LPAR1 ANTAGONISTS AND USES THEREOF

BACKGROUND

Lysophosphatidic acid, or LPA, is a family of bioactive phospholipids that are associated with multiple cellular functions. While the family members differ with regards to the length and the degree of saturation of their respective long-chain fatty acid backbone (Fujiwara et al., J. Biol. Chem., 2005, 280, 35038-35050), they are all capped by a glycerol-phosphate group through an ester linkage. LPAs are produced biologically from membrane phospholipids through a multi-step cascade mediated by enzymes that include lysophospholipase D (lysoPLD), autotaxin (ATX), phospholipase A1 (PLA1), phospholipase A2 (PLA2) and acylglycerol kinase (AGK) (Mutoh et al., British J Pharmacol., 2012, 165, 829-844). Once formed, the LPAs can regulate numerous cellular signaling pathways by binding to a class of 7-membrane domain G protein-coupled receptors (GPCRs), collectively known as LPA receptors (LPARs), of which six have been characterized: LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 (Choi, J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186). The biological responses elicited by the binding of LPAs to LPARs are both wide-ranging and context-dependent (Yung et al., J. Lipid Res. 2014, 55 1192-1214; Yung et al., Neuron 2015, 85, 669-682). These can include induction of cell proliferation, stimulation of cell migration and contraction, promotion of neurite retraction, suppression of apoptosis, initiation of chemotaxis, closure of gap junction, and others (Chun et al., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley, ISBN: 978-O-470-56905-4). Furthermore, aberrant upregulation of the LPA pathway has been implicated in multiple diseases, including cancer, inflammatory diseases, infertility, neuropathic pain, psychotic and neurodegenerative disorders, atherosclerosis, as well as fibrosis of the skin, kidney, lung, and liver (Choi, J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186; Noguchi et al., Curr. Opin Pharmacol., 2009, 9 15-23; Yanagida et al., J. Biochem., 2011, 150, 223-232). Consequently, the targeting of LPA receptors has been, and continues to be an area of intense interest for the identification of potential treatments for these disorders. Disclosed herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY

In an aspect is provided a compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

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R¹is unsubstituted C₂-C₅alkyl.

W²is N or C(R²).

R²is hydrogen, halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX²₂, —CN, —SO_n2R^2D, —SO_v2NR^2AR^2B, —NR^2CNR^2AR^2B, —ONR^2AR^2B, —NHC(O)NR^2CNR^2AR^2B, —NHC(O)NR^2AR^2B, —N(O)_m2, —NR^2AR^2B, —C(O)R^2C, —C(O)OR^2C, —C(O)NR^2AR^2B, —OR^2D, —SR^2D, —NR^2ASO₂R^2D, —NR^2AC(O)R^2C, —NR^2AC(O)OR^2C, —NR^2AOR^2C, —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.

W⁴is N or C(R⁴).

W⁵is N or C(R⁵).

R²and R³substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R³and R⁴substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁴and 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.

W⁶is N or C(R⁶).

W⁷is N, N⁺—O−⁻, or C(R⁷).

R⁸is independently halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8D, —SO_v8NR^8AR^8B, —NR^8CNR^8AR^8B, —ONR^8AR^8B, —NHC(O)NR^8CNR^8AR^8B, —NHC(O)NR^8AR^8B, —N(O)_m8, —NR^8AR^8B, —C(O)R^8C, —C(O)OR^8C, —C(O)NR^8AR^8B, —OR^8D, —SR^8D, —NR^8ASO₂R^8D, —NR^8AC(O)R^8C, —NR^8AC(O)OR^8C, —NR^8AOR^8C, —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 R⁸substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Z is O, C(R¹¹)(R¹²), or C(O)N(R¹³).

R¹¹and R¹²substituents may optionally be joined to form an oxo, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

R¹³is hydrogen, halogen, —CX¹³₃, —CHX¹³₂, —CH₂X¹³, —OCX¹³₃, —OCH₂X¹³, —OCHX¹³₂, —SO_n13R^13D, —SO_v13NR^13AR^13B, —C(O)R^13C, —C(O)OR^13C, —C(O)NR^13AR^13B, —OR^13D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R^2A, R^2B, R^2C, R^2D, R^3A, R^3B, R^3C, R^3D, R^4A, R^4B, R^4C, R^4D, R^5A, R^5B, R^5C, R^5D, R^6AR^6B, R^6C, R^6D, R^7A, R^7B, R^7C, R^7D, R^8A, R^8B, R^8C, R^8D, R^11A, R^11B, R^11C, R^11D, R^12A, R^12B, R^12CR^12D, R^13A, R^13B, R^13C, and R^13Dare 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; R^2Aand R^2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^3Aand R^3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^4Aand R^4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^5Aand R^5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^6Aand R^6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^7Aand R^7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^8Aand R^8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^11Aand R^11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^12Aand R^12Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^13Aand R^13Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, X¹¹, X¹², and X¹³are independently —F, —Cl, —Br, or —I.

The symbols n2, n3, n4, n5, n6, n7, n8, n1l, n12, and n13 are independently an integer from 0 to 4. The symbols m2, m3, m4, m5, m6, m7, m8, m11, m12, v2, v3, v4, v5, v6, v7, v8, v11, v12, and v13 are independently 1 or 2.

The symbol z8 is an integer from 0 to 3.

The symbol p is 1 or 2. The symbol q is 1 or 2.

In an aspect is provided a compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

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W², R³, W⁴, W⁵, W⁶, W⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments. At least one of W⁶or W⁷is N. If W⁶is N and W⁷is C(R⁷), then R¹⁰is not hydrogen, —F, —Cl, —CH₃, or —OCH₃. If W⁶is C(R⁶) and W⁷is N, then R¹⁰is not hydrogen, —F, —Cl, —CH₃or —OCH₃. If W⁶and W⁷are N and Z is 0 or CH₂, then R¹⁰is not hydrogen, —F, —Cl, —CH₃or —OCH₃.

R¹⁰and R²substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

X¹⁰is independently —F, —Cl, —Br, or —I.

The symbol n10 is an integer from 0 to 4. The symbols m10 and v10 are independently 1 or 2.

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

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

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 in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

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

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

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

In an aspect is provided a method of treating an LPAR1-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

In an aspect is provided a method of modulating LPAR1 activity in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

DETAILED DESCRIPTION
I. Definitions

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.

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—.

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. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

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.

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 optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

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

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.

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.

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.

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.

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.

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.

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-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be —O— bonded to a ring heteroatom nitrogen.

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 spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

Bridged rings are two or more rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. Individual rings in bridged rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of bridged rings. Possible substituents for individual rings within bridged rings are the possible substituents for the same ring when not part of bridged rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Bridged 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 bridged 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 bridged ring system, heterocyclic bridged rings means bridged rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a bridged ring system, substituted bridged rings means that at least one ring is substituted and each substituent may optionally be different.

The symbol “ custom-character ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

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

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:

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An alkylarylene moiety may be substituted (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.

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.

Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′C(O)NR″R″′, —NR″C(O)₂R′, —NRC(NR′R″R″′)═NR″″, —NRC(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″, —NR′C(O)NR″NR″′ R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′OR″, in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R, R′, R″, R″′, and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R″′, and R″″ group when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

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.

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

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.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)—(CRR′)_q—U—, wherein T and U are independently —NR—, —O—, —CRR′—, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)_s—X′— (C″R″R″′)_d—, where s and d are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″, and R″′ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

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

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-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-C₁₀aryl, C₁₀aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
  - (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-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-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
  - (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-C₁₀aryl, C₁₀aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
    - (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-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-C₁₀aryl, C₁₀aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, or C₅-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).

A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, 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 each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

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-C₇cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

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.

In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₂₀alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-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.

In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

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

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.

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.

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.

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 R^1.1, R²may be substituted with one or more first substituent groups denoted by R^2.1, R³may be substituted with one or more first substituent groups denoted by R^3.1, R⁴may be substituted with one or more first substituent groups denoted by R^4.1, R⁵may be substituted with one or more first substituent groups denoted by R^5.1, and the like up to or exceeding an R¹⁰⁰that may be substituted with one or more first substituent groups denoted by R^100.1. As a further example, R^1Amay be substituted with one or more first substituent groups denoted by R^1A.1, R^2Amay be substituted with one or more first substituent groups denoted by R^2A.1, R^3Amay be substituted with one or more first substituent groups denoted by R^3A.1, R^4Amay be substituted with one or more first substituent groups denoted by R^4A.1, R^5Amay be substituted with one or more first substituent groups denoted by R^5A.1and the like up to or exceeding an R^100Amay be substituted with one or more first substituent groups denoted by R^100A.1. As a further example, L¹may be substituted with one or more first substituent groups denoted by R^L1.1, L²may be substituted with one or more first substituent groups denoted by R^L2.1, L³may be substituted with one or more first substituent groups denoted by R^L3.1L⁴may be substituted with one or more first substituent groups denoted by R^L4.1, L⁵may be substituted with one or more first substituent groups denoted by R^L5.1and the like up to or exceeding an L¹⁰⁰which may be substituted with one or more first substituent groups denoted by R^L100.1. Thus, each numbered R group or L group (alternatively referred to herein as R^WWor L^WWwherein “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 R^WW.1or R^LWW.1respectively. In turn, each first substituent group (e.g., R^1.1, R^2.1, R^3.1, R^4.1, R_5.1. . . R^100.1; R^1A.1, R^2A.1, R^3A.1, R^4A.1, R^5A.1. . . R^100A.1; R^L1.1, R^L2.1, R^L3.1, R^L4.1, R^L5.1. . . R^L100.1) may be further substituted with one or more second substituent groups (e.g., R^1.2, R^2.2, R^3.2, R^4.2, R^5.2. . . R^100.2; R^1A.2, R^2A.2, R^3A.2, R^4A.2, R^5A.2. . . R^100A.2; R^L1.2, R^L2.2, R^L3.2, R^L4.2, R^L5.2. . . R^L100.2, respectively). Thus, each first substituent group, which may alternatively be represented herein as R^WW.1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R^WW.2.

Finally, each second substituent group (e.g., R^1.2, R^2.2, R^3.2, R^4.2, R^5.2. . . R^100.2; R^1A.2, R^2A.2, R^3A.2, R^4A.2, R^5A.2. . . R^100A.2; R^L1.2, R^L2.2, R^L3.2, R^L4.2, R^L5.2. . . R^L100.2) may be further substituted with one or more third substituent groups (e.g., R^1.3, R^2.3, R^3.3, R^4.3, R^5.3. . . R^100.3; R^1A.3, R^2A.3, R^3A.3, R^4A.3, R^5A.3. . . R^100A.3; R^L1.3, R^L2.3, R^L3.3, R^L4.3, R^L5.3. . . R^L100.3; respectively). Thus, each second substituent group, which may alternatively be represented herein as R^WW.2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R^WW.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.

Thus, as used herein, R^WWrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, L^WWis 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 R^WWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^WW.1; each first substituent group, R^WW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^WW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^WW.3. Similarly, each L^WWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^LWW.1; each first substituent group, R^LWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^LWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^LWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if R^WWis phenyl, the said phenyl group is optionally substituted by one or more R^WW.1groups as defined herein below, e.g., when R^WW.1is R^WW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R^WW.2, which R^WW.2is optionally substituted by one or more R^WW.3. By way of example when the R^WWgroup is phenyl substituted by R^WW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to:

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R^WW.1is independently oxo, halogen, —CX^WW1₃, —CHX^WW.1₂, —CH₂X^WW.1, —OCX^WW.1₃, —OCH₂X^WW.1, —OCHX^WW.1₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, R^WW.2-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^WW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^WW.2-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^WW.2-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^WW.1is independently oxo, halogen, —CX^WW.1₃, —CHX^WW.1₂, —CH₂X^WW.1, —OCX^WW.1₃, —OCH₂X^WW.1, —OCHX^WW.1₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 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). X^WW.1is independently —F, —Cl, —Br, or —I.

R^WW.2is independently oxo, halogen, —CX^WW.2₃, —CHX^WW.2₂, —CH₂X^WW.2, —OCX^WW.2₃, —OCH₂X^WW.2, —OCHX^WW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, R^WW.3-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^WW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^WW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^WW.2is independently oxo, halogen, —CX^WW.2₃, —CHX^WW.2₂, —CH₂X^WW.2, —OCX^WW.2₃, —OCH₂X^WW.2, —OCHX^WW.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). X^WW.2is independently —F, —Cl, —Br, or —I.

R^WW.3is independently oxo, halogen, —CX^WW.3₃, —CHX^WW.3₂, —CH₂X^WW.3, —OCX^WW.3₃, —OCH₂X^WW.3, —OCHX^WW.3₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 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). X^WW.3is independently —F, —Cl, —Br, or —I.

Where two different R^WWsubstituents 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 R^WW.1; each first substituent group, R^WW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^WW.2; and each second substituent group, R^WW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^WW.3; and each third substituent group, R^WW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different R^WWsubstituents joined together to form an openly substituted ring, the “WW” symbol in the R^WW.1, R^WW.2and R^WW.3refers to the designated number of one of the two different R^WWsubstituents. For example, in embodiments where R^100Aand R^100Bare optionally joined together to form an openly substituted ring, R^WW.1is R^100A.1, R^WW.2is R^100A.2, and R^WW.3is R^100A.3. Alternatively, in embodiments where R^100Aand R^100Bare optionally joined together to form an openly substituted ring, R^WW.1is R^100A.1, R^WW.2is R^100B.2, and R^WW.3is R^100B.3. R^WW.1, R^WW.2and R^WW.3in this paragraph are as defined in the preceding paragraphs.

R^LWW.1is independently oxo, halogen, —CX^LWW.1₃, —CHX^LWW.1₂, —CH₂X^LWW.1, —OCX^LWW.1₃, —OCH₂X^LWW.1, —OCHX^LWW.1₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, R^LWW.2-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^LWW.2-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^LWW.2-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^LWW.1is independently oxo, halogen, —CX^LWW.1₃, —CHX^LWW.1₂, —CH₂X^LWW.1, —OCX^LWW.1₃, —OCH₂X^LWW.1, —OCHX^LWW.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). X^LWW.1is independently —F, —Cl, —Br, or —I.

R^LWW.2is independently oxo, halogen, —CX^LWW.2₃, —CHX^LWW.2₂, —CH₂X^LWW.2, —OCX^LWW.2₃, —OCH₂X^LWW.2, —OCHX^LWW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, R^LWW.3-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^LWW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^LWW.2is independently oxo, halogen, —CX^LWW.2₃, —CHX^LWW.2₂, —CH₂X^LWW.2, —OCX^LWW.2₃, —OCH₂X^LWW.2, —OCHX^LWW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, 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). X^LWW.2is independently —F, —Cl, —Br, or —I.

R^LWW.3is independently oxo, halogen, —CX^LWW.3₃, —CHX^LWW.3₂, —CH₂X^LWW.3, —OCX^LWW.3₃, —OCH₂X^LWW.3, —OCHX^LWW.3₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 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). X^LWW.3is independently —F, —Cl, —Br, or —I.

In the event that any R group recited in a claim or chemical formula description set forth herein (R^WWsubstituent) is not specifically defined in this disclosure, then that R group (R^WWgroup) is hereby defined as independently oxo, halogen, —CX^WW₃, —CHX^WW₂, —CH₂X^WW, —OCX^WW₃, —OCH₂X^WW, —OCHX^WW₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, R^WW.1-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^WW.1-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^WW.1-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^WW.1-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^WWis 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.). R^WW.1, R^WW.2, and R^WW.3are as defined above.

In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an L^WWsubstituent) is not explicitly defined, then that L group (L^WWgroup) 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—, R^LWW.1-substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW.1_substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^LWW.1-substituted or unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^LWW.1-substituted or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.1-substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R^LWW.1, as well as R^LWW.2and R^LWW.3are as defined above.

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.

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.

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.

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.

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.

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 by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure.

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.

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.

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).

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 to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin-biotin complex or streptavidin-biotin complex.

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.

“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.

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-C₂₀alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³substituents are present, each R¹³substituent may be distinguished as R^13.A, R^13.B, R^13.C, R^13.D, etc., wherein each of R^13.A, R^13.B, R^13.C, R^13.D, etc. is defined within the scope of the definition of R¹³and optionally differently.

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.

The term “protecting group” is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group. Typically a protecting group is bound to a heteroatom (e.g., O) during a part of a multipart synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with the reagent. Following protection the protecting group may be removed (e.g., by modulating the pH). In embodiments the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS)). In embodiments the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), and tosyl (Ts).

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.

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.

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.

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.

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.

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

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.

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

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).

“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).

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

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.

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.

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.

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

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.

The term “lysophosphatidic acid receptor 1 antagonist” or “LPAR1 antagonist” refers to any exogenously administered compound or agent that is capable of partially or completely inhibiting, or reversing, the effect of an agonist (e.g., lysophosphatidic acid) on the LPAR1 receptor. The term is inclusive of compounds or agents characterized or described as antagonists, partial antagonists, and negative allosteric modulators.

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.

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.).

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.

“Patient” 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 some embodiments, a patient is human.

“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 neurodegenerative disease. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is post-hemorrhagic encephalitis. In embodiments, the disease is a demyelinating disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is a fibrotic disease. In embodiments, the disease is pulmonary fibrosis. In embodiments, the disease is idiopathic pulmonary fibrosis. In embodiments, the disease is a cancer. In embodiments, the disease is glioblastoma.

As used herein, the term “neurodegenerative disease” refers to a disease or condition in which the function of a subject's nervous system becomes impaired. Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, or Tabes dorsalis.

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, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

As used herein, the term “demyelinating disease” refers to any disease or condition characterized by damage to the protective covering (e.g., myelin sheath) that surrounds nerve fibers (e.g., in the brain, optic nerves, or spinal cord). In embodiments, the demyelinating disease is a demyelinating disease of the central nervous system. In embodiments, the demyelinating disease is multiple sclerosis. In embodiments, the demyelinating disease is a demyelinating disease of the peripheral nervous system.

As used herein, the terms “fibrotic disease” and “fibrosis” refer to any disease or condition characterized by the formation of excess fibrous connective tissue. The formation of excess fibrous connective tissue may be in response to a reparative or reactive process. Fibrotic diseases include but are not limited to pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), liver fibrosis (e.g., nonalcoholic steatohepatitis (NASH)), myelofibrosis, skin fibrosis (e.g., scleroderma), ocular fibrosis, mediastinal fibrosis, cardiac fibrosis, kidney fibrosis, stromal fibrosis, epidural fibrosis, epithelial fibrosis, or idiopathic fibrosis.

As used herein, the term “cardiovascular disorder” or “cardiovascular disease” is used in accordance with its plain ordinary meaning. In embodiments, cardiovascular diseases that may be treated with a compound, pharmaceutical composition, or method described herein include, but are not limited to, stroke, heart failure, hypertension, hypertensive heart disease, myocardial infarction, angina pectoris, tachycardia, cardiomyopathy, rheumatic heart disease, cardiomyopathy, heart arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.

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

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

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.

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.

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

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.

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

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

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

As used herein, the term “LPAR1-associated disease” refers to any disease or condition caused by aberrant activity or signaling of LPAR1. In embodiments, the LPAR1-associated disease is a neurodegenerative disease. In embodiments, the LPAR1-associated disease is an inflammatory disease. In embodiments, the LPAR1-associated disease is post-hemorrhagic encephalitis. In embodiments, the LPAR1-associated disease is a demyelinating disease. In embodiments, the LPAR1-associated disease is multiple sclerosis. In embodiments, the LPAR1-associated disease is a fibrotic disease. In embodiments, the LPAR1-associated disease is pulmonary fibrosis. In embodiments, the LPAR1-associated disease is idiopathic pulmonary fibrosis. In embodiments, the LPAR1-associated disease is a cancer. In embodiments, the LPAR1-associated disease is glioblastoma.

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

A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include ¹⁸F, ³²P ³³P, ⁴⁵Ti, ⁴⁷Sc, ^5.2Fe, 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, ^154-1581Gd, 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.

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, ^5.2Fe, 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, ^154-1581Gd ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁶⁹Er, ¹⁷⁵Lu, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹⁴r ¹⁹⁸Au, ¹⁹⁹Au, ²¹¹At, ²¹¹Pb, ²¹²Bi, ²¹²Pb, ²¹³Bi, ²²³Ra and ²²⁵Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

“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.

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.

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.

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

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.

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.

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., multiple sclerosis, fibrotic disease, encephalitis, or cancer) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

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., multiple sclerosis, fibrotic disease, encephalitis, or cancer) 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.

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

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

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 a 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.

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.

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

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.

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.

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.

The term “lysophosphatidic acid receptor” or “LPAR” refers to one or more of the family of G protein-coupled receptors for lysophosphatidic acid (LPA). In embodiments, LPAR includes LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6.

The term “lysophosphatidic acid receptor 1” or “LPAR1” refers to a G protein-coupled receptor (including homologs, isoforms, and functional fragments thereof) that binds the lipid signaling molecule lysophosphatidic acid (LPA). The term includes any recombinant or naturally-occurring form of LPAR1 variants thereof that maintain LPAR1 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype LPAR1). In embodiments, the LPAR1 protein encoded by the LPAR1 gene has the amino acid sequence set forth in or corresponding to Entrez 1902, UniProt Q92633, RefSeq (protein) NP_001392.2 or RefSeq (protein) NP 476500.1. In embodiments, the LPAR1 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_001401.3 or RefSeq (mRNA) NM_057159.2. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

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 lysophosphatidic acid receptor 1 (LPAR1) would preferentially inhibit LPAR1 over other lysophosphatidic acid receptors). In embodiments, an “lysophosphatidic acid receptor 1 selective compound” or “LPAR1-selective compound” refers to a compound (e.g., compound described herein) having selectivity towards lysophosphatidic acid receptor 1 (LPAR1). 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 lysophosphatidic acid receptor 1 (LPAR1) over one or more of LPAR2, LPAR3, LPAR4, LPAR5, or LPAR6. 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 lysophosphatidic acid receptor 1 (LPAR1) over one or more of LPAR2, LPAR3, LPAR4, LPAR5, or LPAR6.

II. Compounds

In an aspect is provided a compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

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- R¹is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).
- W²is N or C(R²).
- R²is hydrogen, halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX²₂, —CN, —SO_n2R^2D, —SO_v2NR^2AR^2B, —NR^2CNR^2AR^2B, —ONR^2AR^2B, —NHC(O)NR^2CNR^2AR^2B, —NHC(O)NR^2AR^2B, —N(O)_m2, —NR^2AR^2B, —C(O)R^2C, —C(O)OR^2C, —C(O)NR^2AR^2B, —OR^2D, —SR^2D, —NR^2ASO₂R^2D, —NR^2AC(O)R^2C, —NR^2AC(O)OR^2C, —NR^2AOR^2C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³is hydrogen, halogen, —CX³₃, —CHX³₂, —CH₂X³, —OCX³₃, —OCH₂X³, —OCHX³₂, —CN, —SO_n3R^3D, —SO_v3NR^3AR^3B, —NR^3CNR^3AR^3B, —ONR^3AR^3B, —NHC(O)NR^3CNR^3AR^3B, —NHC(O)NR^3AR^3B, —N(O)_m3, —NR^3AR^3B, —C(O)R^3C, —C(O)OR^3C, —C(O)NR^3AR^3B, —OR^3D, —SR^3D, —NR^3ASO₂R^3D, —NR^3AC(O)R^3C, —NR^3AC(O)OR^3C, —NR^3AOR^3C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

W⁴is N or C(R⁴).

R⁴is hydrogen, halogen, —CX⁴₃, —CHX⁴₂, —CH₂X⁴, —OCX⁴₃, —OCH₂X⁴, —OCHX⁴₂, —CN, —SO_n4R^4D, —SO_v4NR^4AR^4B, —NR^4CNR^4AR^4B, —ONR^4AR^4B, —NHC(O)NR^4CNR^4AR^4B, —NHC(O)NR^4AR^4B, —N(O)_m4, —N^4AR^4B, —C(O)R^4C, —C(O)OR^4C, —C(O)NR^4AR^4B, —OR^4D, —SR^4D, —NR^4ASO₂R^4D—NR^4AC(O)R^4C, —NR^4AC(O)OR^4C, —NR^4AOR^4C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

W⁵is N or C(R⁵).

R⁵is hydrogen, halogen, —CX⁵₃, —CHX⁵₂, —CH₂X⁵, —OCX⁵₃, —OCH₂X⁵, —OCHX⁵₂, —CN, —SO_n5R^5D, —SO_v5NR^5AR^5B, —N^5CNR^5AR^5B, —ONR^5AR^5B, —NHC(O)NR^5CNR^5AR^5B, —NHC(O)NR^5AR^5B, —N(O)_m5, —NR^5AR^5B, —C(O)R^5C, —C(O)OR^5C, —C(O)NR^5AR^5B, —OR^5D, —SR^5D, —NR^5ASO₂R^5D, —NR^5AC(O)R^5C, —NR^5AC(O)OR^5C, —NR^5AOR^5C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R²and R³substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³and R⁴substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴and R⁵substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

W⁶is N or C(R⁶).

R⁶is hydrogen, halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, —OCHX⁶₂, —CN, —SO_n6R^6D, —SO_v6NR^6AR^6B, —NR^6CNR^6AR^6B, —ONR^6AR^6B, —NHC(O)NR^6CNR^6AR^6B, —NHC(O)NR^6AR^6B, —N(O)_m6, —NR^6AR^6B, —C(O)R^6C, —C(O)OR^6C, —C(O)NR^6AR^6B, —OR^6D, —SR^6D, —NR^6ASO₂R^6D, —NR^6AC(O)R^6C, —NR^6AC(O)OR^6C, —NR^6AOR^6C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

W⁷is N, N⁺—O−⁻, or C(R⁷).

R⁷is hydrogen, halogen, —CX⁷₃, —CHX⁷₂, —CH₂X⁷, —OCX⁷₃, —OCH₂X⁷, —OCHX⁷₂, —CN, —SO_n7R^7D, —SO_v7NR^7AR^7B, —NR^7CNR^7AR^7B, —ONR^7AR^7B, —NHC(O)NR^7CNR^7AR^7B, —NHC(O)NR^7AR^7B, —N(O)_m7, —N^7AR^7B, —C(O)R^7C, —C(O)OR^7C, —C(O)NR^7AR^7B, —OR^7D, —SR^7D, —NR^7ASO₂R^7D, —NR^7AC(O)R^7C, —NR^7AC(O)OR^7C, —NR^7AOR^7C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁸is independently halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SOng₈R^8D, —SO_v8NR^8AR^8B, —NR^8CNR^8AR^8B, —ONR^8AR^8B, —NHC(O)NR^8CNR^8AR^8B, —NHC(O)NR^8AR^8B, —N(O)_m8, —NR^8AR^8B, —C(O)R^8C, —C(O)OR^8C, —C(O)NR^8AR^8B, —OR^8D, —SR^8D, —NR^8ASO₂R^8D, —NR^8AC(O)R^8C, —NR^8AC(O)OR^8C, —NR^8AOR^8C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R⁸substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

Z is O, C(R¹¹)(R¹²), or C(O)N(R¹³).

R¹¹is hydrogen, halogen, —CX¹¹₃, —CHX¹¹₂, —CH₂X¹¹, —OCX¹¹₃, —OCH₂X¹¹, —OCHX¹¹₂, —CN, —SO_n11R^11D, —SO_v11NR^11AR^11B, —NR^11CNR^11AR^11B, —ONR^11AR^11B, —NHC(O)NR^11CNR^11AR^11B, —NHC(O)NR^11AR^11B, —N(O)_m11, —NR¹AR^11B, —C(O)R^11C, —C(O)OR^11C, —C(O)NR^11AR^11B, —OR^11D, —SR^11D, —NR^11ASO₂R^11D, —NR^11AC(O)R^11C, —NR^11AC(O)OR^11C, —NR^11AOR^11C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹²is hydrogen, halogen, —CX¹²₃, —CHX¹²₂, —CH₂X¹², —OCX¹²₃, —OCH₂X¹², —OCHX¹²₂, —CN, —SO_n12R^12D, —SO_v12NR^12AR^12B, —NR^12CNR^12AR^12B, —ONR^12AR^12B, —NHC(O)NR^12CNR^12AR^12B, —NHC(O)NR^12AR^12B, —N(O)_m12, —NR^12AR^12B, —C(O)R^12C, —C(O)OR^12C, —C(O)NR^12AR^12B, —OR^12D, —SR^12D, —NR^12ASO₂R^12D, —NR^12AC(O)R^12C, —NR^12AC(O)OR^12C, —NR^12AOR^12C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹¹and R¹²substituents may optionally be joined to form an oxo, substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), or 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).

R¹³is hydrogen, halogen, —CX¹³₃, —CHX¹³₂, —CH₂X¹³, —OCX¹³₃, —OCH₂X¹³, —OCHX¹³₂, —SO_n13R^13D, —SO_v13NR^13AR^13B, —C(O)R^13C, —C(O)OR^13C, —C(O)NR^13AR^13B, —OR^13D, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^2A, R^2B, R^2C, R^2D, R^3A, R^3B, R^3C, R^3D, R^4A, R^4B, R^4C, R^4D, R^5A, R^5B, R^5C, R^5D, R^6AR^6B, R^6C, R^6D, R^7A, R^7B, R^7C, R^7D, R^8A, R^8B, Rsc, R^8D, R^11A, R^11B, R^11C, R^11D, R^12A, R^12B, R^12C, R^12D, R^13A, R^13B, R^13C, and R^13Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^2Aand R^2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^3Aand R^3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^4Aand R^4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^5Aand R^5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^6Aand R^6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^7Aand R^7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^8Aand R^8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^11Aand R^11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^12Aand R^12Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^13Band R^13Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, X¹¹, X¹², and X¹³are independently —F, —Cl, —Br, or —I.

The symbols n2, n3, n4, n5, n6, n7, n8, n1l, n12, and n13 are independently an integer from 0 to 4.

The symbols m2, m3, m4, m5, m6, m7, m8, m11, m12, v2, v3, v4, v5, v6, v7, v8, v11, v12, and v13 are independently 1 or 2.

The symbol z8 is an integer from 0 to 3.

The symbol p is 1 or 2.

The symbol q is 1 or 2.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R¹, R⁶, R⁷, R⁸, z8, Z, p, and q are as described herein, including in embodiments.

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

In embodiments, R¹is unsubstituted alkyl. In embodiments, R¹is unsubstituted C₂-C₅alkyl. In embodiments, R¹is unsubstituted C₂alkyl. In embodiments, R¹is unsubstituted ethyl. In embodiments, R¹is unsubstituted C₃alkyl. In embodiments, R¹is unsubstituted propyl. In embodiments, R¹is unsubstituted n-propyl. In embodiments, R¹is unsubstituted isopropyl (i.e., isopropyl). In embodiments, R¹is unsubstituted C₄alkyl. 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 unsubstituted C₅alkyl. In embodiments, R¹is unsubstituted pentyl. In embodiments, R¹is unsubstituted n-pentyl. In embodiments, R¹is unsubstituted tert-pentyl. In embodiments, R¹is unsubstituted neopentyl. In embodiments, R¹is unsubstituted isopentyl. In embodiments, R¹is unsubstituted sec-pentyl. In embodiments, R¹is unsubstituted 3-pentyl. In embodiments, R¹is unsubstituted sec-isopentyl. In embodiments, R¹is unsubstituted 2-methylbutyl.

In an aspect is provided a compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

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R¹⁰is hydrogen, halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)OR^10C, —C(O)NR^10AR^10B, —OR^10D, —SR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁰and R²substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

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

X¹⁰is independently —F, —Cl, —Br, or —I.

The symbol n10 is an integer from 0 to 4.

The symbols m10 and v10 are independently 1 or 2.

In embodiments, the compound has the formula:

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R², R³, R⁴, W⁵, R⁶, R⁸, z8, R¹⁰, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R², R³, R⁴, W⁵, R⁷, R⁸, z8, R¹⁰, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R², R³, R⁴, W⁵, R⁸, z8, R¹⁰, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R⁶, R⁸, z8, R¹⁰, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R⁶, R⁸, z8, R¹⁰, Z, p, and q are as described herein, including in embodiments.

In embodiments, the compound has the formula:

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R⁶, R⁸, z8, R¹⁰, Z, p, and q are as described herein, including in embodiments.

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.

In embodiments, a substituted R^10A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^10Ais 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 R^10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^10Bis 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 R^10Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^10Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^10Cis 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 R^10Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^10Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^10Dis 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 R^10Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^10Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹⁰is hydrogen, halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NHC(O)NR^10AR^10B, —NR^10AR^10B, —C(O)R^10C, —C(O)OR^10C, —C(O)NR^10AR^10B, —OR^10D, —SR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R¹⁰is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R¹⁰is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R¹⁰is hydrogen, —CHF₂, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹⁰is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R¹⁰is hydrogen. In embodiments, R¹⁰is unsubstituted C₁alkyl. In embodiments, R¹⁰is unsubstituted methyl. In embodiments, R¹⁰is unsubstituted C₂alkyl. In embodiments, R¹⁰is unsubstituted ethyl. In embodiments, R¹⁰is unsubstituted C₃alkyl. In embodiments, R¹⁰is unsubstituted propyl. In embodiments, R¹⁰is unsubstituted n-propyl. In embodiments, R¹⁰is unsubstituted isopropyl (i.e., isopropyl). In embodiments, R¹⁰is unsubstituted C₄alkyl. In embodiments, R¹⁰is unsubstituted butyl. In embodiments, R¹⁰is unsubstituted n-butyl. In embodiments, R¹⁰is unsubstituted isobutyl. In embodiments, R¹⁰is unsubstituted tert-butyl. In embodiments, R¹⁰is unsubstituted C₅alkyl. In embodiments, R¹⁰is unsubstituted pentyl. In embodiments, R¹⁰is unsubstituted n-pentyl. In embodiments, R¹⁰is unsubstituted tert-pentyl. In embodiments, R¹⁰is unsubstituted neopentyl. In embodiments, R¹⁰is unsubstituted isopentyl. In embodiments, R¹⁰is unsubstituted sec-pentyl. In embodiments, R¹⁰is unsubstituted 3-pentyl. In embodiments, R¹⁰is unsubstituted sec-isopentyl. In embodiments, R¹⁰is unsubstituted 2-methylbutyl. In embodiments, R¹⁰is unsubstituted C₆alkyl. In embodiments, R¹⁰is unsubstituted hexyl.

In embodiments, W²is N. In embodiments, W²is C(R²). In embodiments, W²is CH.

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

In embodiments, a substituted R^2A(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 R^2Ais 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 R^2Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^2Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^2B(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 R^2Bis 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 R^2Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^2Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^2Aand R^2Bsubstituents 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 R^2Aand R^2Bsubstituents 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 R^2Aand R^2Bsubstituents 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 R^2Aand R^2Bsubstituents 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 R^2Aand R^2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^2C(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 R^2Cis 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 R^2Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^2Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^2D(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 R^2Dis 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 R^2Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^2Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R²is hydrogen, halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX²₂, —CN, —SO_n2R^2D, —SO_v2NR^2AR^2B, —NHC(O)NR^2AR^2B, —NR^2AR^2B, —C(O)R^2C, —C(O)OR^2C, —C(O)NR^2AR^2B, —OR^2D, —SR^2D, —NR^2ASO₂R^2D, —NR^2AC(O)R^2C, —NR^2AC(O)OR^2C, —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.

In embodiments, R²is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R²is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R²is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R²is hydrogen. 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. In embodiments, R²is unsubstituted pentyl. In embodiments, R²is unsubstituted hexyl.

In embodiments, a substituted ring formed when R¹⁰and R²substituents 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 R¹⁰and R²substituents 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 R¹⁰and R²substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R¹⁰and R²substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R¹⁰and R²substituents are joined is substituted, it is substituted with at least one lower substituent group.

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

In embodiments, a substituted R^3A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^3Ais 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 R^3Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^3Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^3B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^3Bis 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 R^3Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^3Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^3Aand R^3Bsubstituents 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 R^3Aand R^3Bsubstituents 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 R^3Aand R^3Bsubstituents 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 R^3Aand R^3Bsubstituents 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 R^3Aand R^3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^3C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^3Cis 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 R^3Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^3Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^3D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R^3Dis 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 R^3Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^3Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R³is hydrogen, halogen, —CX³₃, —CHX³₂, —CH₂X³, —OCX³₃, —OCH₂X³, —OCHX³₂, —CN, —SO_n3R^3D, —SO_v3NR^3AR^3B, —NHC(O)NR^3AR^3B, —NR^3AR^3B, —C(O)R^3C, —C(O)OR^3C, —C(O)NR^3AR^3B, —OR^3D, —SR^3D, —NR^3ASO₂R^3D, —NR^3AC(O)R^3C, —NR^3AC(O)OR^3C, —SF₅, —N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R³is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R³is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R³is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R³is hydrogen. 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 pentyl. In embodiments, R³is unsubstituted hexyl.

In embodiments, a substituted ring formed when R²and R³substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R²and R³substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R²and R³substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R²and R³substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R²and R³substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, W⁴is N. In embodiments, W⁴is C(R⁴). In embodiments, W⁴is CH.

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

In embodiments, a substituted R^4A(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 R^4Ais 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 R^4Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^4Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4B(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 R^4Bis 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 R^4Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^4Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^4Aand R^4Bsubstituents 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 R^4Aand R^4Bsubstituents 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 R^4Aand R^4Bsubstituents 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 R^4Aand R^4Bsubstituents 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 R^4Aand R^4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4C(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 R^4Cis 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 R^4Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^4Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4D(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 R^4Dis 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 R^4Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^4Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁴is hydrogen, halogen, —CX⁴₃, —CHX⁴₂, —CH₂X⁴, —OCX⁴₃, —OCH₂X⁴, —OCHX⁴₂, —CN, —SO_n4R^4D, —SO_v4NR^4AR^4B, —NHC(O)NR^4AR^4B, —N^4AR^4B, —C(O)R^4C, —C(O)OR^4C, —C(O)NR^4AR^4B, —OR^4D, —SR^4D, —NR^4ASO₂R^4D, —NR^4AC(O)R^4C, —NR^4AC(O)OR^4C, —SF₅, —N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁴is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R⁴is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R⁴is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R⁴is hydrogen. In embodiments, R⁴is unsubstituted methyl. In embodiments, R⁴is unsubstituted ethyl. In embodiments, R⁴is unsubstituted propyl. In embodiments, R⁴is unsubstituted n-propyl. In embodiments, R⁴is unsubstituted isopropyl. In embodiments, R⁴is unsubstituted butyl. In embodiments, R⁴is unsubstituted n-butyl. In embodiments, R⁴is unsubstituted isobutyl. In embodiments, R⁴is unsubstituted tert-butyl. In embodiments, R⁴is unsubstituted pentyl. In embodiments, R⁴is unsubstituted hexyl.

In embodiments, a substituted ring formed when R³and R⁴substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R³and R⁴substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R³and R⁴substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R³and R⁴substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R³and R⁴substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, W⁵is N. In embodiments, W⁵is C(R⁵). In embodiments, W⁵is CH.

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.

In embodiments, a substituted R^5A(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 R^5Ais 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 R^5Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^5Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^5B(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 R^5Bis 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 R^5Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^5Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^5Aand R^5Bsubstituents 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 R^5Aand R^5.1substituents 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 R^5Aand R^5Bsubstituents 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 R^5Aand R^5Bsubstituents 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 R^5Aand R^5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^5C(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 R^5Cis 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 R^5Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^5Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^5D(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 R^5Dis 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 R^5Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^5Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁵is hydrogen, halogen, —CX⁵₃, —CHX⁵₂, —CH₂X⁵, —OCX⁵₃, —OCH₂X⁵, —OCHX⁵₂, —CN, —SO_n5R^5D, —SO_v5NR^5AR^5B, —NHC(O)NR^5AR^5B, —NR^5AR^5B, —C(O)R^5C, —C(O)OR^5C, —C(O)NR^5AR^5B, —OR^5D, —SR^5D, —NR^5ASO_2R^5D, —NR^5AC(O)R^5C, —NR^5AC(O)OR^5C, —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.

In embodiments, R⁵is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R⁵is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R⁵is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R⁵is hydrogen. In embodiments, R⁵is unsubstituted methyl. In embodiments, R⁵is unsubstituted ethyl. In embodiments, R⁵is unsubstituted propyl. In embodiments, R⁵is unsubstituted n-propyl. In embodiments, R⁵is unsubstituted isopropyl. In embodiments, R⁵is unsubstituted butyl. In embodiments, R⁵is unsubstituted n-butyl. In embodiments, R⁵is unsubstituted isobutyl. In embodiments, R⁵is unsubstituted tert-butyl. In embodiments, R⁵is unsubstituted pentyl. In embodiments, R⁵is unsubstituted hexyl.

In embodiments, a substituted ring formed when R⁴and 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 R⁴and 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 R⁴and R⁵substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R⁴and R⁵substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R⁴and R⁵substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, W⁶is N. In embodiments, W⁶is C(R⁶). In embodiments, W⁶is CH.

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

In embodiments, a substituted R^6A(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 R^6Ais 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 R^6Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^6Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^6B(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 R^6Bis 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 R^6Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^6Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^6Aand R^6Bsubstituents 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 R^6Aand R^6Bsubstituents 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 R^6Aand R^6B, substituents 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 R^6Aand R^6Bsubstituents 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 R^6Aand R^6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^6C(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 R^6Cis 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 R^6Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^6Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^6D(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 R^6Dis 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 R^6Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^6Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁶is hydrogen, halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, —OCHX⁶₂, —CN, —SO_n6R^6D, —SO_v6NR^6AR^6B, —NHC(O)NR^6AR^6B, —NR^6AR^6B, —C(O)R^6C, —C(O)OR^6C, —C(O)NR^6AR^6B, —OR^6D, —SR^6D, —NR^6ASO₂R^6D, —NR^6AC(O)R^6C, —NR^6AC(O)OR^6C, —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.

In embodiments, R⁶is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R⁶is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R⁶is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R⁶is hydrogen. In embodiments, R⁶is unsubstituted methyl. In embodiments, R⁶is unsubstituted ethyl. In embodiments, R⁶is unsubstituted propyl. In embodiments, R⁶is unsubstituted n-propyl. In embodiments, R⁶is unsubstituted isopropyl. In embodiments, R⁶is unsubstituted butyl. In embodiments, R⁶is unsubstituted n-butyl. In embodiments, R⁶is unsubstituted isobutyl. In embodiments, R⁶is unsubstituted tert-butyl. In embodiments, R⁶is unsubstituted pentyl. In embodiments, R⁶is unsubstituted hexyl. In embodiments, R⁶is —F. In embodiments, R⁶is —Cl. In embodiments, R⁶is —Br. In embodiments, R⁶is —CHF₂. In embodiments, R⁶is —CHF₂. In embodiments, R⁶is —OCHF₂. In embodiments, R⁶is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁶is unsubstituted methoxy. In embodiments, R⁶is unsubstituted ethoxy. In embodiments, R⁶is unsubstituted propoxy. In embodiments, R⁶is unsubstituted n-propoxy. In embodiments, R⁶is unsubstituted isopropoxy. In embodiments, R⁶is unsubstituted butoxy. In embodiments, R⁶is

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In embodiments, R⁶is

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In embodiments, R⁶is

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In embodiments, R⁶is —O-(unsubstituted cyclopropyl). In embodiments, R⁶is —O-(unsubstituted cyclobutyl). In embodiments, R⁶is —O-(unsubstituted cyclopentyl). In embodiments, R⁶is —O-(unsubstituted cyclohexyl). In embodiments, R⁶is -(unsubstituted C₁-C₄alkylene)-OTBS. In embodiments, R⁶is —CH₂OTBS. In embodiments, R⁶is -(unsubstituted C₁-C₄alkylene)-OH. In embodiments, R⁶is —CH₂OH.

In embodiments, W⁷is N. In embodiments, W⁷is N⁺—O⁻. In embodiments, W⁷is C(R⁷). In embodiments, W⁷is CH.

In embodiments, a substituted R⁷(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R⁷is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R⁷is substituted, it is substituted with at least one substituent group. In embodiments, when R⁷is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁷is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^7A(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 R^7Ais 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 R^7Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^7Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^7B(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 R^7Bis 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 R^7Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^7Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^7Aand R^7Bsubstituents 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 R^7Aand R^7Bsubstituents 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 R^7Aand R^7Bsubstituents 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 R^7Aand R^7Bsubstituents 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 R^7Aand R^7Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^7C(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 R^7Cis 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 R^7Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^7Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^7D(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 R^7Dis 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 R^7Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^7Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁷is hydrogen, halogen, —CX⁷₃, —CHX⁷₂, —CH₂X⁷, —OCX⁷₃, —OCH₂X⁷, —OCHX⁷₂, —CN, —SO_n7R^7D, —SO_v7NR^7AR^7B, —NHC(O)NR^7AR^7B, —NR^7AR^7B, —C(O)R^7C, —C(O)OR^7C, —C(O)NR^7AR^7B, —OR^7D, —SR^7D, —NR^7ASO₂R^7D, —NR^7AC(O)R^7C, —NR^7AC(O)OR^7C, —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.

In embodiments, R⁷is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R⁷is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R⁷is hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R⁷is hydrogen. In embodiments, R⁷is unsubstituted methyl. In embodiments, R⁷is unsubstituted ethyl. In embodiments, R⁷is unsubstituted propyl. In embodiments, R⁷is unsubstituted n-propyl. In embodiments, R⁷is unsubstituted isopropyl. In embodiments, R⁷is unsubstituted butyl. In embodiments, R⁷is unsubstituted n-butyl. In embodiments, R⁷is unsubstituted isobutyl. In embodiments, R⁷is unsubstituted tert-butyl. In embodiments, R⁷is unsubstituted pentyl. In embodiments, R⁷is unsubstituted hexyl. In embodiments, R⁷is —F. In embodiments, R⁷is —Cl. In embodiments, R⁷is —Br. In embodiments, R⁷is —CHF₂. In embodiments, R⁷is —CHF₂. In embodiments, R⁷is —OCHF₂. In embodiments, R⁷is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁷is unsubstituted methoxy. In embodiments, R⁷is unsubstituted ethoxy. In embodiments, R⁷is unsubstituted propoxy. In embodiments, R⁷is unsubstituted n-propoxy. In embodiments, R⁷is unsubstituted isopropoxy. In embodiments, R⁷is unsubstituted butoxy. In embodiments, R⁷is

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In embodiments, R⁷is

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In embodiments, R⁷is

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In embodiments, R⁷is —O-(unsubstituted cyclopropyl). In embodiments, R⁷is —O-(unsubstituted cyclobutyl). In embodiments, R⁷is —O-(unsubstituted cyclopentyl). In embodiments, R⁷is —O-(unsubstituted cyclohexyl). In embodiments, R⁷is -(unsubstituted C₁-C₄alkylene)-OTBS. In embodiments, R⁷is —CH₂OTBS. In embodiments, R⁷is -(unsubstituted C₁-C₄alkylene)-OH. In embodiments, R⁷is —CH₂OH.

In embodiments, a substituted R⁸(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R⁸is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R⁸is substituted, it is substituted with at least one substituent group. In embodiments, when R⁸is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁸is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^8A(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 R^8Ais 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 R^8Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^8Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^8B(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 R^8Bis 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 R^8Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^8Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^8Aand R^8Bsubstituents 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 R^8Aand R^8Bsubstituents 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 R^8Aand R^8B, substituents 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 R^8Aand R^8Bsubstituents 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 R^8Aand R^8Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^8C(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 R^8Cis 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 R^8Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^8Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^8D(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 R^8Dis 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 R^8Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^8Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁸is independently halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8D, —SO_v8NR^8AR^8B, —NHC(O)NR^8AR^8B, —NR^8AR^8B, —C(O)R^8C, —C(O)OR^8C, —C(O)NR^8AR^8B, —OR^8D, —SR^8D, —NR^8ASO₂R^8D, —NR^8AC(O)R^8C, —NR^8AC(O)OR^8C, —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 R⁸substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁸is independently 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R⁸is independently 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R⁸is independently halogen, —CF₃, —CHF₂, —OCHF₂, —OR^8D, unsubstituted C₁-C₆alkyl, or unsubstituted 2 to 8 membered heteroalkyl.

In embodiments, R^8Dis independently unsubstituted C₁-C₆alkyl or unsubstituted C₃-C₈cycloalkyl. In embodiments, R^8Dis independently unsubstituted methyl. In embodiments, R^8Dis independently unsubstituted ethyl. In embodiments, R^8Dis independently unsubstituted propyl. In embodiments, R^8Dis independently unsubstituted n-propyl. In embodiments, R^8Dis independently unsubstituted isopropyl. In embodiments, R^8Dis independently unsubstituted butyl. In embodiments, R^8Dis independently unsubstituted n-butyl. In embodiments, R^8Dis independently unsubstituted isobutyl. In embodiments, R^8Dis independently unsubstituted tert-butyl. In embodiments, R^8Dis independently unsubstituted pentyl. In embodiments, R^8Dis independently unsubstituted hexyl. In embodiments, R^8Dis independently unsubstituted cyclopropyl. In embodiments, R^8Dis independently unsubstituted cyclobutyl. In embodiments, R^8Dis independently unsubstituted cyclopentyl. In embodiments, R^8Dis independently unsubstituted cyclohexyl.

In embodiments, R^8Dis independently —F, —Cl, —Br, —CHF₂, —OCHF₂, —OCH₃, —OCH(CH₃)₂, —OCH(CH₃)CH₂OCH₃, —O-(unsubstituted cyclopropyl), or unsubstituted methyl. In embodiments, R^8Dis independently —F, —Cl, —Br, —CH₂F, —CHF₂, —OCHF₂, —OCH₃, —OCH(CH₃)₂, —OCH(CH₃)CH₂OCH₃, —O-(unsubstituted cyclopropyl), or substituted or unsubstituted methyl.

In embodiments, R⁸is independently —F. In embodiments, R⁸is independently —Cl. In embodiments, R⁸is independently —Br. In embodiments, R⁸is independently —CH₂F. In embodiments, R⁸is independently —CHF₂. In embodiments, R⁸is independently —OCHF₂. In embodiments, R⁸is independently unsubstituted C₁-C₆alkyl. In embodiments, R⁸is independently unsubstituted methyl. In embodiments, R⁸is independently unsubstituted ethyl. In embodiments, R⁸is independently unsubstituted propyl. In embodiments, R⁸is independently unsubstituted n-propyl. In embodiments, R⁸is independently unsubstituted isopropyl. In embodiments, R⁸is independently unsubstituted butyl. In embodiments, R⁸is independently unsubstituted n-butyl. In embodiments, R⁸is independently unsubstituted isobutyl. In embodiments, R⁸is independently unsubstituted tert-butyl. In embodiments, R⁸is independently unsubstituted pentyl. In embodiments, R⁸is independently unsubstituted hexyl. In embodiments, R⁸is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁸is independently unsubstituted methoxy. In embodiments, R⁸is independently unsubstituted ethoxy. In embodiments, R⁸is independently unsubstituted propoxy. In embodiments, R⁸is independently unsubstituted n-propoxy. In embodiments, R⁸is independently unsubstituted isopropoxy. In embodiments, R⁸is independently unsubstituted butoxy. In embodiments, R⁸is independently

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In embodiments, R⁸is independently

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In embodiments, R⁸is independently

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In embodiments, R⁸is independently —O-(unsubstituted cyclopropyl). In embodiments, R⁸is independently —O-(unsubstituted cyclobutyl). In embodiments, R⁸is independently —O-(unsubstituted cyclopentyl). In embodiments, R⁸is independently —O-(unsubstituted cyclohexyl). In embodiments, R⁸is independently-(unsubstituted C₁-C₄alkylene)-OTBS. In embodiments, R⁸is independently —CH₂OTBS. In embodiments, R⁸is independently -(unsubstituted C₁-C₄alkylene)-OH. In embodiments, R⁸is independently —CH₂OH.

In embodiments, z8 is 0. In embodiments, z8 is 1. In embodiments, z8 is 2. In embodiments, z8 is 3.

In embodiments,

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wherein R⁶and R⁷are as described herein, including in embodiments. R^8.1, R^8.2, and R^8.3are independently hydrogen or any value of R⁸as described herein, including in embodiments.

In embodiments,

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wherein R⁶is as described herein, including in embodiments. R^8.1, R^8.2, and R^8.3are independently hydrogen or any value of R⁸as described herein, including in embodiments.

In embodiments,

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wherein R⁶is as described herein, including in embodiments. R^8.1, R^8.2, and R^8.3are independently hydrogen or any value of R⁸as described herein, including in embodiments.

In embodiments, a substituted R^8.1(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 R^8.1is 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 R^8.1is substituted, it is substituted with at least one substituent group. In embodiments, when R^8.1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8.1is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^8.2(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 R^8.2is 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 R^8.2is substituted, it is substituted with at least one substituent group. In embodiments, when R^8.2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8.2is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^8.3(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 R^8.3is 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 R^8.3is substituted, it is substituted with at least one substituent group. In embodiments, when R^8.3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8.3is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^8.2and R^8.3substituents are joined (e.g., substituted cycloalkyl and/or substituted heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R^8.2and R^8.3substituents 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 R^8.2and R^8.3substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R^8.2and R^8.3substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R^8.2and R^8.3substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, R^0.1, R^8.2, and R^8.3are independently hydrogen, halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8D, —SO_v8NR^8AR^8B, —NR^8CNR^8AR^8B, —ONR^8AR^8B, —NHC(O)NR^8CNR^8AR^8B, —NHC(O)NR^8AR^8B, —N(O)_m8, —NR^8AR^8B, —C(O)R^8C, —C(O)OR^8C, —C(O)NR^8AR^8B, —OR^8D, —SR^8D, —NR^8ASO₂R^8D, —NR^8AC(O)R^8C, —NR^8AC(O)OR^8C, —NR^8AOR^8C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^8.2and R^8.3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^0.1, R^8.2, and R^8.3are independently hydrogen, halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8D, —SO_v8NR^8AR^8B, —NHC(O)NR^8AR^8B, —NR^8AR^8B, —C(O)R^8C, —C(O)OR^8C, —C(O)NR^8AR^8B, —OR^8D, —SR^8D, —NR^8ASO₂R^8D, —NR^8AC(O)R^8C, —NR^8AC(O)OR^8C, —SF₅, —N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^8.2and R^8.3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^8.1, R^8.2, and R^8.3are independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂J, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CN, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R^8.1, R², and R^8.3are independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂J, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CN, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R^8.1is —F. In embodiments, R^8.1is —Cl. In embodiments, R^8.1is —Br. In embodiments, R^8.1is —CH₂F. In embodiments, R^8.1is —CHF₂. In embodiments, R^8.1is —OCHF₂. In embodiments, R^8.1is unsubstituted C₁-C₆alkyl. In embodiments, R^8.1is unsubstituted methyl. In embodiments, R^8.1is unsubstituted ethyl. In embodiments, R^8.1is unsubstituted propyl. In embodiments, R^8.1is unsubstituted n-propyl. In embodiments, R^8.1is unsubstituted isopropyl. In embodiments, R^8.1is unsubstituted butyl. In embodiments, R^8.1is unsubstituted n-butyl. In embodiments, R^8.1is unsubstituted isobutyl. In embodiments, R^8.1is unsubstituted tert-butyl. In embodiments, R^8.1is unsubstituted pentyl. In embodiments, R^8.1is unsubstituted hexyl. In embodiments, R^8.1is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R^8.1is unsubstituted methoxy. In embodiments, R^8.1is unsubstituted ethoxy. In embodiments, R^8.1is unsubstituted propoxy. In embodiments, R^8.1is unsubstituted n-propoxy. In embodiments, R^8.1is unsubstituted isopropoxy. In embodiments, R^8.1is unsubstituted butoxy. In embodiments, R^8.1is

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In embodiments, R^8.1is

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In embodiments, R^8.1is

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In embodiments, R^8.1is —O-(unsubstituted cyclopropyl). In embodiments, R^8.1is —O-(unsubstituted cyclobutyl). In embodiments, R^8.1is —O-(unsubstituted cyclopentyl). In embodiments, R^8.1is —O-(unsubstituted cyclohexyl). In embodiments, R^8.1is -(unsubstituted C₁-C₄alkylene)-OTBS. In embodiments, R^8.1is —CH₂OTBS. In embodiments, R^8.1is -(unsubstituted C₁-C₄alkylene)-OH. In embodiments, R^8.1is —CH₂OH.

In embodiments, R^8.2is —F. In embodiments, R^8.2is —Cl. In embodiments, R^8.2is —Br. In embodiments, R^8.2is —CH₂F. In embodiments, R^8.2is —CHF₂. In embodiments, R^8.2is —OCHF₂. In embodiments, R^8.2is unsubstituted C₁-C₆alkyl. In embodiments, R^8.2is unsubstituted methyl. In embodiments, R^8.2is unsubstituted ethyl. In embodiments, R^8.2is unsubstituted propyl. In embodiments, R^8.2is unsubstituted n-propyl. In embodiments, R^8.2is unsubstituted isopropyl. In embodiments, R^8.2is unsubstituted butyl. In embodiments, R^8.2is unsubstituted n-butyl. In embodiments, R^8.2is unsubstituted isobutyl. In embodiments, R^8.2is unsubstituted tert-butyl. In embodiments, R^8.2is unsubstituted pentyl. In embodiments, R^8.2is unsubstituted hexyl. In embodiments, R^8.2is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R^8.2is unsubstituted methoxy. In embodiments, R^8.2is unsubstituted ethoxy. In embodiments, R^8.2is unsubstituted propoxy. In embodiments, R^8.2is unsubstituted n-propoxy. In embodiments, R^8.2is unsubstituted isopropoxy. In embodiments, R^8.2is unsubstituted butoxy. In embodiments, R^8.2is

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In embodiments R^8.2is

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In embodiments, R^8.2is

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In embodiments, R^8.2is —O-(unsubstituted cyclopropyl). In embodiments, R^8.2is —O-(unsubstituted cyclobutyl). In embodiments, R^8.2is —O-(unsubstituted cyclopentyl). In embodiments, R^8.2is —O-(unsubstituted cyclohexyl). In embodiments, R^8.2is -(unsubstituted C₁-C₄alkylene)-OTBS. In embodiments, R^8.2is —CH₂OTBS. In embodiments, R^8.2is -(unsubstituted C₁-C₄alkylene)-OH. In embodiments, R^8.2is —CH₂OH.

In embodiments, R^8.3is —F. In embodiments, R^8.3is —Cl. In embodiments, R^8.3is —Br. In embodiments, R^8.3is —CH₂F. In embodiments, R^8.3is —CHF₂. In embodiments, R^8.3is —OCHF₂. In embodiments, R^8.3is unsubstituted C₁-C₆alkyl. In embodiments, R^8.3is unsubstituted methyl. In embodiments, R^8.3is unsubstituted ethyl. In embodiments, R^8.3is unsubstituted propyl. In embodiments, R^8.3is unsubstituted n-propyl. In embodiments, R^8.3is unsubstituted isopropyl. In embodiments, R^8.3is unsubstituted butyl. In embodiments, R^8.3is unsubstituted n-butyl. In embodiments, R^8.3is unsubstituted isobutyl. In embodiments, R^8.3is unsubstituted tert-butyl. In embodiments, R^8.3is unsubstituted pentyl. In embodiments, R^8.3is unsubstituted hexyl. In embodiments, R^8.3is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R^8.3is unsubstituted methoxy. In embodiments, R^8.3is unsubstituted ethoxy. In embodiments, R^8.3is unsubstituted propoxy. In embodiments, R^8.3is unsubstituted n-propoxy. In embodiments, R^8.3is unsubstituted isopropoxy. In embodiments, R^8.3is unsubstituted butoxy. In embodiments, R^8.3is

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In embodiments, R^8.3is

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In embodiments, R^8.3is

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In embodiments, R^8.3is —O-(unsubstituted cyclopropyl). In embodiments, R^8.3is —O-(unsubstituted cyclobutyl). In embodiments, R^8.3is —O-(unsubstituted cyclopentyl). In embodiments, R^8.3is —O-(unsubstituted cyclohexyl). In embodiments, R^8.3is -(unsubstituted C₁-C₄alkylene)-OTBS. In embodiments, R^8.3is —CH₂OTBS. In embodiments, R^8.3is -(unsubstituted C₁-C₄alkylene)-OH. In embodiments, R^8.3is —CH₂OH.

In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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wherein R¹¹, R¹², and R¹³are as described herein, including in embodiments. In embodiments,

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wherein R¹¹, R¹², and R¹³are as described herein, including in embodiments. In embodiments,

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In embodiments,

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In embodiments,

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wherein R¹¹and R¹²are as described herein, including in embodiments. In embodiments,

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wherein R¹¹and R¹²are as described herein, including in embodiments. In embodiments

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wherein R¹³is as described herein, including in embodiments. In embodiments,

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wherein R¹³is as described herein, including in embodiments.

In embodiments, a substituted R¹¹(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R¹¹is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R¹¹is substituted, it is substituted with at least one substituent group. In embodiments, when R¹¹is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹¹is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^11A(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 R^11Ais 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 R^11Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^11Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^11B(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 R^11Bis 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 R^11Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^11Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^11Aand R^11Bsubstituents 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 R^11Aand R^11Bsubstituents 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 R^11Aand R^11Bsubstituents 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 R^11Aand R^11Bsubstituents 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 R^11Aand R^11Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^11C(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 R^11Cis 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 R^11Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^11Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^11D(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 R^11Dis 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 R^11Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^11Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹¹is hydrogen, halogen, —CX¹¹₃, —CHX¹¹₂, —CH₂X¹¹, —OCX¹¹₃, —OCH₂X¹¹, —OCHX¹¹₂, —CN, —SO_n11R^11D, —SO_v11NR^11AR^11B, —NHC(O)NR^11AR^11B, —NR^11AR^11B, —C(O)R^11C, —C(O)OR^11C, —C(O)NR^11AR^11B, —OR^11D, —SR^11D, —NR^11ASO₂R^11D, —NR^11AC(O)R^11C, —NR^11AC(O)OR^11C, —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.

In embodiments, R¹¹is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R¹¹is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R¹¹is hydrogen, halogen, —SO_n11R^11D, —SO_v11NR^11AR^11B, —NR^11AR^11B, —C(O)OR^11C, —C(O)NR^11AR^11B, —OR^11D, —NR^11ASO₂R^11D, —NR^11AC(O)R^11Csubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R^11Aand R^11Bare independently hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₈cycloalkyl. In embodiments, R^11Cis hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R^11Dis hydrogen or unsubstituted C₁-C₆alkyl.

In embodiments, R^11Ais hydrogen. In embodiments, R^11Ais unsubstituted C₁-C₆alkyl. In embodiments, R^11Ais unsubstituted C₃-C₈cycloalkyl. In embodiments, R^11Ais unsubstituted methyl. In embodiments, R^11Ais unsubstituted ethyl. In embodiments, R^11Ais unsubstituted propyl. In embodiments, R^11Ais unsubstituted n-propyl. In embodiments, R^11Ais unsubstituted isopropyl. In embodiments, R^11Ais unsubstituted butyl. In embodiments, R^11Ais unsubstituted n-butyl. In embodiments, R^11Ais unsubstituted isobutyl. In embodiments, R^11Ais unsubstituted tert-butyl. In embodiments, R^11Ais unsubstituted pentyl. In embodiments, R^11Ais unsubstituted hexyl. In embodiments, R^11Ais unsubstituted cyclopropyl. In embodiments, R^11Ais unsubstituted cyclobutyl. In embodiments, R^11Ais unsubstituted cyclopentyl. In embodiments, R^11Ais unsubstituted cyclohexyl.

In embodiments, R^11Bis hydrogen. In embodiments, R^11Bis unsubstituted C₁-C₆alkyl. In embodiments, R^11Bis unsubstituted C₃-C₈cycloalkyl. In embodiments, R^11Bis unsubstituted methyl. In embodiments, R^11Bis unsubstituted ethyl. In embodiments, R^11Bis unsubstituted propyl. In embodiments, R^11Bis unsubstituted n-propyl. In embodiments, R^11Bis unsubstituted isopropyl. In embodiments, R^11Bis unsubstituted butyl. In embodiments, R^11Bis unsubstituted n-butyl. In embodiments, R^11Bis unsubstituted isobutyl. In embodiments, R^11Bis unsubstituted tert-butyl. In embodiments, R^11Bis unsubstituted pentyl. In embodiments, R^11Bis unsubstituted hexyl. In embodiments, R^11Bis unsubstituted cyclopropyl. In embodiments, R^11Bis unsubstituted cyclobutyl. In embodiments, R^11Bis unsubstituted cyclopentyl. In embodiments, R^11Bis unsubstituted cyclohexyl.

In embodiments, R^11Cis hydrogen. In embodiments, R^11Cis unsubstituted C₁-C₆alkyl. In embodiments, R^11Cis unsubstituted methyl. In embodiments, R^11Cis unsubstituted ethyl. In embodiments, R^11Cis unsubstituted propyl. In embodiments, R^11Cis unsubstituted n-propyl. In embodiments, R^11Cis unsubstituted isopropyl. In embodiments, R^11Cis unsubstituted butyl. In embodiments, R^11Cis unsubstituted n-butyl. In embodiments, R^11Cis unsubstituted isobutyl. In embodiments, R^11Cis unsubstituted tert-butyl. In embodiments, R^11Cis unsubstituted pentyl. In embodiments, R^11Cis unsubstituted hexyl.

In embodiments, R^11Dis hydrogen. In embodiments, R^11Dis unsubstituted C₁-C₆alkyl. In embodiments, R^11Dis unsubstituted methyl. In embodiments, R^11Dis unsubstituted ethyl. In embodiments, R^11Dis unsubstituted propyl. In embodiments, R^11Dis unsubstituted n-propyl. In embodiments, R^11Dis unsubstituted isopropyl. In embodiments, R^11Dis unsubstituted butyl. In embodiments, R^11Dis unsubstituted n-butyl. In embodiments, R^11Dis unsubstituted isobutyl. In embodiments, R^11Dis unsubstituted tert-butyl. In embodiments, R^11Dis unsubstituted pentyl. In embodiments, R^11Dis unsubstituted hexyl.

In embodiments, R¹¹is hydrogen, —F, —OH, —CH₃, —CH₂CH₃, —NHCH₃, —N(CH₃)₂, —C(O)OH, —C(O)N(CH₃)₂, —S(O)₂CH₃, —S(O)₂NH₂, —S(O)₂NH(CH₃)₂,

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In embodiments, R¹¹is hydrogen, —F, —OH, —CN, —CH₃, —CH₂CH₃, —NHCH₃, —N(CH₃)₂, —C(O)OH, —C(O)NH₂, —C(O)N(CH₃)₂, —S(O)₂CH₃, —S(O)₂CH₃, —S(O)₂NH₂(CH₃), —S(O)₂N(CH₃)₂, —N₃,

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In embodiments, R¹¹is hydrogen. In embodiments, R¹¹is halogen. In embodiments, R¹¹is —F. In embodiments, R¹¹is —OH. In embodiments, R¹¹is —CN. In embodiments, R¹¹is —NHCH₃. In embodiments, R¹¹is —N(CH₃)₂. In embodiments, R¹¹is —C(O)OH. In embodiments, R¹¹is —C(O)NH₂. In embodiments, R¹¹is —C(O)N(CH₃)₂. In embodiments, R¹¹is —S(O)₂CH₃. In embodiments, R¹¹is —S(O)₂NH₂. In embodiments, R¹¹is —S(O)₂NH(CH₃). In embodiments, R¹¹is —S(O)₂N(CH₃)₂. In embodiments, R¹¹is —N₃. In embodiments, R¹¹is unsubstituted C₁-C₆alkyl. In embodiments, R¹¹is unsubstituted methyl. In embodiments, R¹¹is -CD₃. In embodiments, R¹¹is unsubstituted ethyl. In embodiments, R¹¹is unsubstituted propyl. In embodiments, R¹¹is unsubstituted n-propyl. In embodiments, R¹¹is unsubstituted isopropyl. In embodiments, R¹¹is unsubstituted butyl. In embodiments, R¹¹is unsubstituted n-butyl. In embodiments, R¹¹is unsubstituted isobutyl. In embodiments, R¹¹is unsubstituted tert-butyl. In embodiments, R¹¹is unsubstituted pentyl. In embodiments, R¹¹is unsubstituted hexyl. In embodiments, R¹¹is unsubstituted C₂-C₆alkynyl. In embodiments, R¹¹is unsubstituted ethynyl. In embodiments, R¹¹is unsubstituted propynyl. In embodiments, R¹¹is unsubstituted butynyl. In embodiments, R¹¹is unsubstituted pentynyl. In embodiments, R¹¹is unsubstituted hexynyl. In embodiments, R¹¹is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹¹is unsubstituted methoxy. In embodiments, R¹¹is unsubstituted ethoxy. In embodiments, R¹¹is unsubstituted propoxy. In embodiments, R¹¹is unsubstituted n-propoxy. In embodiments, R¹¹is unsubstituted isopropoxy. In embodiments, R¹¹is unsubstituted butoxy. In embodiments, R¹¹is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹¹is substituted or unsubstituted azetidinyl. In embodiments, R¹¹is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹¹is substituted or unsubstituted triazolyl. In embodiments, R¹¹is substituted or unsubstituted pyridyl. In embodiments, R¹¹is

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In embodiments, a substituted R¹²(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R¹²is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R¹²is substituted, it is substituted with at least one substituent group. In embodiments, when R¹²is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹²is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^12A(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 R^12Ais 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 R^12Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^12Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^12B(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 R^12Bis 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 R^12Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^12Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^12Aand R^12Bsubstituents 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 R^12Aand R^12Bsubstituents 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 R^12Aand R^12Bsubstituents 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 R^12Aand R^12Bsubstituents 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 R^12Aand R^12Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^12C(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 R^12Cis 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 R^12Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^12Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^12D(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 R^12Dis 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 R^12Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^12Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹²is hydrogen, halogen, —CX¹²₃, —CHX¹²₂, —CH₂X¹², —OCX¹²₃, —OCH₂X¹², —OCHX¹²₂, —CN, —SO_n12R^12D, —SO_v12NR^12AR^12B, —NHC(O)NR^12AR^12B, —NR^12AR^12B, —C(O)R^12C, —C(O)OR^12C, —C(O)NR^12AR^12B, —OR^12D, —SR^12D, —NR^12ASO₂R^12D, —NR^12AC(O)R^12C, —NR^12AC(O)OR^12C, —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.

In embodiments, R¹²is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —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.

In embodiments, R¹²is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —NHC(O)NH₂, —NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, —SH, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —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.

In embodiments, R¹²is hydrogen, halogen, —SO_n12R^12D, —SO_v12NR^12AR^12B, —NR^12AR^12B, —C(O)OR^12C, —C(O)NR^12AR^12B, —OR^12D, —NR^12ASO₂R^12D, —NR^12AC(O)R^12Csubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R^12Aand R^12Bare independently hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₈cycloalkyl. In embodiments, R^12Cis hydrogen or unsubstituted C₁-C₆alkyl. In embodiments, R^12Dis hydrogen or unsubstituted C₁-C₆alkyl.

In embodiments, R^12Ais hydrogen. In embodiments, R^12Ais unsubstituted C₁-C₆alkyl. In embodiments, R^12Ais unsubstituted C₃-C₈cycloalkyl. In embodiments, R^12Ais unsubstituted methyl. In embodiments, R^12Ais unsubstituted ethyl. In embodiments, R^12Ais unsubstituted propyl. In embodiments, R^12Ais unsubstituted n-propyl. In embodiments, R^12Ais unsubstituted isopropyl. In embodiments, R^12Ais unsubstituted butyl. In embodiments, R^12Ais unsubstituted n-butyl. In embodiments, R^12Ais unsubstituted isobutyl. In embodiments, R^12Ais unsubstituted tert-butyl. In embodiments, R^12Ais unsubstituted pentyl. In embodiments, R^12Ais unsubstituted hexyl. In embodiments, R^12Ais unsubstituted cyclopropyl. In embodiments, R^12Ais unsubstituted cyclobutyl. In embodiments, R^12Ais unsubstituted cyclopentyl. In embodiments, R^12Ais unsubstituted cyclohexyl.

In embodiments, R^12Bis hydrogen. In embodiments, R^12Bis unsubstituted C₁-C₆alkyl. In embodiments, R^12Bis unsubstituted C₃-C₈cycloalkyl. In embodiments, R^12Bis unsubstituted methyl. In embodiments, R^12Bis unsubstituted ethyl. In embodiments, R^12Bis unsubstituted propyl. In embodiments, R^12Bis unsubstituted n-propyl. In embodiments, R^12Bis unsubstituted isopropyl. In embodiments, R^12Bis unsubstituted butyl. In embodiments, R^12Bis unsubstituted n-butyl. In embodiments, R^12Bis unsubstituted isobutyl. In embodiments, R^12Bis unsubstituted tert-butyl. In embodiments, R^12Bis unsubstituted pentyl. In embodiments, R^12Bis unsubstituted hexyl. In embodiments, R^12Bis unsubstituted cyclopropyl. In embodiments, R^12Bis unsubstituted cyclobutyl. In embodiments, R^12Bis unsubstituted cyclopentyl. In embodiments, R^12Bis unsubstituted cyclohexyl.

In embodiments, R^12Cis hydrogen. In embodiments, R^12Cis unsubstituted C₁-C₆alkyl. In embodiments, R^12Cis unsubstituted methyl. In embodiments, R^12Cis unsubstituted ethyl. In embodiments, R^12Cis unsubstituted propyl. In embodiments, R^12Cis unsubstituted n-propyl. In embodiments, R^12Cis unsubstituted isopropyl. In embodiments, R^12Cis unsubstituted butyl. In embodiments, R^12Cis unsubstituted n-butyl. In embodiments, R^12Cis unsubstituted isobutyl. In embodiments, R^12Cis unsubstituted tert-butyl. In embodiments, R^12Cis unsubstituted pentyl. In embodiments, R^12Cis unsubstituted hexyl.

In embodiments, R^12Dis hydrogen. In embodiments, R^12Dis unsubstituted C₁-C₆alkyl. In embodiments, R^12Dis unsubstituted methyl. In embodiments, R^12Dis unsubstituted ethyl. In embodiments, R^12Dis unsubstituted propyl. In embodiments, R^12Dis unsubstituted n-propyl. In embodiments, R^12Dis unsubstituted isopropyl. In embodiments, R^12Dis unsubstituted butyl. In embodiments, R^12Dis unsubstituted n-butyl. In embodiments, R^12Dis unsubstituted isobutyl. In embodiments, R^12Dis unsubstituted tert-butyl. In embodiments, R^12Dis unsubstituted pentyl. In embodiments, R^12Dis unsubstituted hexyl.

In embodiments, R¹²is hydrogen, —F, —OH, —CH₃, —CH₂CH₃, —NHCH₃, —N(CH₃)₂, —C(O)OH, —C(O)N(CH₃)₂, —S(O)₂CH₃, —S(O)₂NH₂, —S(O)₂NH(CH₃)₂,

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In embodiments, R¹²is hydrogen, —F, —OH, —CN, —CH₃, —CH₂CH₃, —NHCH₃, —N(CH₃)₂, —C(O)OH, —C(O)NH₂, —C(O)N(CH₃)₂, —S(O)₂CH₃, —S(O)₂NH₂, —S(O)₂NH(CH₃), —S(O)₂N(CH₃)₂, —N₃,

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In embodiments, R¹²is hydrogen. In embodiments, R¹²is halogen. In embodiments, R¹²is —F. In embodiments, R¹²is —OH. In embodiments, R¹²is —CN. In embodiments, R¹²is —NHCH₃. In embodiments, R¹²is —N(CH₃)₂. In embodiments, R¹²is —C(O)OH. In embodiments, R¹²is —C(O)NH₂. In embodiments, R¹²is —C(O)N(CH₃)₂. In embodiments, R¹²is —S(O)₂CH₃. In embodiments, R¹²is —S(O)₂NH₂. In embodiments, R¹²is —S(O)₂NH(CH₃). In embodiments, R¹²is —S(O)₂N(CH₃)₂. In embodiments, R¹²is —N₃. In embodiments, R¹²is unsubstituted C₁-C₆alkyl. In embodiments, R¹²is unsubstituted methyl. In embodiments, R¹²is -CD₃. In embodiments, R¹²is unsubstituted ethyl. In embodiments, R¹²is unsubstituted propyl. In embodiments, R¹²is unsubstituted n-propyl. In embodiments, R¹²is unsubstituted isopropyl. In embodiments, R¹²is unsubstituted butyl. In embodiments, R¹²is unsubstituted n-butyl. In embodiments, R¹²is unsubstituted isobutyl. In embodiments, R¹²is unsubstituted tert-butyl. In embodiments, R¹²is unsubstituted pentyl. In embodiments, R¹²is unsubstituted hexyl. In embodiments, R¹²is unsubstituted C₂-C₆alkynyl. In embodiments, R¹²is unsubstituted ethynyl. In embodiments, R¹²is unsubstituted propynyl. In embodiments, R¹²is unsubstituted butynyl. In embodiments, R¹²is unsubstituted pentynyl. In embodiments, R¹²is unsubstituted hexynyl. In embodiments, R¹²is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹²is unsubstituted methoxy. In embodiments, R¹²is unsubstituted ethoxy. In embodiments, R¹²is unsubstituted propoxy. In embodiments, R¹²is unsubstituted n-propoxy. In embodiments, R¹²is unsubstituted isopropoxy. In embodiments, R¹²is unsubstituted butoxy. In embodiments, R¹²is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹²is substituted or unsubstituted azetidinyl. In embodiments, R¹²is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹²is substituted or unsubstituted triazolyl. In embodiments, R¹²is substituted or unsubstituted pyridyl. In embodiments, R¹²is

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In embodiments, a substituted ring formed when R¹¹and R¹²substituents are joined (e.g., substituted cycloalkyl and/or substituted heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R¹¹and R¹²substituents 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 R¹¹and R¹²substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R¹¹and R¹²substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R¹¹and R¹²substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹¹and R¹²substituents are joined to form a substituted or unsubstituted C₃-C₈cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹¹and R¹²substituents are joined to form a substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹¹and R¹²substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹¹and R¹²substituents are joined to form a substituted azetidinyl. In embodiments, R¹¹and R¹²substituents are joined to form an unsubstituted dioxolanyl. In embodiments, R¹¹and R¹²substituents are joined to form

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In embodiments, R¹¹and R¹²substituents are joined to form an oxo.

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In embodiments,

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In embodiments, a substituted R¹³(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R¹³is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R¹³is substituted, it is substituted with at least one substituent group. In embodiments, when R¹³is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹³is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^13B(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 R^13Bis 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 R^13Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^13Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^13Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^13Band R^13Bsubstituents 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 R^13Aand R^13Bsubstituents 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 R^13Band R^13Bsubstituents 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 R^13Band R^13Bsubstituents 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 R^13Band R^13Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^13C(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 R^13Cis 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 R^13Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^13Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^13Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^13D(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 R^13Dis 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 R^13Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^13Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^13Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹³is hydrogen, 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, —SO₃H, —OSO₃H, —SO₂NH₂, —C(O)H, —C(O)OH, —CONH₂, —OH, 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.

In embodiments, R¹³is hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹³is hydrogen. In embodiments, R¹³is unsubstituted C₁-C₆alkyl. In embodiments, R¹³is unsubstituted methyl. In embodiments, R¹³is unsubstituted ethyl. In embodiments, R¹³is unsubstituted propyl. In embodiments, R¹³is unsubstituted n-propyl. In embodiments, R¹³is unsubstituted isopropyl. In embodiments, R¹³is unsubstituted butyl. In embodiments, R¹³is unsubstituted n-butyl. In embodiments, R¹³is unsubstituted isobutyl. In embodiments, R¹³is unsubstituted tert-butyl. In embodiments, R¹³is unsubstituted pentyl. In embodiments, R¹³is unsubstituted hexyl. In embodiments, R¹³is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹³is —CH₂OCH₂CH₃.

In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments,

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In embodiments, when R¹is substituted, R¹is substituted with one or more first substituent groups denoted by R^1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.1substituent group is substituted, the R^1.1substituent group is substituted with one or more second substituent groups denoted by R^1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.2substituent group is substituted, the R^1.2substituent group is substituted with one or more third substituent groups denoted by R^1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹, R^1.1, R^1.2, and R^1.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW2and R^WW.3correspond to R¹, R^1.1, R^1.2, and R^1.3, respectively.

In embodiments, when R²is substituted, R²is substituted with one or more first substituent groups denoted by R^2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1substituent group is substituted, the R^2.1substituent group is substituted with one or more second substituent groups denoted by R^2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.2substituent group is substituted, the R^2.2substituent group is substituted with one or more third substituent groups denoted by R^2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R², R^2.1, R^2.2, and R^2.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R², R^2.1, R^2.2, and R^2.3, respectively.

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

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

In embodiments, when R^2Aand R^2Bsubstituents 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 R^2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2A.1substituent group is substituted, the R^2A.1substituent group is substituted with one or more second substituent groups denoted by R^2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2A.2substituent group is substituted, the R^2A.2substituent group is substituted with one or more third substituent groups denoted by R^2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^2A.1, R^2A.2, and R^2A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^2A.1, R^2A.2, and R^2A.3, respectively.

In embodiments, when R^2Aand R^2Bsubstituents 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 R^2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2B.1substituent group is substituted, the R^2B.1substituent group is substituted with one or more second substituent groups denoted by R^2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2B.2substituent group is substituted, the R^2B.2substituent group is substituted with one or more third substituent groups denoted by R^2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^2B.1, R^2B.2, and R^2B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^2B.1, R^2B.2, and R^2B.3, respectively.

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

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

In embodiments, when R³is substituted, R³is substituted with one or more first substituent groups denoted by R^3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.1substituent group is substituted, the R^3.1substituent group is substituted with one or more second substituent groups denoted by R^3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.2substituent group is substituted, the R^3.2substituent group is substituted with one or more third substituent groups denoted by R^3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R³, R^3.1, R^3.2, and R^3.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R³, R^3.1, R^3.2, and R^3.3, respectively.

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

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

In embodiments, when R^3Aand R^3Bsubstituents 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 R^3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3A.1substituent group is substituted, the R^3A.1substituent group is substituted with one or more second substituent groups denoted by R^3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3A.2substituent group is substituted, the R^3A.2substituent group is substituted with one or more third substituent groups denoted by R^3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^3A.1, R^3A.2, and R^3A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^3A.1, R^3A.2, and R^3A.3, respectively.

In embodiments, when R^3Aand R^3Bsubstituents 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 R^3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3B.1substituent group is substituted, the R^3B.1substituent group is substituted with one or more second substituent groups denoted by R^3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3B.2substituent group is substituted, the R^3B.2substituent group is substituted with one or more third substituent groups denoted by R^3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^3B.1, R^3B.2, and R^3B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^3B.1, R^3B.2, and R^3B.3, respectively.

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

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

In embodiments, when R⁴is substituted, R⁴is substituted with one or more first substituent groups denoted by R^4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.1substituent group is substituted, the R^4.1substituent group is substituted with one or more second substituent groups denoted by R^4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.2substituent group is substituted, the R^4.2substituent group is substituted with one or more third substituent groups denoted by R^4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁴, R^4.1, R^4.2, and R^4.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R⁴, R^4.1, R^4.2, and R^4.3, respectively.

In embodiments, when R^4Ais substituted, R^4Ais substituted with one or more first substituent groups denoted by R^4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4A.1substituent group is substituted, the R^4A.1substituent group is substituted with one or more second substituent groups denoted by R^4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4A.2substituent group is substituted, the R^4A.2substituent group is substituted with one or more third substituent groups denoted by R^4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4A, R^4A.1, R^4A.2, and R^4A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^4A, R^4A.1, R^4A.2, and R^4A.3, respectively.

In embodiments, when R^4Bis substituted, R^4Bis substituted with one or more first substituent groups denoted by R^4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4B.1substituent group is substituted, the R^4B.1substituent group is substituted with one or more second substituent groups denoted by R^4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4B.2substituent group is substituted, the R^4B.2substituent group is substituted with one or more third substituent groups denoted by R^4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4B, R^4B.1, R^4B.2, and R^4B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW2and R^WW.3correspond to R^4B, R^4B.1, R^4B.2, and R^4B.3, respectively.

In embodiments, when R^4Aand R^4Bsubstituents 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 R^4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4A.1substituent group is substituted, the R^4A.1substituent group is substituted with one or more second substituent groups denoted by R^4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4A.2substituent group is substituted, the R^4A.2substituent group is substituted with one or more third substituent groups denoted by R^4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4A.1, R^4A.2, and R^4A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^4A.1, R^4A.2, and R^4A.3, respectively.

In embodiments, when R^4Aand R^4Bsubstituents 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 R^4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4B.1substituent group is substituted, the R^4B.1substituent group is substituted with one or more second substituent groups denoted by R^4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4B.2substituent group is substituted, the R^4B.2substituent group is substituted with one or more third substituent groups denoted by R^4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4B.1, R^4B.2, and R^4B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^4B.1, R^4B.2, and R^4B.3, respectively.

In embodiments, when R^4Cis substituted, R^4Cis substituted with one or more first substituent groups denoted by R^4C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4C.1substituent group is substituted, the R^4C.1substituent group is substituted with one or more second substituent groups denoted by R^4C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4C.2substituent group is substituted, the R^4C.2substituent group is substituted with one or more third substituent groups denoted by R^4C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4C, R^4C.1, R^4C.2, and R^4C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^4C, R^4C.1, R^4C.2, and R^4C.3, respectively.

In embodiments, when R^4Dis substituted, R^4Dis substituted with one or more first substituent groups denoted by R^4D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4D.1substituent group is substituted, the R^4D.1substituent group is substituted with one or more second substituent groups denoted by R^4D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4D.2substituent group is substituted, the R^4D.2substituent group is substituted with one or more third substituent groups denoted by R^4D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4D, R^4D.1, R^4D.2, and R^4D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^4D, R^4D.1, R^4D.2, and R^4D.3, respectively.

In embodiments, when R⁵is substituted, R⁵is substituted with one or more first substituent groups denoted by R^5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.1substituent group is substituted, the R^5.1substituent group is substituted with one or more second substituent groups denoted by R^5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.2substituent group is substituted, the R^5.2substituent group is substituted with one or more third substituent groups denoted by R^5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁵, R^5.1, R^5.2, and R^5.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R⁵, R^5.1, R^5.2, and R^5.3, respectively.

In embodiments, when R^5Ais substituted, R^5Ais substituted with one or more first substituent groups denoted by R^5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.1substituent group is substituted, the R^5A.1substituent group is substituted with one or more second substituent groups denoted by R^5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.2substituent group is substituted, the R^5A.2substituent group is substituted with one or more third substituent groups denoted by R^5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5A, R^5A.1, R^5A.2, and R^5A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^5A, R^5A.1, R^5A.2, and R^5A.3, respectively.

In embodiments, when R^5Bis substituted, R^5Bis substituted with one or more first substituent groups denoted by R^5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.1substituent group is substituted, the R^5B.1substituent group is substituted with one or more second substituent groups denoted by R^5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.2substituent group is substituted, the R^5B.2substituent group is substituted with one or more third substituent groups denoted by R^5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5B, R^5B.1, R^5B.2, and R^5B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^5B, R^5B.1, R^5B.2, and R^5B.3, respectively.

In embodiments, when R^5Aand R^5Bsubstituents 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 R^5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.1substituent group is substituted, the R^5A.1substituent group is substituted with one or more second substituent groups denoted by R^5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.2substituent group is substituted, the R^5A.2substituent group is substituted with one or more third substituent groups denoted by R^5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5A.1, R^5A.2, and R^5A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^5A.1, R^5A.2, and R^5A.3, respectively.

In embodiments, when R^5Aand R^5Bsubstituents 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 R^5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.1substituent group is substituted, the R^5B.1substituent group is substituted with one or more second substituent groups denoted by R^5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.2substituent group is substituted, the R^5B.2substituent group is substituted with one or more third substituent groups denoted by R^5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5B.1, R^5B.2, and R^5B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^5B.1, R^5B.2, and R^5B.3, respectively.

In embodiments, when R^5Cis substituted, R^5Cis substituted with one or more first substituent groups denoted by R^5C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.1substituent group is substituted, the R^5C.1substituent group is substituted with one or more second substituent groups denoted by R^5C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.2substituent group is substituted, the R^5C.2substituent group is substituted with one or more third substituent groups denoted by R^5C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5C, R^5C.1, R^5C.2, and R^5C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^5C, R^5C.1, R^5C.2, and R^5C.3, respectively.

In embodiments, when R^5Dis substituted, R^5Dis substituted with one or more first substituent groups denoted by R^5D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5D.1substituent group is substituted, the R^5D.1substituent group is substituted with one or more second substituent groups denoted by R^5D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5D.2substituent group is substituted, the R^5D.2substituent group is substituted with one or more third substituent groups denoted by R^5D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5D, R^5D.1, R^5D.2, and R^5D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^5D, R^5D.1, R^5D.2, and R^5D.3, respectively.

In embodiments, when R⁶is substituted, R⁶is substituted with one or more first substituent groups denoted by R^6.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6.1substituent group is substituted, the R^6.1substituent group is substituted with one or more second substituent groups denoted by R^6.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6.2substituent group is substituted, the R^6.2substituent group is substituted with one or more third substituent groups denoted by R^6.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁶, R^6.1, R^6.2, and R^6.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R⁶, R^6.1, R^6.2, and R^6.3, respectively.

In embodiments, when R^6Ais substituted, R^6Ais substituted with one or more first substituent groups denoted by R^6A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6A.1substituent group is substituted, the R^6A.1substituent group is substituted with one or more second substituent groups denoted by R^6A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6A.2substituent group is substituted, the R^6A.2substituent group is substituted with one or more third substituent groups denoted by R^6A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^6A, R^6A.1, R^6A.2, and R^6A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^6A, R^6A.1, R^6A.2, and R^6A.3, respectively.

In embodiments, when R^6Bis substituted, R^6Bis substituted with one or more first substituent groups denoted by R^6B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6B.1substituent group is substituted, the R^6B.1substituent group is substituted with one or more second substituent groups denoted by R^6B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6B.2substituent group is substituted, the R^6B.2substituent group is substituted with one or more third substituent groups denoted by R^6B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^6B, R^6B.1, R^6B.2, and R^6B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^6B, R^6B.1, R^6B.2, and R^6B.3, respectively.

In embodiments, when R^6Aand R^6Bsubstituents 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 R^6A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6A.1substituent group is substituted, the R^6A.1substituent group is substituted with one or more second substituent groups denoted by R^6A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6A.2substituent group is substituted, the R^6A.2substituent group is substituted with one or more third substituent groups denoted by R^6A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^6A.1, R^6A.2, and R^6A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^6A.1, R^6A.2, and R^6A.3, respectively.

In embodiments, when R^6Aand R^6Bsubstituents 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 R^6B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6B.1substituent group is substituted, the R^6B.1substituent group is substituted with one or more second substituent groups denoted by R^6B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6B.2substituent group is substituted, the R^6B.2substituent group is substituted with one or more third substituent groups denoted by R^6B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^6B.1, R^6B.2, and R^6B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^6B.1, R^6B.2, and R^6B.3, respectively.

In embodiments, when R^6Cis substituted, R^6Cis substituted with one or more first substituent groups denoted by R^6C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6C.1substituent group is substituted, the R^6C.1substituent group is substituted with one or more second substituent groups denoted by R^6C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6C.2substituent group is substituted, the R^6C.2substituent group is substituted with one or more third substituent groups denoted by R^6C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^6C, R^6C.1, R^6C.2, and R^6C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^6C, R^6C.1, R^6C.2, and R^6C.3, respectively.

In embodiments, when R^6Dis substituted, R^6Dis substituted with one or more first substituent groups denoted by R^6D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6D.1substituent group is substituted, the R^6D.1substituent group is substituted with one or more second substituent groups denoted by R^6D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6D.2substituent group is substituted, the R^6D.2substituent group is substituted with one or more third substituent groups denoted by R^6D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^6D, R^6D.1, R^6D.2, and R^6D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^6D, R^6D.1, R^6D.2, and R^6D.3, respectively.

In embodiments, when R⁷is substituted, R⁷is substituted with one or more first substituent groups denoted by R^7.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7.1substituent group is substituted, the R^7.1substituent group is substituted with one or more second substituent groups denoted by R^7.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7.2substituent group is substituted, the R^7.2substituent group is substituted with one or more third substituent groups denoted by R^7.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁷, R^7.1, R^7.2, and R^7.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R⁷, R^7.1, R^7.2, and R^7.3, respectively.

In embodiments, when R^7Ais substituted, R^7Ais substituted with one or more first substituent groups denoted by R^7A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7A.1substituent group is substituted, the R^7A.1substituent group is substituted with one or more second substituent groups denoted by R^7A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7A.2substituent group is substituted, the R^7A.2substituent group is substituted with one or more third substituent groups denoted by R^7A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7A, R^7A.1, R^7A.2, and R^7A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^7A, R^7A.1, R^7A.2, and R^7A.3, respectively.

In embodiments, when R^7Bis substituted, R^7Bis substituted with one or more first substituent groups denoted by R^7B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7B.1substituent group is substituted, the R^7B.1substituent group is substituted with one or more second substituent groups denoted by R^7B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7B.2substituent group is substituted, the R^7B.2substituent group is substituted with one or more third substituent groups denoted by R^7B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7B, R^7B.1, R^7B.2, and R^7B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^7B, R^7B.1, R^7B.2, and R^7B.3, respectively.

In embodiments, when R^7Aand R^7Bsubstituents 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 R^7A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7A.1substituent group is substituted, the R^7A.1substituent group is substituted with one or more second substituent groups denoted by R^7A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7A.2substituent group is substituted, the R^7A.2substituent group is substituted with one or more third substituent groups denoted by R^7A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7A.1, R^7A.2, and R^7A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^7A.1, R^7A.2, and R^7A.3, respectively.

In embodiments, when R^7Aand R^7Bsubstituents 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 R^7B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7B.1substituent group is substituted, the R^7B.1substituent group is substituted with one or more second substituent groups denoted by R^7B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7B.2substituent group is substituted, the R^7B.2substituent group is substituted with one or more third substituent groups denoted by R^7B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7B.1, R^7B.2, and R^7B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^7B.1, R^7B.2, and R^7B.3, respectively.

In embodiments, when R^7Cis substituted, R^7Cis substituted with one or more first substituent groups denoted by R^7C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7C.1substituent group is substituted, the R^7C.1substituent group is substituted with one or more second substituent groups denoted by R^7C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7C.2substituent group is substituted, the R^7C.2substituent group is substituted with one or more third substituent groups denoted by R^7C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7C, R^7C.1, R^7C.2, and R^7C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^7C, R^7C.1, R^7C.2, and R^7C.3, respectively.

In embodiments, when R^7Dis substituted, R^7Dis substituted with one or more first substituent groups denoted by R^7D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7D.1substituent group is substituted, the R^7D.1substituent group is substituted with one or more second substituent groups denoted by R^7D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7D.2substituent group is substituted, the R^7D.2substituent group is substituted with one or more third substituent groups denoted by R^7D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7D, R^7D.1, R^7D.2, and R^7D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^7D, R^7D.1, R^7D.2, and R^7D.3, respectively.

In embodiments, when R⁸is substituted, R⁸is substituted with one or more first substituent groups denoted by R^8.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.1substituent group is substituted, the R^8.1substituent group is substituted with one or more second substituent groups denoted by R^8.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.2substituent group is substituted, the R^8.2substituent group is substituted with one or more third substituent groups denoted by R^8.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁸, R^8.1, R^8.2, and R^8.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R⁸, R^8.1, R^8.2, and R^8.3, respectively.

In embodiments, when R^8Ais substituted, R^8Ais substituted with one or more first substituent groups denoted by R^8A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8A.1substituent group is substituted, the R^8A.1substituent group is substituted with one or more second substituent groups denoted by R^8A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8A.2substituent group is substituted, the R^8A.2substituent group is substituted with one or more third substituent groups denoted by R^8A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8A, R^8A.1, R^8A.2, and R^8A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^8A, R^8A.1, R^8A.2, and R^8A.3, respectively.

In embodiments, when R^8Bis substituted, R^8Bis substituted with one or more first substituent groups denoted by R^8B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8B.1substituent group is substituted, the R^8B.1substituent group is substituted with one or more second substituent groups denoted by R^8B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8B.2substituent group is substituted, the R^8B.2substituent group is substituted with one or more third substituent groups denoted by R^8B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8B, R^8B.1, R^8B.2, and R^8B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^8B, R^8B.1, R^8B.2, and R^8B.3, respectively.

In embodiments, when R^8Aand R^8Bsubstituents 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 R^8A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8A.1substituent group is substituted, the R^8A.1substituent group is substituted with one or more second substituent groups denoted by R^8A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8A.2substituent group is substituted, the R^8A.2substituent group is substituted with one or more third substituent groups denoted by R^8A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8A.1, R^8A.2, and R^8A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^8A.1, R^8A.2, and R^8A.3, respectively.

In embodiments, when R^8Aand R^8Bsubstituents 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 R^8B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8B.1substituent group is substituted, the R^8B.1substituent group is substituted with one or more second substituent groups denoted by R^8B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8B.2substituent group is substituted, the R^8B.2substituent group is substituted with one or more third substituent groups denoted by R^8B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8B.1, R^8B.2, and R^8B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^8B.1, R^8B.2, and R^8B.3, respectively.

In embodiments, when R^8Cis substituted, R^8Cis substituted with one or more first substituent groups denoted by R^8C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8C.1substituent group is substituted, the R^8C.1substituent group is substituted with one or more second substituent groups denoted by R^8C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8C.2substituent group is substituted, the R^8C.2substituent group is substituted with one or more third substituent groups denoted by R^8C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8C, R^8C.1, R^8C.2, and R^8C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^8C, R^8C.1, R^8C.2, and R^8C.3, respectively.

In embodiments, when R^8Dis substituted, R^8Dis substituted with one or more first substituent groups denoted by R^8D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8D.1substituent group is substituted, the R^8D.1substituent group is substituted with one or more second substituent groups denoted by R^8D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8D.2substituent group is substituted, the R^8D.2substituent group is substituted with one or more third substituent groups denoted by R^8D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8D, R^8D.1, R^8D.2, and R^8D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^8D, R^8D.1, R^8D.2, and R^8D.3, respectively.

In embodiments, when R^8.1is substituted, R^8.1is substituted with one or more first substituent groups denoted by R^8.1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.1.1substituent group is substituted, the R^8.1.1substituent group is substituted with one or more second substituent groups denoted by R^8.1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.1.2substituent group is substituted, the R^8.1.2substituent group is substituted with one or more third substituent groups denoted by R^8.1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8.1, R^8.1.1, R^8.1.2, and R^8.1.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R¹, R^8.1.1, R^8.1.2, and R^8.1.3, respectively.

In embodiments, when R^8.2is substituted, R^8.2is substituted with one or more first substituent groups denoted by R^8.2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.2.1substituent group is substituted, the R^8.2.1substituent group is substituted with one or more second substituent groups denoted by R^8.2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.2.2substituent group is substituted, the R^8.2.2substituent group is substituted with one or more third substituent groups denoted by R^8.2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8.2, R^8.2.1, R^8.2.2, and R^8.2.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^8.2, R^8.2.1, R^8.2.2, and R^8.2.3, respectively.

In embodiments, when R^8.3is substituted, R^8.3is substituted with one or more first substituent groups denoted by R^8.3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.3.1substituent group is substituted, the R^8.3.1substituent group is substituted with one or more second substituent groups denoted by R^8.3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.3.2substituent group is substituted, the R^8.3.2substituent group is substituted with one or more third substituent groups denoted by R^8.3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8.3, R^8.3.1, R^8.3.2, and R^8.3.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R^8.3, R^8.3.1, R^8.3.2, and R^8.3.3, respectively.

In embodiments, when R^8.2and R^8.3substituents 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 R^8.2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.2.1substituent group is substituted, the R^8.2.1substituent group is substituted with one or more second substituent groups denoted by R^8.2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.2.2substituent group is substituted, the R^8.2.2substituent group is substituted with one or more third substituent groups denoted by R^8.2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8.2.1, R^8.2.2, and R^8.2.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^8.2.1, R^8.2.2, and R^8.2.3, respectively.

In embodiments, when R^8.2and R^8.3substituents 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 R^8.3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.3.1substituent group is substituted, the R^8.3.1substituent group is substituted with one or more second substituent groups denoted by R^8.3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^8.3.2substituent group is substituted, the R^8.3.2substituent group is substituted with one or more third substituent groups denoted by R^8.3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^8.3.1, R^8.3.2, and R^8.3.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^8.3.1, R^8.3.2, and R^8.3.3, respectively.

In embodiments, when R¹⁰is substituted, R¹⁰is substituted with one or more first substituent groups denoted by R^10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.1substituent group is substituted, the R^10.1substituent group is substituted with one or more second substituent groups denoted by R^10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.2substituent group is substituted, the R^10.2substituent group is substituted with one or more third substituent groups denoted by R^10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁰, R^10.1, R^10.2, and R^10.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R¹⁰, R^10.1, R^10.2, and R^10.3, respectively.

In embodiments, when R^10Ais substituted, R^10Ais substituted with one or more first substituent groups denoted by R^10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.1substituent group is substituted, the R^10A.1substituent group is substituted with one or more second substituent groups denoted by R^10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.2substituent group is substituted, the R^10A.2substituent group is substituted with one or more third substituent groups denoted by R^10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10A, R^10A.1, R^10A.2, and R^10A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10A, R^10A.1, R^10A.2, and R^10A.3respectively.

In embodiments, when R^10Bis substituted, R^10Bis substituted with one or more first substituent groups denoted by R^10Bas explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.1substituent group is substituted, the R^10B.1substituent group is substituted with one or more second substituent groups denoted by R^10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.2substituent group is substituted, the R^10B.2substituent group is substituted with one or more third substituent groups denoted by R^10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10B, R^10B.1, R^10B.2, and R^10B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10B, R^10B.1, R^10B.2, and R^10B.3, respectively.

In embodiments, when R^10Aand R^10Bsubstituents 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 R^10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.1substituent group is substituted, the R^10A.1substituent group is substituted with one or more second substituent groups denoted by R^10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.2substituent group is substituted, the R^10A.2substituent group is substituted with one or more third substituent groups denoted by R^10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10A.1, R^10A.2, and R^10A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^10A.1, R^10A.2, and R^10A.3, respectively.

In embodiments, when R^10Aand R^10Bsubstituents 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 R^10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.1substituent group is substituted, the R^10B.1substituent group is substituted with one or more second substituent groups denoted by R^10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.2substituent group is substituted, the R^10B.2substituent group is substituted with one or more third substituent groups denoted by R^10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10B.1, R^10B.2, and R^10B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^10B.1, R^10B.2, and R^10B.3, respectively.

In embodiments, when R^10Cis substituted, R^10Cis substituted with one or more first substituent groups denoted by R^10C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10C.1substituent group is substituted, the R^10C.1substituent group is substituted with one or more second substituent groups denoted by R^10C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10C.2substituent group is substituted, the R^10C.2substituent group is substituted with one or more third substituent groups denoted by R^10C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10C, R^10C.1, R^10C.2, and R^10C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10C, R^10C.1, R^10C.2, and R^10C.3respectively.

In embodiments, when R^10Dis substituted, R^10Dis substituted with one or more first substituent groups denoted by R^10Das explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10D.1substituent group is substituted, the R^10D.1substituent group is substituted with one or more second substituent groups denoted by R^10D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10D.2substituent group is substituted, the R^10D.2substituent group is substituted with one or more third substituent groups denoted by R^10D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10D, R^10D.1, R^10D.2, and R^10D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10D, R^10D.1, R^10D.2, and R^10D.3respectively.

In embodiments, when R¹¹is substituted, R¹¹is substituted with one or more first substituent groups denoted by R^11.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11.1substituent group is substituted, the R^11.1substituent group is substituted with one or more second substituent groups denoted by R^11.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11.2substituent group is substituted, the R^11.2substituent group is substituted with one or more third substituent groups denoted by R^11.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹¹, R^11.1, R^11.2, and R^11.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R¹¹, R^11.1, R^11.2, and R^11.3, respectively.

In embodiments, when R^11Ais substituted, R^11Ais substituted with one or more first substituent groups denoted by R^11A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11A.1substituent group is substituted, the R^11A.1substituent group is substituted with one or more second substituent groups denoted by R^11A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11A.2substituent group is substituted, the R^11A.2substituent group is substituted with one or more third substituent groups denoted by R^11A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11A, R^11A.1, R^11A.2, and R^11A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^11A, R^11A.1, R^11A.2, and R^11A.3respectively.

In embodiments, when R^11Bis substituted, R^11Bis substituted with one or more first substituent groups denoted by R^11B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11B.1substituent group is substituted, the R^11B.1substituent group is substituted with one or more second substituent groups denoted by R^11B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11B.2substituent group is substituted, the R^11B.2substituent group is substituted with one or more third substituent groups denoted by R^11B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11B, R^11B.1, R^11B.2, and R^11B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^11B, R^11B.1, R^11B.2, and R^11B.3respectively.

In embodiments, when R^11Aand R^11Bsubstituents 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 R^11A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11A.1substituent group is substituted, the R^11A.1substituent group is substituted with one or more second substituent groups denoted by R^11A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11A.2substituent group is substituted, the R^11A.2substituent group is substituted with one or more third substituent groups denoted by R^11A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11A.1, R^11A.2, and R^11A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^11A.1, R^11A.2, and R^11A.3, respectively.

In embodiments, when R^11Aand R^11Bsubstituents 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 R^11B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11B.1substituent group is substituted, the R^11B.1substituent group is substituted with one or more second substituent groups denoted by R^11B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11B.2substituent group is substituted, the R^11B.2substituent group is substituted with one or more third substituent groups denoted by R^11B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11B.1, R^11B.2, and R^11B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^11B.1, R^11B.2, and R^11B.3, respectively.

In embodiments, when R^11Cis substituted, R^11Cis substituted with one or more first substituent groups denoted by R^11C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11C.1substituent group is substituted, the R^11C.1substituent group is substituted with one or more second substituent groups denoted by R^11C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11C.2substituent group is substituted, the R^11C.2substituent group is substituted with one or more third substituent groups denoted by R^11C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11C, R^11C.1, R^11C.2, and R^11C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^11C, R^11C.1, R^11C.2, and R^11C.3respectively.

In embodiments, when R^11Dis substituted, R^11Dis substituted with one or more first substituent groups denoted by R^11D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11D.1substituent group is substituted, the R^11D.1substituent group is substituted with one or more second substituent groups denoted by R^11D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11D.2substituent group is substituted, the R^11D.2substituent group is substituted with one or more third substituent groups denoted by R^11D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11D, R^11D.1, R^11D.2, and R^11D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^11D, R^11D.1, R^11D.2, and R^11D.3respectively.

In embodiments, when R¹²is substituted, R¹²is substituted with one or more first substituent groups denoted by R^12.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12.1substituent group is substituted, the R^12.1substituent group is substituted with one or more second substituent groups denoted by R^12.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12.2substituent group is substituted, the R^12.2substituent group is substituted with one or more third substituent groups denoted by R^12.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹², R^12.1, R^12.2, and R^12.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2and R^WW.3correspond to R¹², R^12.1, R^12.2, and R^12.3, respectively.

In embodiments, when R^12Ais substituted, R^12Ais substituted with one or more first substituent groups denoted by R^12A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12A.1substituent group is substituted, the R^12A.1substituent group is substituted with one or more second substituent groups denoted by R^12A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12A.2substituent group is substituted, the R^12A.2substituent group is substituted with one or more third substituent groups denoted by R^12A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12A, R^12A.1, R^12A.2, and R^12A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^12A, R^12A.1, R^12A.2, and R^12A.3respectively.

In embodiments, when R^12Bis substituted, R^12Bis substituted with one or more first substituent groups denoted by R^12B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12B.1substituent group is substituted, the R^12B.1substituent group is substituted with one or more second substituent groups denoted by R^12B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12B.2substituent group is substituted, the R^12B.2substituent group is substituted with one or more third substituent groups denoted by R^12B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12B, R^12B.1, R^12B.2, and R^12B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^12B, R^12B.1, R^12B.2, and R^12B.3, respectively.

In embodiments, when R^12Aand R^12Bsubstituents 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 R^12A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12A.1substituent group is substituted, the R^12A.1substituent group is substituted with one or more second substituent groups denoted by R^12A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12A.2substituent group is substituted, the R^12A.2substituent group is substituted with one or more third substituent groups denoted by R^12A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12A.1, R^12A.2, and R^12A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^12A.1, R^12A.2, and R^12A.3, respectively.

In embodiments, when R^12Aand R^12Bsubstituents 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 R^12B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12B.1substituent group is substituted, the R^12B.1substituent group is substituted with one or more second substituent groups denoted by R^12B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12B.2substituent group is substituted, the R^12B.2substituent group is substituted with one or more third substituent groups denoted by R^12B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12B.1, R^12B.2, and R^12B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^12B.1, R^12B.2, and R^12B.3, respectively.

In embodiments, when R^12Cis substituted, R^12Cis substituted with one or more first substituent groups denoted by R^12C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12C.1substituent group is substituted, the R^12C.1substituent group is substituted with one or more second substituent groups denoted by R^12C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12C.2substituent group is substituted, the R^12C.2substituent group is substituted with one or more third substituent groups denoted by R^12C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12C, R^12C.1, R^12C.2, and R^12C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^12C, R^12C.1, R^12C.2, and R^12C.3respectively.

In embodiments, when R^12Dis substituted, R^12Dis substituted with one or more first substituent groups denoted by R^12D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12D.1substituent group is substituted, the R^12D.1substituent group is substituted with one or more second substituent groups denoted by R^12D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12D.2substituent group is substituted, the R^12D.2substituent group is substituted with one or more third substituent groups denoted by R^12D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12D, R^12D.1, R^12D.2, and R^12D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^12D, R^12D.1, R^12D.2, and R^12D.3respectively.

In embodiments, when R¹³is substituted, R¹³is substituted with one or more first substituent groups denoted by R^13.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13.1substituent group is substituted, the R^13.1substituent group is substituted with one or more second substituent groups denoted by R^13.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13.2substituent group is substituted, the R^13.2substituent group is substituted with one or more third substituent groups denoted by R^13.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹³, R^13.1, R^13.2, and R^13.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW2and R^WW.3correspond to R¹³, R^13.1, R^13.2, and R^13.3, respectively.

In embodiments, when R^13Bis substituted, R^13Bis substituted with one or more first substituent groups denoted by R^13A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13A.1substituent group is substituted, the R^13A.1substituent group is substituted with one or more second substituent groups denoted by R^13A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13A.2substituent group is substituted, the R^13A.2substituent group is substituted with one or more third substituent groups denoted by R^13A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^13A, R^13A.1, R^13A.2, and R^13A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^13A, R^13A.1, R^13A.2, and R^13A.3respectively.

In embodiments, when R^13Bis substituted, R^13Bis substituted with one or more first substituent groups denoted by R^13B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13B.1substituent group is substituted, the R^13B.1substituent group is substituted with one or more second substituent groups denoted by R^13B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13B.2substituent group is substituted, the R^13B.2substituent group is substituted with one or more third substituent groups denoted by R^13B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^13B, R^13B.1, R^13B.2, and R^13B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^13B, R^13B.1, R^13B.2, and R^13B.3respectively.

In embodiments, when R^13Band R^13Bsubstituents 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 R^13A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13A.1substituent group is substituted, the R^13A.1substituent group is substituted with one or more second substituent groups denoted by R^13A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13A.2substituent group is substituted, the R^13A.2substituent group is substituted with one or more third substituent groups denoted by R^13A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^13A.1, R^13A.2, and R^13A.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^13A.1, R^13A.2, and R^13A.3, respectively.

In embodiments, when R^13Band R^13Bsubstituents 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 R^13B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13B.1substituent group is substituted, the R^13B.1substituent group is substituted with one or more second substituent groups denoted by R^13B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13B.2substituent group is substituted, the R^13B.2substituent group is substituted with one or more third substituent groups denoted by R^13B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^13B.1, R^13B.2, and R^13B.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^13B.1, R^13B.2, and R^13B.3, respectively.

In embodiments, when R^13Cis substituted, R^13Cis substituted with one or more first substituent groups denoted by R^13C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13C.1substituent group is substituted, the R^13C.1substituent group is substituted with one or more second substituent groups denoted by R^13C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13C.2substituent group is substituted, the R^13C.2substituent group is substituted with one or more third substituent groups denoted by R^13C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^13C, R^13C.1, R^13C.2, and R^13C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^13CR^13C.1, R^13C.2, and R^13C.3respectively.

In embodiments, when R^13Dis substituted, R^13Dis substituted with one or more first substituent groups denoted by R^13D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13D.1substituent group is substituted, the R^13D.1substituent group is substituted with one or more second substituent groups denoted by R^13D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^13D.2substituent group is substituted, the R^13D.2substituent group is substituted with one or more third substituent groups denoted by R^13D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^13D, R^13D.1, R^13D.2, and R^13D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^13D, R^13D.1, R^13D.2, and R^13D.3, respectively.

In embodiments, when R²and R³substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R^2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1substituent group is substituted, the R^2.1substituent group is substituted with one or more second substituent groups denoted by R^2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1substituent group is substituted, the R^2.2substituent group is substituted with one or more third substituent groups denoted by R^2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^2.1, R^2.2, and R^2.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^2.1, R^2.2, and R^2.3, respectively.

In embodiments, when R²and R³substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R^3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.1substituent group is substituted, the R^3.1substituent group is substituted with one or more second substituent groups denoted by R^3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.2substituent group is substituted, the R^3.2substituent group is substituted with one or more third substituent groups denoted by R^3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^3.1, R^3.2, and R^3.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^3.1, R^3.2, and R^3.3, respectively.

In embodiments, when R³and R⁴substituents 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 R^3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.1substituent group is substituted, the R^3.1substituent group is substituted with one or more second substituent groups denoted by R^3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.2substituent group is substituted, the R^3.2substituent group is substituted with one or more third substituent groups denoted by R^3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^3.1, R^3.2, and R^3.3have values corresponding to the values of R^WW.1, R^WW.2and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^3.1, R^3.2, and R^3.3, respectively.

In embodiments, when R³and R⁴substituents 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 R^4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.1substituent group is substituted, the R^4.1substituent group is substituted with one or more second substituent groups denoted by R^4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.2substituent group is substituted, the R^4.2substituent group is substituted with one or more third substituent groups denoted by R^4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.1, R^4.2, and R^4.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^4.1, R^4.2, and R^4.3, respectively.

In embodiments, when R⁴and 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 R^4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.1substituent group is substituted, the R^4.1substituent group is substituted with one or more second substituent groups denoted by R^4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.2substituent group is substituted, the R^4.2substituent group is substituted with one or more third substituent groups denoted by R^4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.1, R^4.2, and R^4.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^4.1, R^4.2, and R^4.3, respectively.

In embodiments, when R⁴and 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 R^5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.1substituent group is substituted, the R^5.1substituent group is substituted with one or more second substituent groups denoted by R^5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.2substituent group is substituted, the R^5.2substituent group is substituted with one or more third substituent groups denoted by R^5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5.1, R^5.2, and R^5.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^5.1, R^5.2, and R^5.3., respectively.

In embodiments, when R¹⁰and R²substituents 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 R^10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.1substituent group is substituted, the R^10.1substituent group is substituted with one or more second substituent groups denoted by R^10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.2substituent group is substituted, the R^10.2substituent group is substituted with one or more third substituent groups denoted by R^10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁰, R^10.2, and R^10.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R¹⁰, R^10.2, and R^10.3, respectively.

In embodiments, when R¹⁰and R²substituents 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 R^2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1substituent group is substituted, the R^2.1substituent group is substituted with one or more second substituent groups denoted by R^2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1substituent group is substituted, the R^2.2substituent group is substituted with one or more third substituent groups denoted by R^2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^2.1, R^2.2, and R^2.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^2.1, R^2.2, and R^2.3, respectively.

In embodiments, when R¹¹and R¹²substituents 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 R^11.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11.1substituent group is substituted, the R^11.1substituent group is substituted with one or more second substituent groups denoted by R^11.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11.2substituent group is substituted, the R^11.2substituent group is substituted with one or more third substituent groups denoted by R^11.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^11.1, R^11.2, and R^11.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^11.1, R^11.2, and R^11.3, respectively.

In embodiments, when R¹¹and R¹²substituents 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 R^12.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12.1substituent group is substituted, the R^12.1substituent group is substituted with one or more second substituent groups denoted by R^12.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^12.2substituent group is substituted, the R^12.2substituent group is substituted with one or more third substituent groups denoted by R^12.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^12.1, R^12.2, and R^12.3have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3correspond to R^12.1, R^12.2, and R^12.3, respectively.