groups denoted by R3D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D.2substituent group is substituted, the R3D.2substituent group is substituted with one or more third substituent groups denoted by R3D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3D, R3D.1, R3D.2, and R3D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3D, R3D.1, R3D.2, and R3D.3, respectively.

[0264] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituent groups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0265] In embodiments, when R4.1is substituted, R4.1is substituted with one or more first substituent groups denoted by R4.1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1.1substituent group is substituted, the R4.1.1substituent group is substituted with one or more second substituent groups denoted by R4.1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1.2substituent group is substituted, the R4.1.2substituent group is substituted with one or more third substituent groups denoted by R4.1.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R4.1, R4.1.1, R4.1.2, and R4.1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.1, R4.1.1, R4.1.2, and R4.1.3, respectively.

[0266] In embodiments, when R4.2is substituted, R4.2is substituted with one or more first substituent groups denoted by R4.2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2.1substituent group is substituted, the R4.2.1substituent group is substituted with one or more second substituent groups denoted by R4.2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2.2substituent group is substituted, the R4.2.2substituent group is substituted with one or more third substituent groups denoted by R4.2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.2, R4.2.1, R4.2.2, and R4.2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.2, R4.2.1, R4.2.2, and R4.2.3, respectively.

[0267] In embodiments, when R4Ais substituted, R4Ais substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4A, R4A.1, R4A.2, and R4A.3, respectively.

[0268] In embodiments, when R4Bis substituted, R4Bis substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituentgroups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4B, R4B.1, R4B.2, and R4B.3, respectively.

[0269] In embodiments, when R4Aand R4Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4A, R4A.1, R4A.2, and R4A.3, respectively.

[0270] In embodiments, when R4Aand R4Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R4B, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4B, R4B.1, R4B.2, and R4B.3, respectively.

[0271] In embodiments, when R4Cis substituted, R4Cis substituted with one or more first substituent groups denoted by R4C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4C.1substituent group is substituted, the R4C.1substituent group is substituted with one or more second substituent groups denoted by R4C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4C.2substituent group is substituted, the R4C.2substituent group is substituted with one or more third substituent groups denoted by R4C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4C, R4C.1, R4C.2, and R4C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4C, R4C.1, R4C.2, and R4C.3, respectively.

[0272] In embodiments, when R4Dis substituted, R4Dis substituted with one or more first substituent groups denoted by R4D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D.1substituent group is substituted, the R4D.1substituent group is substituted with one or more second substituent groups denoted by R4D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D.2substituent group is substituted, the R4D.2substituent group is substituted with one or more third substituent groups denoted by R4D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4D, R4D.1, R4D.2, and R4D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4D, R4D.1, R4D.2, and R4D.3, respectively.

[0273] In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituentgroups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

[0274] In embodiments, when two R5substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

[0275] In embodiments, when R5Ais substituted, R5Ais substituted with one or more first substituent groups denoted by R5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.1substituent group is substituted, the R5A.1substituent group is substituted with one or more second substituent groups denoted by R5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.2substituent group is substituted, the R5A.2substituent group is substituted with one or more third substituent groups denoted by R5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A, R5A.1, R5A.2, and R5A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5A, R5A.1, R5A.2, and R5A.3, respectively.

[0276] In embodiments, when R5Bis substituted, R5Bis substituted with one or more first substituent groups denoted by R5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.1substituent group is substituted, the R5B.1substituent group is substituted with one or more second substituent groups denoted by R5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.2substituent group is substituted, the R5B.2substituent group is substituted with one or more third substituent groups denoted by R5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B, R5B.1, R5B.2, and R5B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5B, R5B.1, R5B.2, and R5B.3, respectively.

[0277] In embodiments, when R5Aand R5Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.1substituent group is substituted, the R5A.1substituent group is substituted with one or more second substituent groups denoted by R5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.2substituent group is substituted, the R5A.2substituent group is substituted with one or more third substituent groups denoted by R5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A.1, R5A.2, and R5A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R5A.1, R5A.2, and R5A.3, respectively.

[0278] In embodiments, when R5Aand R5Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5B.1as explained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R5B.1substituent group is substituted, the R5B.1substituent group is substituted with one or more second substituent groups denoted by R5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.2substituent group is substituted, the R5B.2substituent group is substituted with one or more third substituent groups denoted by R5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B.1, R5B.2, and R5B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R5B.1, R5B.2, and R5B.3, respectively.

[0279] In embodiments, when R5Cis substituted, R5Cis substituted with one or more first substituent groups denoted by R5C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.1substituent group is substituted, the R5C.1substituent group is substituted with one or more second substituent groups denoted by R5C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.2substituent group is substituted, the R5C.2substituent group is substituted with one or more third substituent groups denoted by R5C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5C, R5C.1, R5C.2, and R5C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5C, R5C.1, R5C.2, and R5C.3, respectively.

[0280] In embodiments, when R5Dis substituted, R5Dis substituted with one or more first substituent groups denoted by R5D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5D.1substituent group is substituted, the R5D.1substituent group is substituted with one or more second substituent groups denoted by R5D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5D.2substituent group is substituted, the R5D.2substituent group is substituted with one or more third substituent groups denoted by R5D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5D, R5D.1, R5D.2, and R5D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5D, R5D.1, R5D.2, and R5D.3, respectively.

[0281] In embodiments, when R10is substituted, R10is substituted with one or more first substituent groups denoted by R10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1substituent group is substituted, the R10.1substituent group is substituted with one or more second substituent groups denoted by R10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2substituent group is substituted, the R10.2substituent group is substituted with one or more third substituent groups denoted by R10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10, R10.1, R10.2, and R10.3, respectively.

[0282] In embodiments, when two R10substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1substituent group is substituted, the R10.1substituent group is substituted with one or more second substituent groups denoted by R10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2substituent group is substituted, the R10.2substituent group is substituted with one or more third substituent groups denoted by R10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10, R10.1, R10.2, and R10.3, respectively.

[0283] In embodiments, when R10Ais substituted, R10Ais substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituentgroups denoted by R10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10A, R10A.1, R10A.2, and R10A.3, respectively.

[0284] In embodiments, when R10Bis substituted, R10Bis substituted with one or more first substituent groups denoted by R10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.1substituent group is substituted, the R10B.1substituent group is substituted with one or more second substituent groups denoted by R10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.2substituent group is substituted, the R10B.2substituent group is substituted with one or more third substituent groups denoted by R10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10B, R10B.1, R10B.2, and R10B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10B, R10B.1, R10B.2, and R10B.3, respectively.

[0285] In embodiments, when R10Aand R10Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituent groups denoted by R10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in thedescription of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R10A.1, R10A.2, and R10A.3, respectively.

[0286] In embodiments, when R10Aand R10Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.1substituent group is substituted, the R10B.1substituent group is substituted with one or more second substituent groups denoted by R10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.2substituent group is substituted, the R10B.2substituent group is substituted with one or more third substituent groups denoted by R10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10B.1, R10B.2, and R10B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R10B.1, R10B.2, and R10B.3, respectively.

[0287] In embodiments, when R10Cis substituted, R10Cis substituted with one or more first substituent groups denoted by R10C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10C.1substituent group is substituted, the R10C.1substituent group is substituted with one or more second substituent groups denoted by R10C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10C.2substituent group is substituted, the R10C.2substituent group is substituted with one or more third substituent groups denoted by R10C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10C, R10C.1, R10C.2, and R10C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10C, R10C.1, R10C.2, and R10C.3, respectively.

[0288] In embodiments, when R10Dis substituted, R10Dis substituted with one or more first substituent groups denoted by R10D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10D.1substituent group is substituted, the R10D.1substituent group is substituted with one or more second substituentgroups denoted by R10D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10D.2substituent group is substituted, the R10D.2substituent group is substituted with one or more third substituent groups denoted by R10D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10D, R10D.1, R10D.2, and R10D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10D, R10D.1, R10D.2, and R10D.3, respectively.

[0289] In embodiments, the compound has the formula:InStheembodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0291] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).III. Pharmaceutical compositions

[0292] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0293] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound.

[0294] In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0295] Solutions of the active compounds as free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[0296] Pharmaceutical compositions can be delivered via intranasal or inhalable solutions or sprays, aerosols or inhalants. Nasal solutions can be aqueous solutions designed to be administered to the nasal passages in drops or sprays. Nasal solutions can be prepared so that they are similar in many respects to nasal secretions. Thus, the aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5 to 7. In addition, antimicrobial preservatives, similar to those used in ophthalmic preparations and appropriate drug stabilizers, if required, may be included in the formulation. Various commercial nasal preparations are known and can include, for example, antibiotics and antihistamines.

[0297] Oral formulations can include excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. In embodiments, oral pharmaceutical compositions will comprise an inert diluent or edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the compositions and preparations may, of course, be varied and mayconveniently be between about 1 to about 80% of the weight of the unit. The amount of active compounds in such compositions is such that a suitable dosage can be obtained.

[0298] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions, in particular, sterile aqueous media, are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1,000 mL of hypodermoclysis fluid or injected at the proposed site of infusion.

[0299] Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium. Vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredients, can be used to prepare sterile powders for reconstitution of sterile injectable solutions. The preparation of more, or highly, concentrated solutions for direct injection is also contemplated. Dimethyl sulfoxide can be used as solvent for extremely rapid penetration, delivering high concentrations of the active agents to a small area.

[0300] The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials. Thus, the composition can be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. Thus, the compositions can be administered in a variety of unit dosage forms depending upon the method of administration. For example, unit dosage forms suitable for oral administration include, but are not limited to, powder, tablets, pills, capsules, and lozenges.

[0301] In embodiments, the pharmaceutical composition is an oral composition. In embodiments, the oral composition is a solid oral composition. In embodiments, the oral composition is a liquid oral composition. In embodiments, the pharmaceutical composition is a tablet or a capsule. In embodiments, the pharmaceutical composition is a tablet. In embodiments, the pharmaceutical composition is a capsule. In embodiments, the pharmaceutical composition is a powder.IV. Methods of use

[0302] In an aspect is provided a method of treating a cancer, an autoimmune disease, or an allergy in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0303] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0304] In embodiments, the cancer is T-cell lymphoma. In embodiments, the cancer is T cell leukemia. In embodiments, the cancer is B cell lymphoma. In embodiments, the cancer is lung cancer. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cell cancer. In embodiments, the cancer is head and neck cancer.

[0305] In embodiments, the cancer is a hematological cancer. In embodiments, the cancer is a blood cancer. In embodiments, the cancer is a metastatic cancer. In embodiments, the cancer is a leukemia (e.g., acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, orundifferentiated cell leukemia). In embodiments, the cancer is a lymphoma (e.g., T-cell lymphoma, precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T- cell lymphoma, adult T-cell leukemia / lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, nasal type, enteropathy-associated intestinal T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma, unspecified).

[0306] In an aspect is provided a method of treating an autoimmune disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0307] In embodiments, the autoimmune disease is autoimmune lymphoproliferative disease. In embodiments, the autoimmune disease is colitis. In embodiments, the autoimmune disease is inflammatory bowel disease. In embodiments, the autoimmune disease is systemic lupus erythematosus (SLE). In embodiments, the autoimmune disease is atopic dermatitis. In embodiments, the autoimmune disease is systemic sclerosis. In embodiments, the autoimmune disease is anklylosing spondylitis. In embodiments, the autoimmune disease is arthritis. In embodiments, the autoimmune disease is rheumatoid arthritis. In embodiments, the autoimmune disease is psoriatic arthritis. In embodiments, the autoimmune disease is juvenile idiopathic arthritis. In embodiments, the autoimmune disease is multiple sclerosis. In embodiments, the autoimmune disease is myasthenia gravis. In embodiments, the autoimmune disease is juvenile onset diabetes. In embodiments, the autoimmune disease is diabetes mellitus type 1. In embodiments, the autoimmune disease is Guillain-Barre syndrome. In embodiments, the autoimmune disease is Hashimoto’s encephalitis. In embodiments, the autoimmune disease is Hashimoto’s thyroiditis. In embodiments, the autoimmune disease is psoriasis. In embodiments, the autoimmune disease is Sjogren’s syndrome. In embodiments, the autoimmune disease is vasculitis. In embodiments, the autoimmune disease is glomerulonephritis. In embodiments, the autoimmune disease is autoimmune thyroiditis. In embodiments, the autoimmune disease is Behcet’s disease. In embodiments, the autoimmune disease is Crohn’s disease. In embodiments, the autoimmune disease is ulcerative colitis. In embodiments, the autoimmune disease is bullous pemphigoid. In embodiments, the autoimmune disease is sarcoidosis. In embodiments, the autoimmune disease is ichthyosis. In embodiments, the autoimmunedisease is Graves ophthalmopathy. In embodiments, the autoimmune disease is Addison’s disease. In embodiments, the autoimmune disease is Vitiligo. In embodiments, the autoimmune disease is asthma. In embodiments, the autoimmune disease is allergic asthma. In embodiments, the autoimmune disease is acne vulgaris. In embodiments, the autoimmune disease is celiac disease. In embodiments, the autoimmune disease is chronic prostatitis. In embodiments, the autoimmune disease is pelvic inflammatory disease. In embodiments, the autoimmune disease is reperfusion injury. In embodiments, the autoimmune disease is sarcoidosis. In embodiments, the autoimmune disease is transplant rejection. In embodiments, the autoimmune disease is interstitial cystitis. In embodiments, the autoimmune disease is atherosclerosis. In embodiments, the autoimmune disease is scleroderma.

[0308] In an aspect is provided a method of treating an allergy in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0309] In embodiments, the allergy is asthma. In embodiments, the allergy is atopic dermatitis. In embodiments, the allergy is rhinitis. In embodiments, the allergy is psoriasis.

[0310] In an aspect is provided a method of treating an inflammatory disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0311] In embodiments, the inflammatory disease is arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke,sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis.

[0312] In an aspect is provided a method of treating a subject having deficient Th1 activity, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof. In embodiments, “deficient Th1 activity” is decreased Th1 activity relative to a control. In embodiments, the control is a healthy subject or a population of healthy subjects.

[0313] In embodiments, the subject has increased Th2 activity. In embodiments, the subject has increased levels of pro-inflammatory cytokines. In embodiments, the subject has an increased level of a pro-inflammatory cytokine selected from the group consisting of IL-4, IL-5, IL10, IL-13, or a combination of two or more thereof. In embodiments, the subject has an increased level of a pro-inflammatory cytokine selected from the group consisting of IL-4, IL-5, IL10, IL-13, IL-17, or a combination of two or more thereof.

[0314] In an aspect is provided a method of treating a subject having deficient Th1 activity, the method including: (i) measuring increased Th2 activity, an increased level of IL-4, an increased level of IL-5, an increased level of IL-10, an increased level of IL-13, an increased level of IL-17, a decreased level of IFNγ, a decreased number of Th1+T cells, a decreased ratio of Th1+T cells to Th2+T cells, a decreased ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells, a decreased number CD8+ cytotoxic lymphocytes, an increased number of Th2+ cells, an increased number of Th17+ T cells, an increased number of eosinophils, or any combination of two or more thereof, relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0315] In embodiments, the method includes: (i) measuring increased Th2 activity relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased level of IL-4 relative to a control, in a biological sample obtainedfrom the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased level of IL-5 relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased level of IL-10 relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased level of IL-13 relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased level of IL-17 relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring a decreased level of IFNγ relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring a decreased number of Th1+T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring a decreased ratio of Th1+T cells to Th2+T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring a decreased ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring a decreased number CD8+ cytotoxic lymphocytes relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compounddescribed herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased number of Th2+ cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased number of Th17+ T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the method includes: (i) measuring an increased number of eosinophils relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity.

[0316] In embodiments, the disclosure provides methods of treating a subject having deficient Th1-type cytokines by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having increased Th2 activity by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having deficient Th1 activity and increased Th2 activity by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having increased levels of a pro-inflammatory cytokine by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having deficient Th1 activity and increased levels of a pro-inflammatory cytokine by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, “deficient Th1-type cytokines” refers to decreased Th1 levels of Th1-type cytokines. In embodiments, Th1-type cytokines include IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, and granulocyte-macrophage colony-stimulating factor (GMCS). In embodiments, the disclosure provides methods of treating a subject having deficient Th1-type cytokines by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having deficient Th1-type cytokines by: (i) measuring decreased levels of Th1, IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, GMCS, or a combination of two or more thereof, relative to a control, in a biological sample from the subject; and (ii) administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having deficient Th1-type cytokines by: (i) measuring increased levels of IL-4, IL-5, IL10, IL-13, IL-17, or a combination of two or more thereof, relative to a control, in a biological sample from the subject; and (ii) administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having increased Th2 activity by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. I n embodiments, the disclosure provides methods of treating a subject having increased Th2 activity by: (i) measuring an increased level of Th2, relative to a control, in a biological sample obtained from the subject, and (ii) administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having deficient Th1 activity and increased Th2 activity by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having increased levels of a pro- inflammatory cytokine by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the disclosure provides methods of treating a subject having deficient Th1 activity and increased levels of a pro-inflammatory cytokine by administering to the subject a compound described herein including in embodiments, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, “deficient Th1-type cytokines” refers to decreased Th1 levels of Th1-type cytokines. In embodiments, Th1-type cytokines include IFNγ, IL-1β,IL-2, IL-12, TNF-α, TNF-γ, and granulocyte-macrophage colony-stimulating factor (GMCS).

[0317] The term “Th1 activity” as used herein refers to the number of Th1 cells and / or to the activity of the Th1 pathway. The Th-1 pathway refers to Th1-type cytokines that activate the immune system to suppress tumors. Th1-type cytokines include IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, GMCS, or a combination of two or more thereof. In embodiments, “deficient Th1 activity” includes reduced number or reduced expression of Th1-type cytokines.

[0318] The term “Th2 activity” as used herein refers to the number of Th2 cells and / or the activity of the Th2 pathway. The Th2 pathway refers to Th2-type cytokines that are related to tumor growth or metastasis. Th2-type cytokines include IL-4, IL-5, IL-10, IL-13, IL-17, or a combination of two or more thereof.

[0319] In embodiments, the subject has increased Th2 activity relative to a control. In embodiments, the subject has an increased level of a pro-inflammatory cytokine relative to a control. In embodiments, the pro-inflammatory cytokine is IL-4, IL-5, IL-10, IL-13, or IL- 17, or a combination of two or more thereof. In embodiments, the control is a healthy subject or a population of healthy subjects.

[0320] In embodiments, the effective amount to increase Th1 activity is an amount that: (a) increases the number of Th1+T cells; (b) increases the ratio of Th1+T cells to Th2+T cells; (c) increases the ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells; (d) increases IFNγ production; (e) increases CD8+ cytotoxic lymphocytes; (f) inhibits IL-4 production; (g) inhibits IL-13 production; (h) decreases Th2+ cells; (i) decreases Th17+ T cells; (j) decreases eosinophils; (k) inhibits Th2; (l) inhibits the differentiation of naïve CD4 cells into Th2 cells; or (m) a combination of two or more of (a)-(j). In embodiments, the effective amount to increase Th1 activity is an amount that increases the number of Th1+T cells. In embodiments, the effective amount to increase Th1 activity is an amount that increases the ratio of Th1+T cells to Th2+T cells. In embodiments, the effective amount to increase Th1 activity is an amount that increases the ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells. In embodiments, the effective amount to increase Th1 activity is an amount that increases IFNγ production. In embodiments, the effective amount to increase Th1 activity is an amount that increases CD8+ cytotoxic lymphocytes. In embodiments, the effective amount to increase Th1 activity is an amount that inhibits IL-4 production. In embodiments, the effective amount to increase Th1 activity is an amount that inhibits IL-13 production. In embodiments, the effective amount to increase Th1 activity is an amount that decreases Th2+ cells. Inembodiments, the effective amount to increase Th1 activity is an amount that decreases Th17+ T cells. In embodiments, the effective amount to increase Th1 activity is an amount that decreases eosinophils. In embodiments, the effective amount to increase Th1 activity is an amount that inhibits Th2. In embodiments, the effective amount to increase Th1 activity is an amount that inhibits the differentiation of naïve CD4 cells into Th2 cells. In embodiments, the effective amount to increase Th1 activity is an amount that inhibits production of cytokines secreted by Th2+ cells.

[0321] In embodiments, an effective amount to increase Th1 activity is from about 0.5 mmol to about 2 mmol of the ITK inhibitor per day. In embodiments, the effective amount to increase Th1 activity is from about 0.6 mmol to about 1.6 mmol of the compound per day. In embodiments, the effective amount to increase Th1 activity is from about 0.6 mmol to about 1.0 mmol of the compound per day. In embodiments, the effective amount to increase Th1 activity is from about 0.7 mmol to about 0.9 mmol of the compound per day. In embodiments, the effective amount to increase Th1 activity is about 0.8 mmol of the compound per day.

[0322] In embodiments, the effective amount to increase Th1 activity is from about 0.3 mmol to about 0.8 mmol of the compound twice per day. In embodiments, the effective amount to increase Th1 activity is from about 0.3 mmol to about 0.5 mmol of the compound twice per day. In embodiments, the effective amount to increase Th1 activity is from about 0.35 mmol to about 0.45 mmol of the compound twice per day. In embodiments, the effective amount to increase Th1 activity is about 0.4 mmol of the compound twice per day.

[0323] In an aspect is provided a method of treating a Th2 / ITK-mediated disease in a subject in need thereof, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0324] In an aspect is provided a method of treating a Th2 / ITK-mediated disease in a subject in need thereof, the method including: (i) measuring a decreased level of Th1+T cells, a decreased ratio of Th1+T cells to Th2+T cells, a decreased ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells, a decreased level of IFNγ, a decreased level CD8+ cytotoxic lymphocytes, an increased level of Th2+ cells, an increased level of IL-4; an increased level of IL-5, an increased level of IL-10, an increased level of IL-13, an increased level of IL-17,an increased level of Th17+ T cells, an increased level of eosinophils, a decreased level of IL- 1β, a decreased level of IL-2, a decreased level of IL-12, a decreased level of TNF-α, a decreased level of TNF-γ, a decreased level of GMCS, or a combination of two or more thereof, relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0325] In embodiments, the method includes: (i) measuring a decreased level of Th1+T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased ratio of Th1+T cells to Th2+T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of IFNγ relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level CD8+ cytotoxic lymphocytes relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of Th2+ cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of IL-4 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of IL-5 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of IL-10 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of IL-13 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of IL-17 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of Th17+ T cells relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring an increased level of eosinophils relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of IL-1β relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of IL-2 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of IL-12 relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of TNF-α relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of TNF-γ relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject atherapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method includes: (i) measuring a decreased level of GMCS relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0326] In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis. In embodiments, the Th2 / ITK-mediated disease is asthma. In embodiments, the Th2 / ITK- mediated disease is rhinitis. In embodiments, the Th2 / ITK-mediated disease is conjunctivitis. In embodiments, the Th2 / ITK-mediated disease is psoriasis. In embodiments, the Th2 / ITK- mediated disease is scleroderma. In embodiments, the Th2 / ITK-mediated disease is pulmonary fibrosis. In embodiments, the Th2 / ITK-mediated disease is cirrhosis. In embodiments, the Th2 / ITK-mediated disease is retroperitoneal fibrosis. In embodiments, the Th2 / ITK-mediated disease is psoriatic arthritis. In embodiments, the Th2 / ITK-mediated disease is vasculitis. In embodiments, the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome. In embodiments, the Th2 / ITK-mediated disease is chronic obstructive pulmonary disease. In embodiments, the Th2 / ITK-mediated disease is an eosinophilic disease. In embodiments, the Th2 / ITK-mediated disease is a mast cell disease. In embodiments, the Th2 / ITK-mediated disease is human immunodeficiency viral disease.

[0327] In an aspect is provided a method of reducing the level of activity of a TEC kinase, the method including contacting the TEC kinase with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the cell is in a subject. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0328] In embodiments, the level of activity of the TEC kinase is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 10-fold relative to acontrol (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by about 1000-fold relative to a control (e.g., absence of the compound).

[0329] In embodiments, the level of activity of the TEC kinase is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the TEC kinase is reduced by at least 1000-fold relative to a control (e.g., absence of the compound).

[0330] In an aspect is provided a method of reducing the level of activity of an interleukin- 2-inducible T-cell kinase, the method including contacting the interleukin-2-inducible T-cell kinase with an effective amount of a compound described herein, or a pharmaceuticallyacceptable salt thereof. In embodiments, the cell is in a subject. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (V), including all embodiments thereof.

[0331] In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2- inducible T-cell kinase is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2- inducible T-cell kinase is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by about 1000-fold relative to a control (e.g., absence of the compound).

[0332] In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 2-fold relative to a control (e.g.,absence of the compound). In embodiments, the level of activity of the Interleukin-2- inducible T-cell kinase is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2- inducible T-cell kinase is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Interleukin-2-inducible T-cell kinase is reduced by at least 1000-fold relative to a control (e.g., absence of...

Claims

WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ;- , - -, - , or -NHC(O)O-; L2is a bond or unsubstituted alkylene; R1is 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; R2is -NR2AR2Bor unsubstituted alkyl; R2Aand R2Bare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, R2C-substituted or unsubstituted alkyl, or R2C-substituted or unsubstituted heteroalkyl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form an R2C-substituted or unsubstituted heterocycloalkyl or R2C-substituted or unsubstituted heteroaryl; R2Cis independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, or unsubstituted alkyl; R3is hydrogen, halogen, -CX33, -CHX32, -CH3X3, -OCX33, -OCH2X3, -OCHX33, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO3R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B,-NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -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; z4 is an integer from 0 to 4; R5is independently oxo, halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -C(NR5C)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R5substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 8; R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare-CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X3, X4, and X5is independently –F, -Cl, -Br, or –I; n3, n4, and n5 are independently an integer from 0 to 4; and m3, m4, m5, v3, v4, and v5 are independently 1 or 2;wherein R2is not a covalent cysteine modifier moiety.

2. The compound of claim 1, having the formula: ; wherein -CX43, -CHX42, -CH2X4, -OCX43, - - - - - ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -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.

3. The compound of claim 2, wherein R4.1and R4.2are 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)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

4. The compound of claim 2, wherein R4.1and R4.2are independently -OR4D, unsubstituted C1-C4alkyl, or unsubstituted 2 to 6 membered heteroalkyl.

5. The compound of claim 2, wherein R4.1is unsubstituted methyl and R4.2is unsubstituted methoxy.

6. The compound of claim 1, wherein L2is a bond or unsubstituted C1-C4alkylene.

7. The compound of claim 1, wherein L2is a bond.

8. The compound of claim 1, wherein L2is unsubstituted methylene.

9. The compound of claim 2, having the formula: ..and R2Bare independently unsubstituted C1-C4 alkyl.

12. The compound of claim 1, wherein R2Aand R2Bare unsubstituted methyl.

13. The compound of claim 1, wherein R2is a saturated unsubstituted alkyl.

14. The compound of claim 1, wherein R2is a saturated unsubstituted C1- C4 alkyl.

15. The compound of claim 1, wherein R2is unsubstituted ethyl.

16. The compound of claim 2, having the formula:V). in L1is -NH-.

18. The compound of claim 1, wherein L1is -NHC(O)-.

19. The compound of claim 1, wherein R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

20. The compound of claim 1, wherein R1is substituted or unsubstituted 3 to 8 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

21. The compound of claim 1, wherein R1is substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrazinyl.

22. The compound of claim 1, wherein R1is ,-N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R10substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z10 is an integer from 0 to 10; R10A, R10B, R10C, and R10Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X10is independently –F, -Cl, -Br, or –I; n10 is an integer from 0 to 4; and m10 and v10 are independently 1 or 2.

23. The compound of claim 22, wherein R10is 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)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

24. The compound of claim 22, wherein R10is independently substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

25. The compound of claim 22, wherein two R10substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

26. The compound of claim 1, wherein R1is ,-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)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

28. The compound of claim 1, wherein R3is hydrogen or unsubstituted C1- C4 alkyl.

29. The compound of claim 1, wherein R3is hydrogen.

30. The compound of claim 1, wherein R5is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

31. The compound of claim 1, wherein R5is independently unsubstituted C1-C4 alkyl.

32. The compound of claim 1, wherein R5is independently unsubstituted methyl.

33. The compound of claim 1, wherein two R5substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

34. The compound of claim 1, wherein two R5substituents are joined to form an unsubstituted cyclopropyl.

35. The compound of claim 1, having the formula: ,. ound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

37. A method of treating a cancer, an autoimmune disease, or an allergy in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the compound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein the cancer is T-cell lymphoma, T cell leukemia, B cell lymphoma, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, renal cell cancer, or head and neck cancer.

39. The method of claim 37, wherein the autoimmune disease is autoimmune lymphoproliferative disease, colitis, inflammatory bowel disease, systemic lupus erythematosus, atopic dermatitis, systemic sclerosis, or anklylosing spondylitis.

40. The method of claim 37, wherein the allergy is asthma, atopic dermatitis, rhinitis, or psoriasis.

41. A method of treating a subject having deficient Th1 activity, said method comprising administering to the subject the compound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity.

42. The method of claim 41, wherein the subject has increased Th2 activity relative to a control.

43. The method of claim 41, wherein the subject has an increased level of a pro-inflammatory cytokine relative to a control.

44. The method of claim 43, wherein the pro-inflammatory cytokine is IL- 4, IL-5, IL-10, IL-13, or IL-17, or a combination of two or more thereof.

45. The method of claim 41, wherein the effective amount to increase Th1 activity is an amount that: (a) increases the number of Th1+T cells; (b) increases the ratio of Th1+T cells to Th2+T cells; (c) increases the ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells; (d) increases IFNγ production; (e) increases CD8+ cytotoxic lymphocytes; (f) inhibits IL-4 production; (g) inhibits IL-13 production; (h) decreases Th2+ cells; (i) decreases Th17+ T cells; (j) decreases eosinophils; (k) inhibits Th2; (l) inhibits the differentiation of naïve CD4 cells into Th2 cells; or (m) a combination of two or more of (a)-(j).

46. The method of claim 41, wherein the effective amount to increase Th1 activity is an amount that inhibits production of cytokines secreted by Th2+ cells.

47. The method of claim 41, wherein the effective amount to increase Th1 activity is from about 0.6 mmol to about 1.6 mmol of the compound per day.

48. The method of claim 41, wherein the effective amount to increase Th1 activity is from about 0.3 mmol to about 0.8 mmol of the compound twice per day.

49. A method of treating a subject having deficient Th1 activity, said method comprising: (i) measuring increased Th2 activity, an increased level of IL-4, anincreased level of IL-5, an increased level of IL-10, an increased level of IL-13, an increased level of IL-17, a decreased level of IFNγ, a decreased number of Th1+T cells, a decreased ratio of Th1+T cells to Th2+T cells, a decreased ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells, a decreased number CD8+ cytotoxic lymphocytes, an increased number of Th2+ cells, an increased number of Th17+ T cells, an increased number of eosinophils, or any combination of two or morethereof, relative to a control, in a biological sample obtained from the subject; and (ii) administering to the subject the compound of one of claims 1 to 35, ora pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity.

50. The method of claim 49, wherein the subject has increased Th2 activity relative to a control.

51. The method of claim 49, wherein the subject has an increased level of a pro-inflammatory cytokine relative to a control.

52. The method of claim 51, wherein the pro-inflammatory cytokine is IL- 4, IL-5, IL-10, IL-13, or IL-17, or a combination of two or more thereof.

53. The method of claim 49, wherein the effective amount to increase Th1 activity is an amount that: (a) increases the number of Th1+T cells; (b) increases the ratio of Th1+T cells to Th2+T cells; (c) increases the ratio of IFNγ+CD4+T cells to IL-4+CD4+T cells; (d) increases IFNγ production; (e) increases CD8+ cytotoxic lymphocytes; (f) inhibits IL-4 production; (g) inhibits IL-13 production; (h) decreases Th2+ cells; (i) decreases Th17+ T cells; (j) decreases eosinophils; (k) inhibits Th2; (l) inhibits the differentiation of naïve CD4 cells into Th2 cells; or (m) a combination of two or more of (a)-(j).

54. The method of claim 49, wherein the effective amount to increase Th1 activity is an amount that inhibits production of cytokines secreted by Th2+ cells.

55. The method of claim 49, wherein the effective amount to increase Th1 activity is from about 0.6 mmol to about 1.6 mmol of the compound per day.

56. The method of claim 49, wherein the effective amount to increase Th1 activity is from about 0.3 mmol to about 0.8 mmol of the compound twice per day.

57. A method of treating a Th2 / ITK-mediated disease in a subject in need thereof, said method comprising administering to the subject the compound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, at an effective amount to increase Th1 activity.

58. The method of claim 57, wherein the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, an eosinophilic disease, a mast cell disease, or human immunodeficiency viral disease.

59. A method of treating a Th2 / ITK-mediated disease in a subject in need thereof, said method comprising: (i) measuring a decreased level of Th1+ T cells, a decreased ratio of Th1+T cells to Th2+T cells, a decreased ratio of IFNγ+CD4+T cells to IL- 4+CD4+T cells, a decreased level of IFNγ, a decreased level CD8+ cytotoxic lymphocytes, an increased level of Th2+ cells, an increased level of IL-4, an increased level of IL-5, an increased level of IL-10; an increased level of IL-13, an increased level of IL-17, an increased level of Th17+ T cells, an increased level of eosinophils, a decreased level of IL-1β, a decreased level of IL-2, a decreased level of IL-12, a decreased level of TNF-α, a decreased level of TNF-γ, a decreased level of GMCS, or a combination of two or more thereof, relative to a control, in a biological sample obtained from the subject; and (ii) administering to subject a therapeutically effective amount of thecompound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

60. The method of claim 59, wherein the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, an eosinophilic disease, a mast cell disease, or human immunodeficiency viral disease.

61. A method of reducing the level of activity of a TEC kinase, said method comprising contacting the TEC kinase with an effective amount of the compound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

62. A method of reducing the level of activity of an interleukin-2-inducible T-cell kinase, said method comprising contacting the interleukin-2-inducible T-cell kinase with an effective amount of the compound of one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

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