INHIBITORS OF ALPHA-5 BETA-1 INTEGRIN AND USES THEREOF

Abstract

Described herein, inter alia, are alpha-5 beta-1 inhibitors, pharmaceutical compositions including alpha-5 beta-1 inhibitors, methods for treating diseases using alpha-5 beta-1 inhibitors, and processes for making alpha-5 beta-1 inhibitors.

Description

BACKGROUND

Despite its high prevalence, current therapeutic options for asthma are quite limited. There is a paucity of effective treatments for asthma. Pharmacological modulation of the α5β1 integrin by small molecules presents one route to test the role of the α5β1 integrin in asthma. There is a need in the art for potent, selective α5β1 integrin inhibitors. 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 tautomer thereof, having the formula:

A¹ is C(R⁴) or N. A³ is C(R³) or N. A⁴ is C(R⁵) or N.

X is a bond, —C(R¹⁵)(R¹⁶)— or —N(R¹⁵)—. The symbol m is 1 or 2.

L¹ is bond, —C(O)—, —C(O)O—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —S(O)₂—, —S(O)NH—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or —[P(═O)(OH)O—]_n—H.

The symbol n is an integer from 1 to 3.

R² is hydrogen, halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX²₂, —CN, —SO_n2R^2C, —SO_v2NR^2AR^2B, —NR^2CNR^2AR^2B, —ONR^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^2C, —N^2ASO₂R^2C, —N^2AC(O)R^2C, —NR^2AC(O)OR^2C, —NR^2AOR^2C, —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.

R³ is hydrogen, halogen, —CX³₃, —CHX³₂, —CH₂X³, —OCX³₃, —OCH₂X³, —OCHX³₂, —CN, —SO_n3R^3C, —SO_v3NR^3AR^3B, —NR^3CNR^3AR^3B, —ONR^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^3C, —NR^3ASO₂R^3C, —NR^3AC(O)R^3C, —NR^3AC(O)OR^3C, —NR^3AOR^3C, —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.

R⁴ is hydrogen, halogen, —CX⁴₃, —CHX⁴₂, —CH₂X⁴, —OCX⁴₃, —OCH₂X⁴, —OCHX⁴₂, —CN, —SO_n4R^4C, —SO_v4NR^4AR^4B, —NR^4CNR^4AR^4B, ONR^4AR^4B, —NHC(O)NR^4AR^4B, N(O)_m4, —NR^4AR^4B, —C(O)R^4C, —C(O)OR^4C, —C(O)NR^4AR^4B, —OR^4C, —NR^4ASO₂R^4C, —NR^4AC(O)R^4C, —NR^4AC(O)OR^4C, NR^4AOR^4C, —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.

R⁵ is hydrogen, halogen, —CX⁵₃, —CHX⁵₂, —CH₂X⁵, —OCX⁵₃, —OCH₂X⁵, —OCHX⁵₂, —CN, —SO_n5R^5C, —SO_v5NR^5AR^5B, —NR^5CNR^5AR^5B, —ONR^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^5C, —NR^5ASO₂R^5C, —NR^5AC(O)R^5C, —NR^5AC(O)OR^5C, —NR^5AOR^5C, —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.

R⁶ is hydrogen, halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, —OCHX⁶₂, —CN, —SO_v6R^6C, —SO_v6NR^6AR^6B, —NR^6CNR^6AR^6B, —ONR^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^6C, —NR^6ASO₂R^6C, —NR^6AC(O)R^6C, —NR^6AC(O)OR^6C, —NR^6AOR^6C, —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.

R⁷ is hydrogen, halogen, —CX⁷₃, —CHX⁷₂, —CH₂X⁷, —OCX⁷₃, —OCH₂X⁷, —OCHX⁷₂, —CN, —SO_n7R^7C, —SO_v7NR^7AR^7B, —NR^7CNR^7AR^7B, —ONR^7AR^7B, —NHC(O)NR^7AR^7B, —N(O)_m7, —NR^7AR^7B, —C(O)R^7C, —C(O)OR^7C, —C(O)NR^7AR^7B, —OR^7C, —NR^7ASO₂R^7C, —NR^7AC(O)R^7C, —NR^7AC(O)OR^7C, —NR^7AOR^7C, —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.

R⁷ and R¹⁵ are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁸ is hydrogen, halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8C, —SO_v8NR^8AR^8B, —NR^8CNR^8AR^8B, —ONR^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^8C, —NR^8ASO₂R^8C, —R^8AC(O)R^8C, —NR^8AC(O)OR^8C, —NR^8AOR^8C, —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.

R⁹ is hydrogen, halogen, —CX⁹₃, —CHX⁹₂, —CH₂X⁹, —OCX⁹₃, —OCH₂X⁹, —OCHX⁹₂, —CN, —SO_n9R^9C, —SO_v9NR^9AR^9B, —NR^9CNR^9AR^9B, —ONR^9AR^9B, —NHC(O)NR^9AR^9B, —N(O)_m9, —NR^9AR^9B, —C(O)R^9C, —C(O)OR^9C, —C(O)NR^9AR^9B, —OR^9C, —NR^9ASO₂R^9C, —NR^9AC(O)R^9C, —NR^9AC(O)OR^9C, —NR^9AOR^9C, —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.

R⁹ and R¹¹ are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R¹⁰ is hydrogen, halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10C, —SO_v10NR^10AR^10B, —NR_10CNR^10AR^10B, —ONR^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^10C, —NR^10ASO₂R^10C, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —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.

R¹¹ is hydrogen, halogen, —CX¹¹₃, —CHX¹¹₂, —CH₂X¹¹, —OCX¹¹₃, —OCH₂X¹¹, —OCHX¹¹₂, —CN, —SO_n11R^11C, —SO_v11NR^11AR^11B, —NR^11CNR^11AR^11B, —ONR^11AR^11B, —NHC(O)NR^11AR^11B, —N(O)_m11, —NR^11AR^11B, —C(O)R^11C, —C(O)OR^11C, —C(O)NR^11AR^11B, —OR^11C, —NR^11ASO₂R^11C, —NR^11AC(O)R^11C, —NR^11AC(O)OR^11C, —NR^11AOR^11C, —C(NR^11C)NR^11AR^11B, —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.

R¹² is hydrogen, halogen, —CX¹²₃, —CHX¹²₂, —CH₂X¹², —OCX¹²₃, —OCH₂X¹², —OCHX¹²₂, —CN, —SO_n12R^12C, —SO_v12NR^12AR^12B, —NR^12CNR^12AR^12B, —ONR^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^12C, —NR^12ASO₂R^12C, —NR^12AC(O)R^12C, —NR^12AC(O)OR^12C, —NR^12AOR^12C, —C(NR^12C)NR^12AR^12B, —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.

R¹⁵ is hydrogen, —SO₂R^15C, —C(O)R^15C, —C(O)OR^15C, 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.

R¹⁶ is hydrogen, —SO₂R^16C, —C(O)R^16C, —C(O)OR^16C, 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.

R²⁰ is hydrogen, halogen, —CX²⁰₃, —CHX²⁰₂, —CH₂X²⁰, —OCX²⁰₃, —OCH₂X²⁰, —OCHX²⁰₂, —CN, —SO_n20R^20C, —SO_v20NR^20AR^20B, —NR²⁰CN^20AR^20B, —ONR^20AR^20B, —NHC(O)NR^20AR^20B, —N(O)_m20, —NR^20AR^20B, —C(O)R^20C, —C(O)OR^20C, —C(O)NR^20AR^20B, —OR^20C, —NR^20ASO₂R^20C, —NR^20AC(O)R^20C, —NR^20AC(O)OR^20C, —NR^20AOR^20C, —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.

R²¹ is hydrogen, halogen, —CX²¹₃, —CHX²¹₂, —CH₂X²¹, —OCX²¹₃, —OCH₂X²¹, —OCHX²¹₂, —CN, —SO_n21R^21C, —SO_v21NR^21AR^21B, —NR^21CN^21AR^21B, —ONR^21AR^21B, —NHC(O)NR^21AR^21B, —N(O)_n21, —NR^21AR^21B, —C(O)R^21C, —C(O)OR^21C, —C(O)NR^21AR^21B, —OR^21C, —NR^21ASO₂R^21C, —NR^21AC(O)R^21C, —NR^21AC(O)OR^21C, —NR^21AOR^21C, —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^2A, R^2B, R^2C, R^3A, R^3B, R^3C, R^4B, R^4B, R^4C, R^5A, R^5B, R^5C, R^6A, R^6B, R^6C, R^7A, R^7B, R^7C, R^8A, R^8B, R^8C, R^9A, R^9B, R^9C, R_10A, R^10B, R^10C, R^11A, R^11B, R^11C, R^12A, R^12B, R^12C, R^15C, R^16C, R^20A, R^20B, R^20C, R^21A, R^21B, and R^21C are independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂, —OCHBr₂, —OCHF₂, —OCHI₂, —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^2A and R^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^3A and R^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^4A and R^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^6A and R^6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^7A and R^7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^8A and R^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^9A and R^9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^10A and R^10B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^11A and R^11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^12A and R^12B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^20A and R^20B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^21A and R^21B substituents 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, X⁹, X¹⁰, X¹¹, X¹², X²⁰, and X²¹ are independently —F, —Cl, —Br, or —I.

The symbols n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, n20, and n21 are independently an integer from 0 to 4.

The symbols m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m20, m21, v2, v3, v4, v5, v6, v7, v8, v9, v10, v11, v12, v20, and v21 are independently 1 or 2.

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

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 tautomer 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 tautomer thereof.

In an aspect is provided a method of inhibiting angiogenesis 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 tautomer thereof.

In an aspect is provided a method of modulating (e.g., reducing) the level of activity of α5β1 integrin in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer 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-C₁₀ means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

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—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

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

The symbol “” 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:

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-C₅ alkyl 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., —CF₃ and —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-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
  • (B) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
    • (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
    • (ii) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆—C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
      • (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
      • (b) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —OCCl₃, —OCF₃, —OCBr₃, —OC₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(NH)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

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-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, 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-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

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-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, 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-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene, 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-C₇ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

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 substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

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 lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

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, R¹ may be substituted with one or more first substituent groups denoted by R^1.1, R² may be substituted with one or more first substituent groups denoted by R^2.1, R³ may be substituted with one or more first substituent groups denoted by R^3.1, R⁴ may be substituted with one or more first substituent groups denoted by R^4.1, R⁵ may be substituted with one or more first substituent groups denoted by R^5.1, and the like up to or exceeding an R¹⁰⁰ that may be substituted with one or more first substituent groups denoted by R^100.1. As a further example, R^1A may be substituted with one or more first substituent groups denoted by R^1A.1, R^2A may be substituted with one or more first substituent groups denoted by R^2A.1, R^3A may be substituted with one or more first substituent groups denoted by R^3A.1, R^4A may be substituted with one or more first substituent groups denoted by R^4A.1, R^5A may be substituted with one or more first substituent groups denoted by R^5A.1 and the like up to or exceeding an R^100A may be substituted with one or more first substituent groups denoted by R^100A.1 As a further example, L¹ may be substituted with one or more first substituent groups denoted by R^L1.1, L² may be substituted with one or more first substituent groups denoted by R^L2.1, L³ may be substituted with one or more first substituent groups denoted by R^L3.1, L⁴ may be substituted with one or more first substituent groups denoted by R^L4.1, L⁵ may be substituted with one or more first substituent groups denoted by R^L5.1 and the like up to or exceeding an L¹⁰⁰ which 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^WW or L^WW wherein “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.1 or R^LWW.1, respectively. 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.1 as 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.2 as 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^WW represents 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^WW is 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^WW may 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^WW linker 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^WW is phenyl, the said phenyl group is optionally substituted by one or more R^WW.1 groups as defined herein below, e.g., when R^WW.1 is 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.2 is optionally substituted by one or more R^{WW. 3}. By way of example when the R^WW group 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:

R^WW.1 is 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, 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.1 is 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.1 is independently —F, —Cl, —Br, or —I.

R^WW.2 is 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.2 is 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.2 is independently —F, —Cl, —Br, or —I.

R^WW.3 is 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.3 is independently —F, —Cl, —Br, or —I.

Where two different R^WW substituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring 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^WW substituents joined together to form an openly substituted ring, the “WW” symbol in the R^WW.1, R^WW.2 and R^WW.3 refers to the designated number of one of the two different R^WW substituents. For example, in embodiments where R^100A and R^100B are optionally joined together to form an openly substituted ring, R^WW.1 is R^100A.1, R^WW.2 is R^100A.2, and R^{WW. 3} is R^100A.3. Alternatively, in embodiments where R^100A and R^100B are optionally joined together to form an openly substituted ring, R^WW.1 is R^100B.1, R^WW.2 is R^100B.2, and R^{WW. 3} is R^100B.3. R^WW.1, R^WW.2 and R^{WW. 3} in this paragraph are as defined in the preceding paragraphs.

R^LWW.1 is 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.1 is 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.1 is independently —F, —Cl, —Br, or —I.

R^LWW.2 is 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.2 is 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.2 is independently —F, —Cl, —Br, or —I.

R^LWW.3 is 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.3 is 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^WW substituent) is not specifically defined in this disclosure, then that R group (R^WW group) 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^WW is 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.3 are 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^WW substituent) is not explicitly defined, then that L group (L^WW group) 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.2 and R^LWW.3 are 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-C₂₀ alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

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 R¹³ substituents are present, each R¹³ substituent 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 R¹³ and 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 “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.

“Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

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 no 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 “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”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

“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 an inflammatory disease. In embodiments, the disease is asthma. In embodiments, the disease is a cancer. In embodiments, the disease is angiogenesis.

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, diabetic retinopathy, 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, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

The term “asthma” refers to any disease or condition characterized by inflammation within the respiratory system, often accompanied with wheezing, airway restriction, shortness of breath, chest tightness, and coughing. In embodiments, asthma is characterized by airway hyperresponsiveness. In embodiments, asthma is airway hyperresponsiveness. Asthma may refer inflammation in the bronchi and bronchioles. Asthma may refer to atopic asthma. Asthma may refer to non-atopic asthma.

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

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

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

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, ⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr, ⁹⁴Tc, ⁹⁴Tc, ^99mTc, ⁹⁹Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ^154-1581Gd, ¹⁶¹Th, 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, ⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr, ⁹⁴Tc, ⁹⁴Tc, ^99mTc, ⁹⁹Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ^154-1581Gd, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁶⁹Er, ¹⁷⁵Lu, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹⁴Ir, 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 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., inflammatory disease, asthma, cancer, or angiogenesis) 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 “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

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

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 α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

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.

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.

Integrins are transmembrane proteins that mediate interactions between adhesion molecules on adjacent cells and/or the extracellular matrix (ECM). Integrins have diverse roles in several biological processes including, for example, cell migration during development and wound healing, cell differentiation, and apoptosis. Integrins typically exist as heterodimers consisting of a subunits (about 120-170 kDa in size) and p subunits (about 90-100 kDa in size).

The terms “α5β1” and “α5β1 integrin” refer to an integrin comprised of an α5 subunit and a β1 subunit and is used according to its common, ordinary meaning. The term “α5β1” refers to proteins of the same or similar names, homologs, isoforms, and functional fragments thereof, so long as such fragments retain α5β1 integrin activity. The term includes any recombinant or naturally-occurring form of α5β1, or an α5β1 preprotein, or variants thereof that maintain α5β1 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype α5β1). In embodiments, α5 has the protein sequence corresponding to RefSeq NP_002196.3. In embodiments, α5 has the protein sequence corresponding to the proteolytically processed mature version of RefSeq NP_002196.3. In embodiments, α5 has the amino acid sequence corresponding to the reference number GI: 938148811. In embodiments, β1 has the protein sequence corresponding to RefSeq NP_002202.2 In embodiments, β1 has the amino acid sequence corresponding to the reference number GI: 19743813.

An “α5β1-inhibitor” as used herein refers to a composition (e.g., a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) capable of reducing the activity of α5β1 integrin when compared to a control compound (e.g., known to have no reduction in α5β1 integrin activity) or the absence of the α5β1-inhibitor compound. An “α5β1-inhibitor compound” refers to a compound (e.g., compounds described herein) that reduce the activity of α5β1 integrin when compared to a control, such as absence of the compound or a compound with known inactivity.

An “α5β1-specific moiety”, “specific,” “specifically”, “specificity”, or the like of a composition (e.g., a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) refers to the composition's ability to discriminate between particular molecular targets to a significantly greater extent than other proteins in the cell (e.g., a compound having specificity towards α5β1 integrin binds to α5β1 integrin whereas the same compound displays little-to-no binding to other integrins such as αvβ1, α8β1, α2β1, αvβ3, αvβ5, or αvβ6). An “α5β1-specific compound” refers to a compound (e.g. compounds described herein) having specificity towards α5β1 integrin.

The terms “α5β1-selective,” “selective,” or “selectivity” or the like of a compound refers to the composition's (e.g., a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) ability to cause a particular action in a particular molecular target (e.g., a compound having selectivity toward α5β1 integrin would inhibit only α5β1). An “α5β1-selective compound” refers to a compound (e.g. compounds described herein) having selectivity towards α5β1 integrin.

II. Compounds

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

A¹ is C(R⁴) or N.

A³ is C(R³) or N.

A⁴ is C(R⁵) or N.

X is a bond, —C(R¹⁵)(R¹⁶)— or —N(R¹⁵)—.

The symbol m is 1 or 2.

L¹ is bond, —C(O)—, —C(O)O—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —S(O)₂—, —S(O)NH—, substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹ is hydrogen, 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 aryl (e.g., C₆-C₁₀ or phenyl), substituted or unsubstituted hereoaryl (e.g., 5 to 10 membered, 5 to 9 membered, or to 6 membered), or —[P(═O)(OH)O—]_n—H.

The symbol n is an integer from 1 to 3.

R² is hydrogen, halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX²₂, —CN, —SO_n2R^2C, —SO_v2NR^2AR^2B, —N^2CNR^2AR^2B, —ONR^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^2C, —N^2ASO₂R^2C, —N^2AC(O)R^2C, —NR^2AC(O)OR^2C, —N^2AOR^2C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³ is hydrogen, halogen, —CX³₃, —CHX³₂, —CH₂X³, —OCX³₃, —OCH₂X³, —OCHX³₂, —CN, —SO_n3R^3C, —SO_v3NR^3AR^3B, —NR^3CNR^3AR^3B, —ONR^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^3C, —NR^3ASO₂R^3C, —NR^3AC(O)R^3C, —NR^3AC(O)OR^3C, —NR^3AOR^3C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴ is hydrogen, halogen, —CX⁴₃, —CHX⁴₂, —CH₂X⁴, —OCX⁴₃, —OCH₂X⁴, —OCHX⁴₂, —CN, —SO_n4R^4C, —SO_v4NR^4AR^4B, —N^4CNR^4AR^4B, —ONR^4AR^4B, —NHC(O)NR^4AR^4B, —N(O)_m4, —NR^4AR^4B, —C(O)R^4C, —C(O)OR^4C, —C(O)NR^4AR^4B, —OR^4C, —N^4ASO₂R^4C, —N^4AC(O)R^4C, —NR^4AC(O)OR^4C, NR^4AOR^4C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁵ is hydrogen, halogen, —CX⁵₃, —CHX⁵₂, —CH₂X⁵, —OCX⁵₃, —OCH₂X⁵, —OCHX⁵₂, —CN, —SO_n5R^5C, —SO_v5NR^5AR^5B, —NR^5CNR^5AR^5B, —ONR^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^5C, —NR^5ASO₂R^8C, —NR^5AC(O)R^5C, —NR^5AC(O)OR^5C, —NR^5AOR^5C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁—C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁶ is hydrogen, halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, —OCHX⁶₂, —CN, —SO_v6R^6C, —SO_v6NR^6AR^6B, —NR^6CNR^6AR^6B, —ONR^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^6C, —NR^6ASO₂R^6C, —NR^6AC(O)R^6C, —NR^6AC(O)OR^6C, —NR^6AOR^6C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁷ is hydrogen, halogen, —CX⁷₃, —CHX⁷₂, —CH₂X⁷, —OCX⁷₃, —OCH₂X⁷, —OCHX⁷₂, —CN, —SO_n7R^7C, —SO_v7NR^7AR^7B, —NR^7CNR^7AR^7B, —ONR^7AR^7B, —NHC(O)NR^7AR^7B, —N(O)_m7, —NR^7AR^7B, —C(O)R^7C, —C(O)OR^7C, —C(O)NR^7AR^7B, —OR^7C, —NR^7ASO₂R^7C, —NR^7AC(O)R^7C, —NR^7AC(O)OR^7C, —NR^7AOR^7C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁷ and R¹⁵ are optionally joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁸ is hydrogen, halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8C, —SO_v8NR^8AR^8B, —NR^8CN^8AR^8B, —ONR^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^8C, —NR^8ASO₂R^8C, —NR^8AC(O)R^5C, —NR^8AC(O)OR^8C, —NR^8AOR^8C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁹ is hydrogen, halogen, —CX⁹₃, —CHX⁹₂, —CH₂X⁹, —OCX⁹₃, —OCH₂X⁹, —OCHX⁹₂, —CN, —SO_n9R^9C, —SO_v9NR^9AR^9B, —NR^9CNR^9AR^9B, —ONR^9AR^9B, —NHC(O)NR^9AR^9B, —N(O)_m9, —NR^9AR^9B, —C(O)R^9C, —C(O)OR^9C, —C(O)NR^9AR^9B, —OR^9C, —NR^9ASO₂R^9C, —NR^9AC(O)R^9C, —NR^9AC(O)OR^9C, —NR^9AOR^9C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁹ and R¹¹ are optionally joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁰ is hydrogen, halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10C, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^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^10C, —NR^10ASO₂R^10C, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹¹ is hydrogen, halogen, —CX¹¹₃, —CHX¹¹₂, —CH₂X¹¹, —OCX¹¹₃, —OCH₂X¹¹, —OCHX¹¹₂, —CN, —SO_n11R^11C, —SO_v11NR^11AR^11B, —NR^11CNR^11AR^11B, —ONR^11AR^11B, —NHC(O)NR^11AR^11B, —N(O)_m11, —NR^11AR^11B, —C(O)R^11C, —C(O)OR^11C, —C(O)NR^11AR^11B, —OR^11C, —NR^11ASO₂R^11C, —NR^11AC(O)R^11C, —NR^11AC(O)OR^11C, —NR^11AOR^11C, —C(NR^11C)NR^11AR^11B, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹² is hydrogen, halogen, —CX¹²₃, —CHX¹²₂, —CH₂X¹², —OCX¹²₃, —OCH₂X¹², —OCHX¹²₂, —CN, —SO_n12R^12C, —SO_v12NR^12AR^12B, —NR^12CNR^12AR^12B, —ONR^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^12C, —NR^12ASO₂R^12C, —NR^12AC(O)R^12C, —NR^12AC(O)OR^12C, —NR^12AOR^12C, —C(NR^12C)NR^12AR^12B, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁵ is hydrogen, —SO₂R^15C, —C(O)R^15C, —C(O)OR^15C, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁶ is hydrogen, —SO₂R^16C, —C(O)R^16C, —C(O)OR^16C, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R²⁰ is hydrogen, halogen, —CX²⁰₃, —CHX²⁰₂, —CH₂X²⁰, —OCX²⁰₃, —OCH₂X²⁰, —OCHX²⁰₂, —CN, —SO_n20R^20C, —SO₂₀NR^20AR^20B, —NR²⁰CN^20AR^20B, —ONR^20AR^20B, —NHC(O)NR^20AR^20B, —N(O)_m20, —NR^20AR^20B, —C(O)R^20C, —C(O)OR^20C, —C(O)NR^20AR^20B, —OR^20C, —NR^20ASO₂R^20C, —NR^20AC(O)R^20C, —NR^20AC(O)OR^20C, —NR^20AOR^20C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R²¹ is hydrogen, halogen, —CX²¹₃, —CHX²¹₂, —CH₂X²¹, —OCX²¹₃, —OCH₂X²¹, —OCHX²¹₂, —CN, —SO_n21R^21C, —SO_v21NR^21AR^21B, —NR^21CN^21AR^21B, —ONR^21AR^21B, —NHC(O)NR^21AR^21B, —N(O)_n21, —NR^21AR^21B, —C(O)R^21C, —C(O)OR^21C, —C(O)NR^21AR^21B, —OR^21C, —NR^21ASO₂R^21C, —NR^21AC(O)R^21C, —NR^21AC(O)OR^21C, —NR^21AOR^21C, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^2A, R^2B, R^2C, R^3A, R^3B, R^3C, R^4B, R^4B, R^4C, R^5A, R^5B, R^5C, R^6A, R^6B, R^6C, R^7A, R^7B, R^7C, R^8A, R^8B, R^8C, R^9A, R^9B, R^9C, R^10A, R^10B, R^10C, R^11A, R^11B, R^11C, R^12A, R^12B, R^12C, R^15C, R^16C, R^20A, R^20B, R^20C, R^21A, R^21B, and R^21C are independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂, —OCHBr₂, —OCHF₂, —OCHI₂, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^2A and R^2B substituents 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^3A and R^3B substituents 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^4A and R^4B substituents 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^5A and R^5B substituents 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^6A and R^6B substituents 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^7A and R^7B substituents 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^8A and R^8B substituents 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^9A and R^9B substituents 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^10A and R^10B substituents 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^11A and R^11B substituents 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^12A and R^12B substituents 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^20A and R^20B substituents 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^21A and R^21B substituents 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, X⁹, X¹⁰, X¹¹, X¹², X²⁰, and X²¹ are independently —F, —Cl, —Br, or —I.

The symbols n2, n3, n4, n5, n6, n7, n8, n9, n10, n1l, n12, n20, and n21 are independently an integer from 0 to 4.

The symbols m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m20, m21, v2, v3, v4, v5, v6, v7, v8, v9, v10, v11, v12, v20, and v21 are independently 1 or 2.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R²⁰, and R²¹ are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², R²⁰, and R²¹ are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², R²⁰, and R²¹ are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, the compound has the formula:

A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, the compound has the formula:

It will be understood by one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms. For example, a tautomer of formula (I-2) is

wherein A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments. As another example, a tautomer of formula (II-2) is

wherein A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁷, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments. As another example, a tautomer of formula (II-3) is

wherein A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments. As another example, a tautomer of formula (III-2) is

wherein A¹, A³, A⁴, X, m, L¹, R¹, R², R⁶, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including in embodiments.

In embodiments, A¹ is C(R⁴). In embodiments, A¹ is N. In embodiments, A³ is C(R³). In embodiments, A³ is N. In embodiments, A⁴ is C(R⁵). In embodiments, A⁴ is N.

In embodiments, A¹ is C(R⁴), A³ is C(R³), and A⁴ is C(R⁵). In embodiments, A¹ is N, A³ is C(R³), and A⁴ is C(R⁵). In embodiments, A¹ is C(R⁴), A³ is N, and A⁴ is N.

In embodiments, m is 1. In embodiments, m is 2.

In embodiments, X is a bond. In embodiments, X is —C(R¹⁵)(R¹⁶)—. In embodiments, X is —CH₂—. In embodiments, X is —N(R¹⁵)—. In embodiments, X is —NH—.

In embodiments, a substituted L¹ (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L¹ 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 L¹ is substituted, it is substituted with at least one substituent group. In embodiments, when L¹ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L¹ is substituted, it is substituted with at least one lower substituent group.

In embodiments, L¹ is a bond, —NH—, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, L¹ is a bond, —NH—, —(CH₂)_z1—NH—, —(CH₂)_z2—, or —(CH₂)_z3—N((CH₂)_z4CH₃)—C(O)—, wherein z1, z2, and z3 are independently an integer from 1 to 10; and z4 is an integer from 0 to 9. In embodiments, L¹ is a bond. In embodiments, L¹ is —NH—. In embodiments, L¹ is —(CH₂)_z1—NH—, wherein z1 is an integer from 1 to 4. In embodiments, L¹ is —(CH₂)_z2—, wherein z2 is an integer from 1 to 4. In embodiments, L¹ is —(CH₂)_z3—N((CH₂)_z4CH₃)—C(O)—; wherein z3 is an integer from 1 to 4, and z4 is an integer from 0 to 4.

In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. In embodiments, z1 is 6. In embodiments, z1 is 7. In embodiments, z1 is 8. In embodiments, z1 is 9. In embodiments, z1 is 10. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2 is 6. In embodiments, z2 is 7. In embodiments, z2 is 8. In embodiments, z2 is 9. In embodiments, z2 is 10. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments, z3 is 8. In embodiments, z3 is 9. In embodiments, z3 is 10. In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5. In embodiments, z4 is 6. In embodiments, z4 is 7. In embodiments, z4 is 8. In embodiments, z4 is 9.

In embodiments, a substituted R¹ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, 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 R¹ 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 R¹ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹ is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or —[P(═O)(OH)O-]1-H, where n is an integer from 1 to 3. In embodiments, R¹ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In embodiments, R¹ is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl. In embodiments, R¹ is hydrogen. In embodiments, R¹ is unsubstituted C₁-C₆ alkyl. In embodiments, R¹ is unsubstituted methyl. In embodiments, R¹ is unsubstituted ethyl. In embodiments, R¹ is unsubstituted propyl. In embodiments, R¹ is unsubstituted n-propyl. In embodiments, R¹ is unsubstituted isopropyl. In embodiments, R¹ is unsubstituted butyl. In embodiments, R¹ is unsubstituted n-butyl. In embodiments, R¹ is unsubstituted tert-butyl. In embodiments, R¹ is unsubstituted pentyl. In embodiments, R¹ is unsubstituted hexyl. In embodiments, R¹ is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹ is substituted or unsubstituted unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹ is unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹ is —P(═O)(OH)OH. In embodiments, R¹ is —[P(═O)(OH)O—]_n—H, wherein n is 1. In embodiments, R¹ is —[P(═O)(OH)O—]_n—H, wherein n is 2. In embodiments, R¹ is —[P(═O)(OH)O—]_n—H, wherein n is 3.

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 R² 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 R² is substituted, it is substituted with at least one substituent group. In embodiments, when R² is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R² is 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^2A 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 R^2A is substituted, it is substituted with at least one substituent group. In embodiments, when R^2A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2A is 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^2B 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 R^2B is substituted, it is substituted with at least one substituent group. In embodiments, when R^2B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^2A and R^2B substituents 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^2A and R^2B substituents 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^2A and 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^2A and R^2B substituents 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^2A and R^2B substituents 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^2C 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 R^2C is substituted, it is substituted with at least one substituent group. In embodiments, when R^2C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R² is 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, —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, R² is halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², or —OCHX²₂. In embodiments, X² is independently —F or —Cl. In embodiments, R² is halogen. In embodiments, R² is —F. In embodiments, R² is —Cl. In embodiments, R² is —Br. In embodiments, R² is —I.

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 R⁶ 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 R⁶ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁶ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁶ is 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^6A 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 R^6A is substituted, it is substituted with at least one substituent group. In embodiments, when R^6A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6A is 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^6B 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 R^6B is substituted, it is substituted with at least one substituent group. In embodiments, when R^6B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^6A and R^6B substituents 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^6A and R^6B substituents 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^6A and 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^6A and R^6B substituents 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^6A and R^6B substituents 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^6C 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 R^6C is substituted, it is substituted with at least one substituent group. In embodiments, when R^6C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^6C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁶ is 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, —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, R⁶ is halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, or —OCHX⁶₂. In embodiments, X⁶ is independently —F or —Cl. In embodiments, R⁶ is halogen. In embodiments, R⁶ is —F. In embodiments, R⁶ is —Cl. In embodiments, R⁶ is —Br. In embodiments, R⁶ is —I. In embodiments, R⁶ is unsubstituted C₁-C₆ alkyl. In embodiments, R⁶ is unsubstituted methyl. In embodiments, R⁶ is unsubstituted ethyl. In embodiments, R⁶ is unsubstituted propyl. In embodiments, R⁶ is unsubstituted n-propyl. In embodiments, R⁶ is unsubstituted isopropyl. In embodiments, R⁶ is unsubstituted butyl. In embodiments, R⁶ is unsubstituted n-butyl. In embodiments, R⁶ is unsubstituted tert-butyl. In embodiments, R⁶ is unsubstituted pentyl. In embodiments, R⁶ is unsubstituted hexyl.

In embodiments, R² and R⁶ are halogen. In embodiments, R² and R⁶ are —Cl. In embodiments, R² is halogen and R⁶ is unsubstituted C₁-C₆ alkyl.

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 R³ 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 R³ is substituted, it is substituted with at least one substituent group. In embodiments, when R³ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R³ is 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^3A 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 R^3A is substituted, it is substituted with at least one substituent group. In embodiments, when R^3A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3A is 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^3B 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 R^3B is substituted, it is substituted with at least one substituent group. In embodiments, when R^3B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^3A and R^3B substituents 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^3A and R^3B substituents 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^3A and R^3B 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^3A and R^3B substituents 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^3A and R^3B substituents 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^3C 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 R^3C is substituted, it is substituted with at least one substituent group. In embodiments, when R^3C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R³ is 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, —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, R³ is hydrogen.

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 R⁴ 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 R⁴ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁴ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁴ is 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^4A 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 R^4A is substituted, it is substituted with at least one substituent group. In embodiments, when R^4A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4A is 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^4B 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 R^4B is substituted, it is substituted with at least one substituent group. In embodiments, when R^4B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^4A and R^4B substituents 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^4A and R^4B substituents 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^4A and R^4B 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^4A and R^4B substituents 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^4A and R^4B substituents 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^4C 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 R^4C is substituted, it is substituted with at least one substituent group. In embodiments, when R^4C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁴ is 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, —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, R⁴ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is substituted or unsubstituted phenyl. In embodiments, R⁴ is unsubstituted phenyl. In embodiments, R⁴ is halogen, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁴ is halogen. In embodiments, R⁴ is —F. In embodiments, R⁴ is —Cl. In embodiments, R⁴ is —Br. In embodiments, R⁴ is —I. In embodiments, R⁴ is substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R⁴ is substituted or unsubstituted 5 to 6 membered heteroaryl.

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 R⁵ 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 R⁵ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁵ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁵ is 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^5A 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 R^5A is substituted, it is substituted with at least one substituent group. In embodiments, when R^5A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5A is 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^5B 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 R^5B is substituted, it is substituted with at least one substituent group. In embodiments, when R^5B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^5A and R^5B substituents 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^5A and R^5B substituents 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^5A and R^5B 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^5A and R^5B substituents 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^5A and R^5B substituents 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^5C 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 R^5C is substituted, it is substituted with at least one substituent group. In embodiments, when R^5C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁵ is 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, —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, R⁵ is hydrogen.

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 R⁷ 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 R⁷ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁷ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁷ is 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^7A 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 R^7A is substituted, it is substituted with at least one substituent group. In embodiments, when R^7A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7A is 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^7B 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 R^7B is substituted, it is substituted with at least one substituent group. In embodiments, when R^7B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^7A and R^7B substituents 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^7A and R^7B substituents 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^7A and R^7B 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^7A and R^7B substituents 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^7A and R^7B substituents 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^7C 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 R^7C is substituted, it is substituted with at least one substituent group. In embodiments, when R^7C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^7C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁷ is 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, —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, R⁷ is hydrogen.

In embodiments, a substituted R¹⁵ (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 R¹⁵ 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 R¹⁵ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹⁵ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹⁵ is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^15C (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^15C 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 R^15C is substituted, it is substituted with at least one substituent group. In embodiments, when R^15C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^15C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹⁵ is hydrogen, —SO₃H, —SO₂NH₂, —C(O)H, —C(O)OH, —CONH₂, 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, R¹⁵ is hydrogen.

In embodiments, a substituted ring formed when R⁷ and R¹⁵ substituents 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 R⁷ and R¹⁵ substituents 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 R⁷ and R¹⁵ substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R⁷ and R¹⁵ substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R⁷ and R¹⁵ substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁷ and R¹⁵ are joined to form a substituted or unsubstituted C₅-C₆ cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁷ and R¹⁵ are joined to form an unsubstituted cyclohexyl. In embodiments, R⁷ and R¹⁵ are joined to form an unsubstituted 6 membered heterocycloalkyl, wherein the heterocycloalkyl includes (i) an oxygen atom, (ii) a nitrogen atom, or (iii) an oxygen atom and a nitrogen atom. In embodiments, R⁷ and R¹⁵ are joined to form an unsubstituted phenyl.

In embodiments, X is —C(R¹⁵)(R¹⁶)— and R⁷ is bonded to R¹⁵ together with the ring carbon atoms to which they are attached to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₄-C₈, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 4 to 8 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁷ bonded to R¹⁵ together with the ring carbon atoms to which they are attached form:

R⁸, R⁹, R¹⁰, R¹¹, R¹², and L¹ are as described herein, including in embodiments.

R¹³ is independently oxo, halogen, —CX¹³₃, —CHX¹³₂, —CH₂X¹³, —OCX¹³₃, —OCH₂X¹³, —OCHX¹³₂, —CN, —SO_n13R^13C, —SO_v13NR^13AR^13B, —NR^13CNR^13AR^13B, —ONR^13AR^13B, —NHC(O)NR^13AR^13B, —N(O)_m13, —NR^13AR^13B, —C(O)R^13C, —C(O)OR^13C, —C(O)NR^13AR^13B, —OR^13C, —NR^13ASO₂R^13C, —NR^13AC(O)R^13C, —NR^13AC(O)OR^13C, —NR^13AOR^13C, —N₃, Substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^13A, R^13B, and R^13C are independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂, —OCHBr₂, —OCHF₂, —OCHI₂, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^13A and R^13B substituents 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).

X¹³ is independently —F, —Cl, —Br, or —I.

The symbol n13 is an integer from 0 to 4.

The symbols m13 and v13 are independently 1 or 2.

The symbol z13 is an integer from 0 to 7.

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 R¹³ 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 R¹³ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹³ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹³ is substituted, it is substituted with at least one lower substituent group.

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

In embodiments, a substituted ring formed when R^13A and R^13B substituents 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^13A and R^13B substituents 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^13A and R^13B 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^13A and R^13B substituents 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^13A and R^13B substituents 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^13C 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 R^13C is substituted, it is substituted with at least one substituent group. In embodiments, when R^13C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^13C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹³ is independently 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, —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, —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, R¹³ is independently oxo.

In embodiments, R¹³ is 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, —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, z13 is 0. In embodiments, z13 is 1. In embodiments, z13 is 2. In embodiments, z13 is 3. In embodiments, z13 is 4. In embodiments, z13 is 5. In embodiments, z13 is 6. In embodiments, z13 is 7.

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 R⁸ 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 R⁸ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁸ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁸ is 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^8A 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 R^8A is substituted, it is substituted with at least one substituent group. In embodiments, when R^8A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8A is 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^8B 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 R^8B is substituted, it is substituted with at least one substituent group. In embodiments, when R^8B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^8A and R^8B substituents 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^8A and R^8B substituents 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^8A and 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^8A and R^8B substituents 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^8A and R^8B substituents 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^8C 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 R^8C is substituted, it is substituted with at least one substituent group. In embodiments, when R^8C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^8C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁸ is 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, —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, R⁸ is hydrogen.

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

In embodiments, a substituted R^9A (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^9A 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 R^9A is substituted, it is substituted with at least one substituent group. In embodiments, when R^9A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^9A is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^9B (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^9B 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 R^9B is substituted, it is substituted with at least one substituent group. In embodiments, when R^9B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^9B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^9A and R^9B substituents 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^9A and R^9B substituents 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^9A and R^9B 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^9A and R^9B substituents 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^9A and R^9B substituents 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^9C (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^9C 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 R^9C is substituted, it is substituted with at least one substituent group. In embodiments, when R^9C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^9C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁹ is 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, —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, R⁹ is hydrogen.

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 R¹⁰ 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 R¹⁰ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹⁰ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹⁰ is 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^10A 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 R^10A is substituted, it is substituted with at least one substituent group. In embodiments, when R^10A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10A is 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^10B 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 R^10B is substituted, it is substituted with at least one substituent group. In embodiments, when R^10B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^10A and R^10B substituents 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^10A and R^10B substituents 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^10A and R^10B 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^10A and R^10B substituents 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^10A and R^10B substituents 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^10C 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 R^10C is substituted, it is substituted with at least one substituent group. In embodiments, when R^10C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹⁰ is 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, —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, R¹⁰ is hydrogen.

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 R¹¹ 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 R¹¹ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹¹ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹¹ is 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^11A 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 R^11A is substituted, it is substituted with at least one substituent group. In embodiments, when R^11A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11A is 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^11B 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 R^11B is substituted, it is substituted with at least one substituent group. In embodiments, when R^11B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^11A and R^11B substituents 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^11A and R^11B substituents 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^11A and R^11B 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^11A and R^11B substituents 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^11A and R^11B substituents 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^11C 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 R^11C is substituted, it is substituted with at least one substituent group. In embodiments, when R^11C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^11C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹¹ is 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, —C(NH)NH₂, —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, R¹¹ is hydrogen, —C(NR^11C)NR^11AR^11B, 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, R¹¹ is hydrogen. In embodiments, R¹¹ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, R¹¹ is substituted or unsubstituted alkyl. In embodiments, R¹¹ is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R¹¹ is unsubstituted methyl. In embodiments, R¹¹ is unsubstituted ethyl. In embodiments, R¹¹ is unsubstituted propyl. In embodiments, R¹¹ is unsubstituted n-propyl. In embodiments, R¹¹ is unsubstituted isopropyl. In embodiments, R¹¹ is unsubstituted butyl. In embodiments, R¹¹ is unsubstituted n-butyl. In embodiments, R¹¹ is unsubstituted tert-butyl. In embodiments, R¹¹ is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹¹ is substituted or unsubstituted heterocycloalkyl. In embodiments, R¹¹ is substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R¹¹ is unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is substituted or unsubstituted heteroalkyl. In embodiments, R¹¹ is —C(NR^11C)NR^11AR^11B. In embodiments, R¹¹ is

In embodiments R¹¹ is

In embodiments, R¹¹ is

In embodiments, R^11B and R^11C are hydrogen. In embodiments, R^11B and R^11C are not hydrogen. In embodiments, R^11B is hydrogen and R^11C is not hydrogen. In embodiments, R^11B is not hydrogen and R^11C is hydrogen. In embodiments, R^11C is hydrogen. In embodiments, R^11C is —CN. In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is

In embodiments, R¹¹ is substituted or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, a substituted ring formed when R⁹ and R¹¹ substituents 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 R⁹ and R¹¹ substituents 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 R⁹ and R¹¹ substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R⁹ and R¹¹ substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R⁹ and R¹¹ substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, R⁹ and R¹¹ are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R⁹ and R¹¹ are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl containing one nitrogen atom.

In embodiments, R⁹ is bonded to R¹¹ together with the ring carbon atoms to which they are attached to form substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 4 to 8 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). In embodiments, R⁹ bonded to R¹¹ together with the ring carbon atoms to which they are attached form:

R⁷, R⁸, R¹⁰, R¹², R¹³, and z13 are as described herein, including in embodiments.

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 R¹² 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 R¹² is substituted, it is substituted with at least one substituent group. In embodiments, when R¹² is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹² is 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^12A 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 R^12A is substituted, it is substituted with at least one substituent group. In embodiments, when R^12A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12A is 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^12B 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 R^12B is substituted, it is substituted with at least one substituent group. In embodiments, when R^12B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^12A and R^12B substituents 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^12A and R^12B substituents 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^12A and R^12B 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^12A and R^12B substituents 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^12A and R^12B substituents 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^12C 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 R^12C is substituted, it is substituted with at least one substituent group. In embodiments, when R^12C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^12C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹² is 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, —C(NH)NH₂, —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, R¹² is hydrogen. In embodiments, R¹² is —NH₂. In embodiments, R¹² is hydrogen, —C(NR^12C)NR^12AR^12B, 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, R¹² is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, R¹² is substituted or unsubstituted alkyl. In embodiments, R¹² is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R¹² is unsubstituted methyl. In embodiments, R¹² is unsubstituted ethyl. In embodiments, R¹² is unsubstituted propyl. In embodiments, R¹² is unsubstituted n-propyl. In embodiments, R¹² is unsubstituted isopropyl. In embodiments, R¹² is unsubstituted butyl. In embodiments, R¹² is unsubstituted n-butyl. In embodiments, R¹² is unsubstituted tert-butyl. In embodiments, R¹² is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹² is substituted or unsubstituted heterocycloalkyl. In embodiments, R¹² is substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R¹² is unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R¹² is substituted or unsubstituted heteroalkyl. In embodiments, R¹² is —C(NR^12C)NR^12AR^12B. In embodiments, R¹² is or

In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R^12B and R^12C are hydrogen. In embodiments, R^12B and R^12C are not hydrogen. In embodiments, R^12B is hydrogen and R^12C is not hydrogen. In embodiments, R^12B is not hydrogen and R^12C is hydrogen. In embodiments, R^12C is hydrogen. In embodiments, R^12C is —CN. In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R¹² is

or

In embodiments, R¹² is

In embodiments, R¹² is

In embodiments, R¹² is substituted or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, a substituted R¹⁶ (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 R¹⁶ 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 R¹⁶ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹⁶ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹⁶ is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^16C (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^16C 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 R^16C is substituted, it is substituted with at least one substituent group. In embodiments, when R^16C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^16C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R¹⁶ is hydrogen, —SO₃H, —SO₂NH₂, —C(O)H, —C(O)OH, —CONH₂, 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, R¹⁶ is hydrogen.

In embodiments, a substituted R²⁰ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R²⁰ 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 R²⁰ is substituted, it is substituted with at least one substituent group. In embodiments, when R²⁰ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R²⁰ is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^20A (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^20A 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 R^20A is substituted, it is substituted with at least one substituent group. In embodiments, when R^20A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^20A is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^20B (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^20B 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 R^20B is substituted, it is substituted with at least one substituent group. In embodiments, when R^20B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^20B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^20A and R^20B substituents 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^20A and R^20B substituents 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^20A and R^20B 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^20A and R^20B substituents 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^20A and R^20B substituents 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^20C (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^20C 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 R^20C is substituted, it is substituted with at least one substituent group. In embodiments, when R^20C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^20C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R²⁰ is 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, —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, R²⁰ is hydrogen, halogen, or unsubstituted C₁-C₄ alkyl. In embodiments, R²⁰ is hydrogen, —F, or unsubstituted methyl. In embodiments, R²⁰ is hydrogen. In embodiments, R²⁰ is halogen. In embodiments, R²⁰ is —F. In embodiments, R²⁰ is —Cl. In embodiments, R²⁰ is —Br. In embodiments, R²⁰ is —I. In embodiments, R²⁰ is unsubstituted C₁-C₄ alkyl. In embodiments, R²⁰ is unsubstituted methyl. In embodiments, R²⁰ is unsubstituted ethyl. In embodiments, R²⁰ is unsubstituted propyl. In embodiments, R²⁰ is unsubstituted n-propyl. In embodiments, R²⁰ is unsubstituted isopropyl. In embodiments, R²⁰ is unsubstituted butyl. In embodiments, R²⁰ is unsubstituted n-butyl. In embodiments, R²⁰ is unsubstituted tert-butyl.

In embodiments, a substituted R²¹ (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 R²¹ 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 R²¹ is substituted, it is substituted with at least one substituent group. In embodiments, when R²¹ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R²¹ is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^21A (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^21A 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 R^21A is substituted, it is substituted with at least one substituent group. In embodiments, when R^21A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^21A is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^21B (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^21B 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 R^21B is substituted, it is substituted with at least one substituent group. In embodiments, when R^21B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^21B is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^21A and R^21B substituents 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^21A and R^21B substituents 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^21A and R^21B 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^21A and R^21B substituents 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^21A and R^21B substituents 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^21C (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^21C 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 R^21C is substituted, it is substituted with at least one substituent group. In embodiments, when R^21C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^21C is substituted, it is substituted with at least one lower substituent group.

In embodiments, R²¹ is 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, —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, R²¹ is hydrogen, halogen, or unsubstituted C₁-C₄ alkyl. In embodiments, R²¹ is hydrogen, —F, or unsubstituted methyl. In embodiments, R²¹ is hydrogen. In embodiments, R²¹ is halogen. In embodiments, R²¹ is —F. In embodiments, R²¹ is —Cl. In embodiments, R²¹ is —Br. In embodiments, R²¹ is —I. In embodiments, R²¹ is unsubstituted C₁-C₄ alkyl. In embodiments, R²¹ is unsubstituted methyl. In embodiments, R²¹ is unsubstituted ethyl. In embodiments, R²¹ is unsubstituted propyl. In embodiments, R²¹ is unsubstituted n-propyl. In embodiments, R²¹ is unsubstituted isopropyl. In embodiments, R²¹ is unsubstituted butyl. In embodiments, R²¹ is unsubstituted n-butyl. In embodiments, R²¹ is unsubstituted tert-butyl.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

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

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

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

In embodiments, when R^2B is substituted, R^2B is substituted with one or more first substituent groups denoted by R^2B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2B.1 substituent group is substituted, the R^2B substituent group is substituted with one or more second substituent groups denoted by R^2B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2B.2 substituent group is substituted, the R^2B.2 substituent group is substituted with one or more third substituent groups denoted by R^2B3 as 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.3 have 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.3 correspond to R^2B, R^2B.1, R^2B.2, and R^2B.3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In embodiments, when R^5A and R^5B substituents 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.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.1 substituent group is substituted, the R^5B.1 substituent group is substituted with one or more second substituent groups denoted by R^5B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.2 substituent group is substituted, the R^5B.2 substituent group is substituted with one or more third substituent groups denoted by R^5B.3 as 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.3 have 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.3 correspond to R^5B.1, R^5B.2, and R^5B0.3, respectively.

In embodiments, when R^5C is substituted, R^5C is substituted with one or more first substituent groups denoted by R^5C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.1 substituent group is substituted, the R^5C.1 substituent group is substituted with one or more second substituent groups denoted by R^5C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.2 substituent group is substituted, the R^5C.2 substituent group is substituted with one or more third substituent groups denoted by R^5C.3 as 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.3 have 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.3 correspond to R^8C, R^5C.1, R^5C.2, and R^5C.3, respectively.

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

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

In embodiments, when R^6B is substituted, R^B is substituted with one or more first substituent groups denoted by R^6B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6B.1 substituent group is substituted, the R^6B.1 substituent group is substituted with one or more second substituent groups denoted by R^6.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^6B.2 substituent group is substituted, the R^6B.2 substituent group is substituted with one or more third substituent groups denoted by R^6B.3 as 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.3 have 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.3 correspond to R^6B, R^6B.1, R^6B.2, and R^6B.3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In embodiments, when R^8C is substituted, R^8C is substituted with one or more first substituent groups denoted by R^5C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.1 substituent group is substituted, the R^5C.1 substituent group is substituted with one or more second substituent groups denoted by R^5C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.2 substituent group is substituted, the R^5C.2 substituent group is substituted with one or more third substituent groups denoted by R^5C.3 as 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.3 have 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.3 correspond to R^8C, R^8C.1, R^8C.2, and R^8C.3, respectively.

In embodiments, when R⁹ is substituted, R⁹ is substituted with one or more first substituent groups denoted by R^9.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9.1 substituent group is substituted, the R^9.1 substituent group is substituted with one or more second substituent groups denoted by R^9.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9.2 substituent group is substituted, the R^9.2 substituent group is substituted with one or more third substituent groups denoted by R^9.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁹, R^9.1, R^9.2, and R^9.3 have 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.3 correspond to R⁹, R^9.1, R^9.2, and R^9.3, respectively.

In embodiments, when R^9A is substituted, R^9A is substituted with one or more first substituent groups denoted by R^9A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9A.1 substituent group is substituted, the R^9A.1 substituent group is substituted with one or more second substituent groups denoted by R^9A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9A.2 substituent group is substituted, the R^9A.2 substituent group is substituted with one or more third substituent groups denoted by R^9A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^9A, R^9A.1, R^9A.2, and R^9A.3 have 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.3 correspond to R^9A, R^9A.1, R^9A.2, and R^9A.3, respectively.

In embodiments, when R^9B is substituted, R^9B is substituted with one or more first substituent groups denoted by R^9B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9B.1 substituent group is substituted, the R^9B.1 substituent group is substituted with one or more second substituent groups denoted by R^9B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9B.2 substituent group is substituted, the R^9B.2 substituent group is substituted with one or more third substituent groups denoted by R^9B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^9B, R^9B.1, R^9B.2, and R^9B.3 have 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.3 correspond to R^9B, R^9B.1, R^9B.2, and R^9B.3, respectively.

In embodiments, when R^9A and R^9B substituents 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^9A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9A.1 substituent group is substituted, the R^9A.1 substituent group is substituted with one or more second substituent groups denoted by R^9A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9A.2 substituent group is substituted, the R^9A.2 substituent group is substituted with one or more third substituent groups denoted by R^9A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^9A.1, R^9A.2, and R^9A.3 have 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.3 correspond to R^9A.1, R^9A.2, and R^9A.3, respectively.

In embodiments, when R^9A and R^9B substituents 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^9B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9B.1 substituent group is substituted, the R^9B.1 substituent group is substituted with one or more second substituent groups denoted by R^9B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9B.2 substituent group is substituted, the R^9B.2 substituent group is substituted with one or more third substituent groups denoted by R^9B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^9B.1, R^9B.2, and R^9B.3 have 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.3 correspond to R^9B.1, R^9B.2, and R^9B.3, respectively.

In embodiments, when R^9C is substituted, R^9C is substituted with one or more first substituent groups denoted by R^9C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9C.1 substituent group is substituted, the R^9C.1 substituent group is substituted with one or more second substituent groups denoted by R^9C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9C.2 substituent group is substituted, the R^9C.2 substituent group is substituted with one or more third substituent groups denoted by R^9C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^9C, R^9C.1, R^9C.2, and R^9C.3 have 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.3 correspond to R^9C, R^9C.1, R^9C.2, and R^9C.3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

In embodiments, when R⁹ and R¹¹ substituents 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^9.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9.1 substituent group is substituted, the R^9.1 substituent group is substituted with one or more second substituent groups denoted by R^9.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^9.2 substituent group is substituted, the R^9.2 substituent group is substituted with one or more third substituent groups denoted by R^9.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^9.1, R^9.2, and R^9.3 have 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.3 correspond to R^9.1, R^9.2, and R^9.3, respectively.

In embodiments, when R⁹ and R¹¹ substituents 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^11.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11.1 substituent group is substituted, the R^11.1 substituent group is substituted with one or more second substituent groups denoted by R^11.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^11.2 substituent group is substituted, the R^11.2 substituent group is substituted with one or more third substituent groups denoted by R^11.3 as 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^11.3 have 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.3 correspond to R^11.1, R^11.2, and R^11.3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

In embodiments, when R¹⁵ is substituted, R¹⁵ is substituted with one or more first substituent groups denoted by R^15.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^15.1 substituent group is substituted, the R^15.1 substituent group is substituted with one or more second substituent groups denoted by R^15.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^15.2 substituent group is substituted, the R^15.2 substituent group is substituted with one or more third substituent groups denoted by R^15.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁵, R^15.1, R^15.2, and R^15.3 have 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.3 correspond to R¹⁵, R^15.1, R^15.2, and R^15.3, respectively.

In embodiments, when R^15C is substituted, R^15C is substituted with one or more first substituent groups denoted by R^15C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^15C.1 substituent group is substituted, the R^15C.1 substituent group is substituted with one or more second substituent groups denoted by R^15C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^15C.2 substituent group is substituted, the R^15C.2 substituent group is substituted with one or more third substituent groups denoted by R^15C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^15C, R_15C.1, R^15C.2, and R^15C.3 have 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.3 correspond to R^15C, R^15C.1, R^15C.2, and R^15C.3, respectively.

In embodiments, when R⁷ and R¹⁵ substituents 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^7.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7.1 substituent group is substituted, the R^7.1 substituent group is substituted with one or more second substituent groups denoted by R^7.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^7.2 substituent group is substituted, the R^7.2 substituent group is substituted with one or more third substituent groups denoted by R^7.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^7.1, R^7.2, and R^7.3 have 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.3 correspond to R^7.1, R^7.2, and R^7.3, respectively.

In embodiments, when R⁷ and R¹⁵ substituents 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^15.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^15.1 substituent group is substituted, the R^15.1 substituent group is substituted with one or more second substituent groups denoted by R^15.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^15.2 substituent group is substituted, the R^15.2 substituent group is substituted with one or more third substituent groups denoted by R^15.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^15.1, R^15.2, and R^15.3 have 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.3 correspond to R^15.1, R^15.2, and R^15.3, respectively.

In embodiments, when R¹⁶ is substituted, R¹⁶ is substituted with one or more first substituent groups denoted by R^16.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^16.1 substituent group is substituted, the R^16.1 substituent group is substituted with one or more second substituent groups denoted by R^16.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^16.2 substituent group is substituted, the R^16.2 substituent group is substituted with one or more third substituent groups denoted by R^16.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁶, R^16.1, R^16.2, and R^16.3 have 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.3 correspond to R¹⁶, R^16.1, R^16.2, and R^16.3, respectively.

In embodiments, when R^16C is substituted, R^16C is substituted with one or more first substituent groups denoted by R^16C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^16C.1 substituent group is substituted, the R^16C.1 substituent group is substituted with one or more second substituent groups denoted by R^16C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^16C.2 substituent group is substituted, the R^16C.2 substituent group is substituted with one or more third substituent groups denoted by R^16C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^16C, R^16C.1, R^16C.2, and R^16C.3 have 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.3 correspond to R^16C, R^16C.1, R^16C.2, and R^16C.3, respectively.

In embodiments, when R²⁰ is substituted, R²⁰ is substituted with one or more first substituent groups denoted by R^20.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20.1 substituent group is substituted, the R^20.1 substituent group is substituted with one or more second substituent groups denoted by R^20.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20.2 substituent group is substituted, the R^20.2 substituent group is substituted with one or more third substituent groups denoted by R^20.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R²⁰, R^20.1, R^20.2, and R^20.3 have 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.3 correspond to R²⁰, R^20.1, R^20.2, and R^20.3, respectively.

In embodiments, when R^20A is substituted, R^20A is substituted with one or more first substituent groups denoted by R^20A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20A.1 substituent group is substituted, the R^20A.1 substituent group is substituted with one or more second substituent groups denoted by R^20A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20A.2 substituent group is substituted, the R^20A.2 substituent group is substituted with one or more third substituent groups denoted by R^20A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^20A, R^20A.1, R^20A.2, and R^20A.3 have 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.3 correspond to R^20A, R^20A.1, R^20A.2, and R^20A.3, respectively.

In embodiments, when R^20B is substituted, R^20B is substituted with one or more first substituent groups denoted by R^20B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20B.1 substituent group is substituted, the R^20B.1 substituent group is substituted with one or more second substituent groups denoted by R^20B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20B.2 substituent group is substituted, the R^20B.2 substituent group is substituted with one or more third substituent groups denoted by R^20B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^20B, R^20B.1, R^20B.2, and R^20B.3 have 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.3 correspond to R^20B, R^20B.1, R^20B.2, and R^20B.3, respectively.

In embodiments, when R^20A and R^20B substituents 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^20A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20A.1 substituent group is substituted, the R^20A.1 substituent group is substituted with one or more second substituent groups denoted by R^20A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20A.2 substituent group is substituted, the R^20A.2 substituent group is substituted with one or more third substituent groups denoted by R^20A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^20A.1, R^20A.2, and R^20A.3 have 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.3 correspond to R^20A.1, R^20A.2, and R^20A.3, respectively.

In embodiments, when R^20A and R^20B substituents 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^20B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20B.1 substituent group is substituted, the R^20B.1 substituent group is substituted with one or more second substituent groups denoted by R^20B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20B.2 substituent group is substituted, the R^20B.2 substituent group is substituted with one or more third substituent groups denoted by R^20B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^20B.1, R^20B.2, and R^20B.3 have 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.3 correspond to R^20B.1, R^20B.2, and R^20B.3, respectively.

In embodiments, when R^20C is substituted, R^20C is substituted with one or more first substituent groups denoted by R^20C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20C.1 substituent group is substituted, the R^20C.1 substituent group is substituted with one or more second substituent groups denoted by R^20C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^20C.2 substituent group is substituted, the R^20C.2 substituent group is substituted with one or more third substituent groups denoted by R^20C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^20C, R^20C.1, R^20C.2, and R^20C.3 have 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.3 correspond to R^20C, R^20C.1, R^20C.2, and R^20C.3, respectively.

In embodiments, when R²¹ is substituted, R²¹ is substituted with one or more first substituent groups denoted by R^21.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21.1 substituent group is substituted, the R^21.1 substituent group is substituted with one or more second substituent groups denoted by R^21.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21.2 substituent group is substituted, the R^21.2 substituent group is substituted with one or more third substituent groups denoted by R^21.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R²¹, R^21.1, R^21.2, and R^21.3 have 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. 3} correspond to R²¹, R^21.1, R^21.2, and R^21.3, respectively.

In embodiments, when R^21A is substituted, R^21A is substituted with one or more first substituent groups denoted by R^21A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21A.1 substituent group is substituted, the R^21A.1 substituent group is substituted with one or more second substituent groups denoted by R^21A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21A.2 substituent group is substituted, the R^21A.2 substituent group is substituted with one or more third substituent groups denoted by R^21A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^21A, R^21A.1, R^21A.2, and R^21A.3 have 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.3 correspond to R^21A, R^21A.1, R^21A.2, and R^21A.3, respectively.

In embodiments, when R^21B is substituted, R^21B is substituted with one or more first substituent groups denoted by R^21B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21B.1 substituent group is substituted, the R^21B.1 substituent group is substituted with one or more second substituent groups denoted by R^21B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21B.2 substituent group is substituted, the R^21B.2 substituent group is substituted with one or more third substituent groups denoted by R^21B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^21B, R^21B.1, R^21B.2, and R^21B.3 have 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.3 correspond to R^21B, R^21B 1, R^21B.2, and R^21B.3, respectively.

In embodiments, when R^21A and R^21B substituents 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^21A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21A.1 substituent group is substituted, the R^21A.1 substituent group is substituted with one or more second substituent groups denoted by R^21A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21A.2 substituent group is substituted, the R^21A.2 substituent group is substituted with one or more third substituent groups denoted by R^21A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^21A.1, R^21A.2, and R^21A.3 have 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.3 correspond to R^21A.1, R^21A.2, and R^21A.3, respectively.

In embodiments, when R^21A and R^21B substituents 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^21B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21B.1 substituent group is substituted, the R^21B.1 substituent group is substituted with one or more second substituent groups denoted by R^21B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21B.2 substituent group is substituted, the R^21B.2 substituent group is substituted with one or more third substituent groups denoted by R^21B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^21B.1, R^21B.2, and R^21B.3 have 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.3 correspond to R^21B.1, R^21B.2, and R^21B.3, respectively.

In embodiments, when R^21C is substituted, R^21C is substituted with one or more first substituent groups denoted by R^21C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21C.1 substituent group is substituted, the R^21C.1 substituent group is substituted with one or more second substituent groups denoted by R^21C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^21C.2 substituent group is substituted, the R^21C.2 substituent group is substituted with one or more third substituent groups denoted by R^21C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^21C, R^21C.1, R^21C.2, and R^21C.3 have 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. 3} correspond to R^21C, R^21C.1, R^21C.2, and R^21C.3, respectively.

In embodiments, when L¹ is substituted, L¹ is substituted with one or more first substituent groups denoted by R^L1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L1.1 substituent group is substituted, the R^L1.1 substituent group is substituted with one or more second substituent groups denoted by R^L1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L1.2 substituent group is substituted, the R^L1.2 substituent group is substituted with one or more third substituent groups denoted by R^L1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L¹, R^L1.1, R^L1.2, and R^L1.3 have values corresponding to the values of L^WW, R^LWW.1, R^LWW.2, and R^LWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein L^WW, R^LWW.1, R^LWW.2, and R^LWW.3 are L¹, R^L1.1, R^L1.2, and R^L1.3, respectively.

In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

III. Pharmaceutical Compositions

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

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

In embodiments, the compound is a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (III), (III-1), or (III-2); or a tautomer thereof.

IV. Methods of Use

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 tautomer thereof.

In embodiments, the subject is a human. In embodiments, the inflammatory disease is asthma, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, diabetes mellitus type 1, diabetic retinopathy, 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, acne vulgaris, celiac disease, chronic prostatitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, graft-versus-host disease, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis. In embodiments, the inflammatory disease is asthma. In embodiments, the asthma is severe asthma. In embodiments, the asthma is acute severe asthma. In embodiments, the asthma is moderate asthma.

In embodiments, the administering is by inhalation.

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 tautomer thereof.

In embodiments, the cancer is thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. In embodiments, the cancer is Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

In embodiments, the subject is a human.

In an aspect is provided a method of inhibiting angiogenesis 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 tautomer thereof.

In embodiments, the subject is a human.

In embodiments, the compound is a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (III), (III-1), or (III-2); or a tautomer thereof.

In an aspect is provided a method of modulating (e.g., reducing) the level of activity of α5β1 integrin in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof. In embodiments, the level of activity of α5β1 integrin is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of α5β1 integrin is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the method is performed in vitro. In embodiments, the method is perform in situ.

In an aspect is provided a method of modulating (e.g., reducing) the activity of a human α5β1 integrin, the method including contacting the human α5β1 integrin protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof. In embodiments, the activity of α5β1 integrin is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the activity of α5β1 integrin is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the method is performed in vitro. In embodiments, the method is perform in situ.

V. Embodiments

Embodiment P1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

A¹ is C(R⁴) or N;A³ is C(R³) or N;A⁴ is C(R⁵) or N;X is a bond, —C(R¹⁵)(R¹⁶)— or N(R¹⁵)—;m is 1 or 2;L¹ is bond, —C(O)—, —C(O)O—, —O—, —S—, —NH—, —C(O)NH—, —NHC(O)—, —S(O)₂—, —S(O)NH—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or —[P(═O)(OH)O—]_n—H;n is an integer from 1 to 3;R² is hydrogen, halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX²₂, —CN, —SO_n2R^2C, —SO_v2NR^2AR^2B, —NR^2CNR^2AR^2B, —ONR^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^2C, —NR^2ASO₂R^2C, —NR²AC(O)R^2C, —NR^2AC(O)OR^2C, —NR^2AOR^2C, —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;R³ is hydrogen, halogen, —CX³₃, —CHX³₂, —CH₂X³, —OCX³₃, —OCH₂X³, —OCHX³₂, —CN, —SO_n3R^3C, —SO_v3NR^3AR^3B, —NR^3CNR^3AR^3B, —ONR^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^3C, —NR^3ASO₂R^3C, —NR^3AC(O)R^3C, —NR^3AC(O)OR^3C, —NR^3AOR^3C, —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;R⁴ is hydrogen, halogen, —CX⁴₃, —CHX⁴₂, —CH₂X⁴, —OCX⁴₃, —OCH₂X⁴, —OCHX⁴₂, —CN, —SO_n4R^4C, —SO_v4NR^4AR^4B, —NR^4CNR^4AR^4B, —ONR^4AR^4B, —NHC(O)NR^4AR^4B, —N(O)_m4, —NR^4AR^4B, —C(O)R^4C, —C(O)OR^4C, —C(O)NR^4AR^4B, —OR^4C, —NR^4ASO₂R^4C, —NR^4AC(O)R^4C, —NR^4AC(O)OR^4C, NR^4AOR^4C, —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;R⁵ is hydrogen, halogen, —CX⁵₃, —CHX⁵₂, —CH₂X⁵, —OCX⁵₃, —OCH₂X⁵, —OCHX⁵₂, —CN, —SO_n8R^8C, —SO_v5NR^5AR^5B, —NR^5CNR^5AR^5B, —ONR^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^5C, —NR^5ASO₂R^8C, —NR^5AC(O)R^5C, —NR^5AC(O)OR^5C, —NR^5AOR^5C, —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;R⁶ is hydrogen, halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, —OCHX⁶₂, —CN, —SO_n6R^6C, —SO_v6NR^6AR^6B, —NR^6CNR^6AR^6B, —ONR^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^6C, —NR^6ASO₂R^6C, —NR^6AC(O)R^6C, —NR^6AC(O)OR^6C, —NR^6AOR^6C, —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;R⁷ is hydrogen, halogen, —CX⁷₃, —CHX⁷₂, —CH₂X⁷, —OCX⁷₃, —OCH₂X⁷, —OCHX⁷₂, —CN, —SO_n7R^7C, —SO_v7NR^7AR^7B, —NR^7CNR^7AR^7B, —ONR^7AR^7B, —NHC(O)NR^7AR^7B, —N(O)_m7, —NR^7AR^7B, —C(O)R^7C, —C(O)OR^7C, —C(O)NR^7AR^7B, —OR^7C, —NR^7ASO₂R^7C, —NR^7AC(O)R^7C, —NR^7AC(O)OR^7C, —NR^7AOR^7C, —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;R⁷ and R¹⁵ are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R⁸ is hydrogen, halogen, —CX⁸₃, —CHX⁸₂, —CH₂X⁸, —OCX⁸₃, —OCH₂X⁸, —OCHX⁸₂, —CN, —SO_n8R^8C, —SO_v8NR^8AR^8B, —NR^8CNR^8AR^8B, —ONR^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^8C, —NR^8ASO₂R^8C, —NR^8AC(O)R^8C, —NR^8AC(O)OR^8C, —NR^8AOR^8C, —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;R⁹ is hydrogen, halogen, —CX⁹₃, —CHX⁹₂, —CH₂X⁹, —OCX⁹₃, —OCH₂X⁹, —OCHX⁹₂, —CN, —SO_n9R^9C, —SO_v9NR^9AR^9B, —NR^9CNR^9AR^9B, —ONR^9AR^9B, —NHC(O)NR^9AR^9B, —N(O)_m9, —NR^9AR^9B, —C(O)R^9C, —C(O)OR^9C, —C(O)NR^9AR^9B, —OR^9C, —NR^9ASO₂R^9C, —NR^9AC(O)R^9C, —NR^9AC(O)OR^9C, —NR^9AOR^9C, —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;R⁹ and R¹¹ are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R¹⁰ is hydrogen, halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10C, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^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^10C, —NR^10ASO₂R^10C, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —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″ is hydrogen, halogen, —CX¹¹₃, —CHX¹¹₂, —CH₂X¹¹, —OCX¹¹₃, —OCH₂X¹¹, —OCHX¹¹₂, —CN, —SO₁₁R^11C, —SO_V11NR^11AR^11B, —NR^11CNR^11AR^11B, —ONR^11AR^11B, —NHC(O)NR^11AR^11B, —N(O)_m11, —NR^11AR^11B, —C(O)R^11C, —C(O)OR^11C, —C(O)NR^11AR^11B, —OR^11C, —NR^11ASO₂R^11C, —NR^11AC(O)R^11C, —NR^11AC(O)OR^11C, —NR^11AOR^11C, —C(NR^11C)NR^11AR^11B, —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;R¹² is hydrogen, halogen, —CX¹²₃, —CHX¹²₂, —CH₂X¹², —OCX¹²₃, —OCH₂X¹², —OCHX¹²₂, —CN, —SO₂R^12C, —SO_v12NR^12AR^12B, —NR^12CNR^12AR^12B, —ONR^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^12C, —NR^12ASO₂R^12C, —NR^12AC(O)R^12C, —NR^12AC(O)OR^12C, —NR^12AOR^12C, —C(NR^12C)NR^12AR^12B, —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;R¹⁵ is hydrogen, —SO₂R^15C, —C(O)R^15C, —C(O)OR^15C, 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;R¹⁶ is hydrogen, —SO₂R^16C, —C(O)R^16C, —C(O)OR^16C, 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;R²⁰ is hydrogen, halogen, —CX²⁰₃, —CHX²⁰₂, —CH₂X²⁰, —OCX²⁰₃, —OCH₂X²⁰, —OCHX²⁰₂, —CN, —SO_n20R^20C, —SO₂₀NR^20AR^20B, —NR^20CNR^20AR^20B, —ONR^20AR^20B, —NHC(O)NR^20AR^20B, —N(O)_m20, —NR^20AR^20B, —C(O)R^20C, —C(O)OR^20C, —C(O)NR^20AR^20B, —OR^20C, —NR^20ASO₂R^20C, —NR^20AC(O)R^20C, —NR^20AC(O)OR^20C, —NR^20AOR^20C, —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;R²¹ is hydrogen, halogen, —CX²¹₃, —CHX²¹₂, —CH₂X²¹, —OCX²¹₃, —OCH₂X²¹, —OCHX²¹₂, —CN, —SO_n21R^21C, —SO_v21NR^21AR^21B, —NR^21CNR^21AR^21B, —ONR^21AR^21B, —NHC(O)NR^21AR^21B, —N(O)_m21, —NR^21AR^21B, —C(O)R^21C, —C(O)OR^21C, —C(O)NR^21AR^21B, —OR^21C, —NR^21ASO₂R^21C, —NR^21AC(O)R^21C, —NR^21AC(O)OR^21C, —NR^21AOR^21C, —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^2A, R², R^2C, R^3A, R^3B, R^3C, R^4B, R^4B, R^4C, R^5A, R^5B, R^5C, R^6A, R^6B, R^6C, R^7A, R^7B, R^7C, R^8A, R^8B, R^8C, R^9A, R^9B, R^9C, R^10A, R^10B, R^10C, R^11A, R^11B, R^11C, R^12A, R^12B, R^12C, R^15C, R^16C, R^20A, R^20B, R^20C, R^21A, R^21B, and R^21C are independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂, —OCHBr₂, —OCHF₂, —OCHI₂, —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^2A and R^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^3A and R^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^4A and R^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^6A and R^6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^7A and R^7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^8A and R^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^9A and R^9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^10A and R^10B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^11A and R^11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^12A and R^12B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^20A and R^20B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^21A and R^21B substituents 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, X⁹, X¹⁰, X¹¹, X¹², X²⁰, and X²¹ are independently —F, —Cl, —Br, or —I;n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, n20, and n21 are independently an integer from 0 to 4; andm2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m20, m21, v2, v3, v4, v5, v6, v7, v8, v9, v10, v11, v12, v20, and v21 are independently 1 or 2.

Embodiment P2. The compound of embodiment P1, having the formula:

Embodiment P3. The compound of one of embodiments P1 to P2, wherein R²⁰ and R²¹ are independently hydrogen, halogen, or unsubstituted C₁-C₄ alkyl.

Embodiment P4. The compound of one of embodiments P1 to P2, wherein R²⁰ and R²¹ are independently hydrogen, —F, or unsubstituted methyl.

Embodiment P5. The compound of embodiment P1, having the formula:

Embodiment P6. The compound of embodiment P1, having the formula:

Embodiment P7. The compound of embodiment P1, having the formula:

Embodiment P8. The compound of embodiment P1, having the formula:

Embodiment P9. The compound of embodiment P1, having the formula:

Embodiment P10. The compound of one of embodiments P1 to P9, wherein A¹ is C(R⁴), A³ is C(R³), and A⁴ is C(R⁵).

Embodiment P11. The compound of one of embodiments P1 to P9, wherein A¹ is N, A³ is C(R³), and A⁴ is C(R₅).

Embodiment P12. The compound of one of embodiments P1 to P9, wherein A¹ is C(R⁴), A³ is N, and A⁴ is N.

Embodiment P13. The compound of one of embodiments P1 to P12, wherein m is 1.

Embodiment P14. The compound of one of embodiments P1 to P12, wherein m is 2.

Embodiment P15. The compound of one of embodiments P1 to P14, wherein X is a bond.

Embodiment P16. The compound of one of embodiments P1 to P14, wherein X is —C(R¹⁵)(R¹⁶)—.

Embodiment P17. The compound of one of embodiments P1 to P14, wherein X is —N(R¹⁵)—.

Embodiment P18. The compound of one of embodiments P1 to P17, wherein L¹ is a bond, —NH—, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

Embodiment P19. The compound of one of embodiments P1 to P17, wherein L¹ is a bond, —NH—, —(CH₂)_z1—NH—, —(CH₂)_z2—, or —(CH₂)_z3—N((CH₂)_z4CH₃)—C(O)—, wherein z1, z2, and z3 are independently an integer from 1 to 10; and z4 is an integer from 0 to 9.

Embodiment P20. The compound of one of embodiments P1 to P17, wherein L¹ is a bond.

Embodiment P21. The compound of one of embodiments P1 to P17, wherein L¹ is —NH—.

Embodiment P22. The compound of one of embodiments P1 to P17, wherein L¹ is —(CH₂)_z1—NH—, wherein z1 is an integer from 1 to 4.

Embodiment P23. The compound of one of embodiments P1 to P17, wherein L¹ is —(CH₂)_z2—, wherein z2 is an integer from 1 to 4.

Embodiment P24. The compound of one of embodiments P1 to P17, wherein L¹ is —(CH₂)_z3—N((CH₂)_z4CH₃)—C(O)—; wherein z3 is an integer from 1 to 4, and z4 is an integer from 0 to 4.

Embodiment P25. The compound of one of embodiments P1 to P24, wherein R¹ is hydrogen.

Embodiment P26. The compound of one of embodiments P1 to P25, wherein R² is halogen, —CX²₃, —CHX²₂, —CH₂X², —OCX²₃, —OCH₂X², or —OCHX²₂.

Embodiment P27. The compound of embodiment P26, wherein X² is independently —F or —Cl.

Embodiment P28. The compound of one of embodiments P1 to P27, wherein R⁶ is halogen, —CX⁶₃, —CHX⁶₂, —CH₂X⁶, —OCX⁶₃, —OCH₂X⁶, or —OCHX⁶₂.

Embodiment P29. The compound of embodiment P28, wherein X⁶ is independently —F or —Cl.

Embodiment P30. The compound of one of embodiments P1 to P24, wherein R² and R⁶ are halogen.

Embodiment P31. The compound of one of embodiments P1 to P24, wherein R² and R⁶ are —Cl.

Embodiment P32. The compound of one of embodiments P1 to P24, wherein R² is halogen and R⁶ is unsubstituted C₁-C₆ alkyl.

Embodiment P33. The compound of one of embodiments P1 to P32, wherein R⁴ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment P34. The compound of one of embodiments P1 to P32, wherein R⁴ is hydrogen.

Embodiment P35. The compound of one of embodiments P1 to P32, wherein R⁴ is substituted or unsubstituted phenyl.

Embodiment P36. The compound of one of embodiments P1 to P32, wherein R⁴ is unsubstituted phenyl.

Embodiment P37. The compound of one of embodiments P1 to P32, wherein R⁴ is halogen, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P38. The compound of one of embodiments P1 to P37, wherein R³ is hydrogen.

Embodiment P39. The compound of one of embodiments P1 to P38, wherein R⁵ is hydrogen.

Embodiment P40. The compound of one of embodiments P1 to P7 and P10 to P39, wherein R⁷ is hydrogen.

Embodiment P41. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R⁷ and R¹⁵ are joined to form a substituted or unsubstituted C₅-C₆ cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P42. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R⁷ and R¹⁵ are joined to form an unsubstituted cyclohexyl.

Embodiment P43. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R⁷ and R¹⁵ are joined to form an unsubstituted 6 membered heterocycloalkyl, wherein the heterocycloalkyl comprises (i) an oxygen atom, (ii) a nitrogen atom, or (iii) an oxygen atom and a nitrogen atom.

Embodiment P44. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R⁷ and R¹⁵ are joined to form an unsubstituted phenyl.

Embodiment P45. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R⁷ and R¹⁵ are joined to form an unsubstituted 5 to 6 membered heteroaryl, wherein the heteroaryl comprises one or two nitrogen atoms.

Embodiment P46. The compound of one of embodiments P1, P3 to P5, and P10 to P45, wherein R⁸ is hydrogen.

Embodiment P47. The compound of one of embodiments P1 to P46, wherein R¹⁰ is hydrogen.

Embodiment P48. The compound of one of embodiments P1 to P5 and P8 to P47, wherein R⁹ is hydrogen.

Embodiment P49. The compound of one of embodiments P1 to P48, wherein R¹¹ is hydrogen.

Embodiment P50. The compound of one of embodiments P1 to P48, wherein R¹¹ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.

Embodiment P51. The compound of one of embodiments P1 to P48, wherein R¹¹ is substituted or unsubstituted heterocycloalkyl.

Embodiment P52. The compound of one of embodiments P1 to P48, wherein R¹¹ is substituted or unsubstituted 5 to 6 membered heterocycloalkyl.

Embodiment P53. The compound of one of embodiments P1 to P48, wherein R¹¹ is unsubstituted 5 to 6 membered heterocycloalkyl.

Embodiment P54. The compound of one of embodiments P1 to P48, wherein R¹¹ is

Embodiment P55. The compound of one of embodiments P1 to P48, wherein R¹¹ is hydrogen, —C(NR^11C)NR^11AR^11B, 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.

Embodiment P56. The compound of embodiment P55, wherein R¹¹ is

Embodiment P57. The compound of embodiment P56, wherein R¹¹ is

Embodiment P58. The compound of embodiment P56, wherein R¹¹ is

Embodiment P59. The compound of one of embodiments P1 to P5 and P8 to P47, wherein R⁹ and R¹¹ are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl.

Embodiment P60. The compound of embodiment P59, wherein R⁹ and R¹¹ are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl containing one nitrogen atom.

Embodiment P61. The compound of one of embodiments P1 to P60, wherein R¹² is hydrogen, —C(NR^12C)NR^12AR^12B, 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.

Embodiment P62. The compound of one of embodiments P1 to P60, wherein R¹² is hydrogen.

Embodiment P63. The compound of embodiment P1, having the formula:

Embodiment P64. The compound of embodiment P1, having the formula:

Embodiment P65. The compound of embodiment P1, having the formula:

Embodiment P66. The compound of embodiment P1, having the formula:

Embodiment P67. A pharmaceutical composition comprising the compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

Embodiment P68. A method of treating an inflammatory disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

Embodiment P69. The method of embodiment P68, wherein the inflammatory disease is asthma.

Embodiment P70. The method of embodiment P68, wherein the inflammatory disease is asthma, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, diabetes mellitus type 1, diabetic retinopathy, 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, acne vulgaris, celiac disease, chronic prostatitis, chronic obstructive pulmonary disease, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, graft-versus-host disease, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis.

Embodiment P71. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

Embodiment P72. A method of inhibiting angiogenesis in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

Embodiment P73. A method of reducing the level of activity of α5β1 integrin in a cell, said method comprising contacting the cell with an effective of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

EXAMPLES

Example 1

General information: All evaporations were carried out in vacuo with a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates, spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was carried out using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported in 8 values in ppm with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constant (Hz), integration.

SU15210-0204-01

Route for SU15210-0204-01

1. The Synthesis of 5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)nicotinic acid (0204-2)

A solution of 0007-3 (1.5 g, 6.5 mmol) and 5-aminonicotinic acid (0.9 g, 6.5 mmol) in DMA (10 mL) was stirred at 85° C. for 4 days. Cooled to room temperature and purified by reverse flash to give 0204-2 (180 mg, 13% yield) as a white solid.

2. The Synthesis of (S)-benzyl 2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)nicotinamido)acetamido)propanoate (0204-3)

A solution of 0204-2 (180 mg, 0.82 mmol) in SOCl₂ (5 mL) was stirred at reflux for 30 min, then remove the excess SOCl₂ under reduced pressure. The residue was then added to a solution of int-A (409 mg, 0.82 mmol) and TEA (331 mg, 3.28 mmol) in DMF (5 mL) at 0° C., the solution was then allowed to warm to room temperature and stirred for overnight. Poured the solution into water (50 mL), collected the precipitate by filtration, the solid was dried then purified by prep-HPLC to get 0204-3 (80 mg, 14% yield) as a white solid.

3. The Synthesis of (S)-2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)nicotinamido)acetamido)propanoic acid (SU15210-0204-01)

To a solution of 0204-3 (80 mg, 0.11 mmol) in EA (5 mL) was added Pd/C (16 mg), the solution was stirred under H₂ at room temperature for overnight. Filter to remove the catalyst, the filtrate was concentrated and purified by prep-HPLC to give SU15210-0204-01 (6 mg, 9% yield) as a white solid.

Agilent LCMS 1200-6120, Column: Waters X-Bridge-C18 (100 mm*4.6 mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water+10 mM TFA] and 5% [CH₃CN] to 0% [water+10 mM TFA] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water+10 mM TFA] and 5% [CH₃CN] in 0.1 min. Purity is 100%. Rt=1.445 min; MS Calcd.: 611.2; MS Found: 612.2 [M+H]⁺.

Agilent HPLC 1200; Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 30° C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water+0.1% NH₄HCO₃] and 5% [CH₃CN] to 0% [water+0.1% NH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water+0.1% NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 5 min. Purity is 95.23%. Rt=6.377 min.

¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (t, J=5.6 Hz, 1H), 9.10 (br, 1H), 8.75 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.33-8.27 (m, 2H), 8.14 (s, 1H), 7.78-7.74 (m, 4H), 7.52-7.42 (m, 3H), 4.18-4.12 (m, 1H), 3.89 (d, J=5.2 Hz, 2H), 3.74-3.67 (m, 1H), 3.26-3.18 (m, 2H), 3.10-3.03 (m, 1H), 2.46-2.39 (m, 2H), 1.84 (t, J=5.2 Hz, 2H).

SU15210-0206-01

Route for SU15210-0206-01

1. The Synthesis of methyl 5-nitro-6-oxo-1,6-dihydropyridine-3-carboxylate (0206-2)

A solution of 0206-1 (3.0 g, 16.29 mmol) and added H₂SO₄ (3 mL) in MeOH (20 mL) was stirred at reflux for 16 h. Cooled to room temperature and concentrated to remove the solvent, the residue was recrystallized from ethyl acetate, dried in vacuum to give 206-2 (3.0 g, 93% yield) as a yellow solid.

2. The Synthesis of methyl 5-amino-6-oxo-1,6-dihydropyridine-3-carboxylate (0206-3)

To a solution of 0206-2 (3.0 g, 15.14 mmol) in MeOH (30 mL) was added AcOH (6 mL) and Zn (2.0 g, 30 mmol), the solution was stirred at rt for 0.5 h. When the reaction was completed, concentrated to remove the organic solution, extracted with EA, the organic phase was separated and dried over Na₂SO₄, concentrated to give 0206-3 (2.0 g, 80%) as a yellow 10 solid.

3. The Synthesis of methyl 5-(3-benzoylthioureido)-6-oxo-1,6-dihydropyridine-3-carboxylate (0206-4)

To a solution of 0206-3 (2.0 g, 11.90 mmol) in acetone (20 mL) was added benzoyl isothiocyanate (1.9 g, 11.90 mmol), the solution was stirred at reflux for 3 h. Concentrated to remove the solvent to give 0206-4 (3.0 g, 77%) as a yellow solid.

4. The Synthesis of methyl 6-oxo-5-thioureido-1,6-dihydropyridine-3-carboxylate (0206-5)

To a solution of 0206-4 (3.0 g, 9.10 mmol) in DMF (30 mL) was added NaOMe (490 mg, 9.10 mmol). The solution was stirred at 70° C. for 1 h. Cooled to room temperature and collected the precipitate by filtration, the solid was washed with ethyl acetate (20 mL) then dried in vacuum to give 0206-5 (1.3 g, 63% yield) as an off-white solid.

5. The Synthesis of (2S)-benzyl 2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(3-(5-fluoro-1,4,5,6-tetrahydropyrimidin-2-ylamino)benzamido)acetamido)propanoate (0206-6)

A solution of 0206-5 (1.3 g, 5.70 mmol) and CH₃I (810 mg, 5.70 mmol) in MeOH (20 mL) was stirred at reflux for 4 h. The solution was then allowed to warm to room temperature. We concentrated the mixture. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-6 (1.2 g, yield: 87%) as a light-yellow solid.

6. The Synthesis of methyl 6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxylate (0206-7)

A solution of 0206-6 (1.2 g, 4.98 mmol) and propane-1,3-diamine (370 mg, 5.0 mmol) in DMA (10 mL) was stirred at 95° C. for 16 h. The solution was then allowed to warm to room temperature. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-7 (200 mg, yield: 16%) as a white solid.

7. The Synthesis of 6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxylic acid (0206-8)

A solution of 0206-7 (200 mg, 0.80 mmol) in H₂O (5 mL) and THF (5 mL) was stirred at rt. NaOH (38 mg, 0.96 mmol) was added. The solution was then reacted at 40° C. until finished. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-8 (100 mg, yield: 53%) as a white solid.

8. The Synthesis of (S)-benzyl 2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxamido)acetamido)propanoate (0206-9)

A solution of 0206-8 (100 mg, 0.42 mmol) in Py (5 mL) was stirred at rt. SM-1 (210 mg, 0.42 mmol) and EDCI (161 mg, 0.84 mmol) was added. The solution was then reacted at 50° C. for 36 h. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-9 (50 mg, yield: 17%) as a white solid.

9. The Synthesis of (S)-2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxamido)acetamido)propanoic acid (SU15210-0206)

To a solution of 0206-9 (50 mg, 0.07 mmol) in MeOH (5.0 mL) was added Pd/C (10 mg). The mixture was stirred under H₂ in balloon at room temperature for 16 h. When the reaction completed, filtrated to remove the catalyst, the filtrate was concentrated and purified by prep-HPLC to get SU15210-00206-01 (5 mg, 11% yield) as a white solid.

Agilent LCMS 1200-6120, Column: Waters X-Bridge-C₁₈ (100 mm*4.6 mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water+10 mM TFA] and 5% [CH₃CN] to 0% [water+10 mM TFA] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water+10 mM TFA] and 5% [CH₃CN] in 0.1 min. Purity is 100%. Rt=1.366 min; MS Calcd.: 627.1; MS Found: 628.7 [M+H]⁺.

Agilent HPLC 1200; Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 30° C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water+0.1% NH₄HCO₃] and 5% [CH₃CN] to 0% [water+0.1% NH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water+0.1% NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and under this condition for 5 min. Purity is 99.9%. Rt=6.205 min.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.93-8.97 (m, 1H), 8.43-8.45 (m, 1H), 8.25 (s, 1H), 7.95-7.98 (m, 1H), 7.81-7.85 (m, 8H), 7.49-7.58 (m, 4H), 4.15 (s, 1H), 3.57-4.14 (m, 4H), 3.07-3.59 (m, 4H), 1.84-2.31 (m, 2H).

TABLE 1
IC50 for the selected compounds
Compound ID      IC50 (A: <1 μM, B: 1-10 μM, C: >10 μM)
SU15210-00204-01 A
SU15210-00206-01 A

Claims

1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

2. The compound of claim 1, having the formula:

3. The compound of claim 1, wherein R20 and R21 are independently hydrogen, halogen, or unsubstituted C1-C4 alkyl.

4. The compound of claim 1, wherein R20 and R21 are independently hydrogen, —F, or unsubstituted methyl.

5. The compound of claim 1, having the formula:

6. The compound of claim 1, having the formula:

7. The compound of claim 1, having the formula:

8. The compound of claim 1, having the formula:

9. The compound of claim 1, having the formula:

10. The compound of claim 1, wherein A1 is C(R4), A3 is C(R3), and A4 is C(R5).

11. The compound of claim 1, wherein A1 is N, A3 is C(R3), and A4 is C(R5).

12. The compound of claim 1, wherein A1 is C(R4), A3 is N, and A4 is N.

13. The compound of claim 1, wherein m is 1.

14. The compound of claim 1, wherein m is 2.

15. The compound of claim 1, wherein X is a bond.

16. The compound of claim 1, wherein X is —C(R15)(R16)—.

17. The compound of claim 1, wherein X is —N(R15)—.

18. The compound of claim 1, wherein L1 is a bond, —NH—, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

19. The compound of claim 1, wherein L1 is a bond, —NH—, —(CH2)z1—NH—, —(CH2)z2—, or —(CH2)z3—N((CH2)z4CH3)—C(O)—, wherein z1, z2, and z3 are independently an integer from 1 to 10; and z4 is an integer from 0 to 9.

20. The compound of claim 1, wherein L1 is a bond.

21. The compound of claim 1, wherein L1 is —NH—.

22. The compound of claim 1, wherein L1 is —(CH2)z1—NH—, wherein z1 is an integer from 1 to 4.

23. The compound of claim 1, wherein L1 is —(CH2)z2—, wherein z2 is an integer from 1 to 4.

24. The compound of claim 1, wherein L1 is —(CH2)z3—N((CH2)z4CH3)—C(O)—; wherein z3 is an integer from 1 to 4, and z4 is an integer from 0 to 4.

25. The compound of claim 1, wherein R1 is hydrogen.

26. The compound of claim 1, wherein R2 is halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCH2X2, or —OCHX22.

27. The compound of claim 26, wherein X2 is independently —F or —Cl.

28. The compound of claim 1, wherein R6 is halogen, —CX63, —CHX62, —CH2X6, —OCX63, —OCH2X6, or —OCHX62.

29. The compound of claim 28, wherein X6 is independently —F or —Cl.

30. The compound of claim 1, wherein R2 and R6 are halogen.

31. The compound of claim 1, wherein R2 and R6 are —Cl.

32. The compound of claim 1, wherein R2 is halogen and R6 is unsubstituted C1-C6 alkyl.

33. The compound of claim 1, wherein R4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

34. The compound of claim 1, wherein R4 is hydrogen.

35. The compound of claim 1, wherein R4 is substituted or unsubstituted phenyl.

36. The compound of claim 1, wherein R4 is unsubstituted phenyl.

37. The compound of claim 1, wherein R4 is halogen, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

38. The compound of claim 1, wherein R3 is hydrogen.

39. The compound of claim 1, wherein R5 is hydrogen.

40. The compound of claim 1, wherein R7 is hydrogen.

41. The compound of claim 1, wherein R7 and R15 are joined to form a substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

42. The compound of claim 1, wherein R7 and R15 are joined to form an unsubstituted cyclohexyl.

43. The compound of claim 1, wherein R7 and R15 are joined to form an unsubstituted 6 membered heterocycloalkyl, wherein the heterocycloalkyl comprises (i) an oxygen atom, (ii) a nitrogen atom, or (iii) an oxygen atom and a nitrogen atom.

44. The compound of claim 1, wherein R7 and R15 are joined to form an unsubstituted phenyl.

45. The compound of claim 1, wherein R7 and R15 are joined to form an unsubstituted 5 to 6 membered heteroaryl, wherein the heteroaryl comprises one or two nitrogen atoms.

46. The compound of claim 1, wherein R8 is hydrogen.

47. The compound of claim 1, wherein R10 is hydrogen.

48. The compound of claim 1, wherein R9 is hydrogen.

49. The compound of claim 1, wherein R11 is hydrogen.

50. The compound of claim 1, wherein R11 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.

51. The compound of claim 1, wherein R11 is substituted or unsubstituted heterocycloalkyl.

52. The compound of claim 1, wherein R11 is substituted or unsubstituted 5 to 6 membered heterocycloalkyl.

53. The compound of claim 1, wherein R11 is unsubstituted 5 to 6 membered heterocycloalkyl.

54. The compound of claim 1, wherein R11 is

55. The compound of claim 1, wherein R11 is hydrogen, —C(NR11C)NR11AR11B, 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.

56. The compound of claim 55, wherein R11 is

57. The compound of claim 56, wherein R11 is

58. The compound of claim 56, wherein R11 is

59. The compound of claim 1, wherein R9 and R11 are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl.

60. The compound of claim 59, wherein R9 and R11 are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl containing one nitrogen atom.

61. The compound of claim 1, wherein R12 is hydrogen, —C(NR12C)NR12AR12B, 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.

62. The compound of claim 1, wherein R12 is hydrogen.

63. The compound of claim 1, having the formula:

64. The compound of claim 1, having the formula:

65. The compound of claim 1, having the formula:

66. The compound of claim 1, having the formula:

67. A pharmaceutical composition comprising the compound of one of claims 1 to 66, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

68. A method of treating an inflammatory disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 66, or a pharmaceutically acceptable salt or tautomer thereof.

69. The method of claim 68, wherein the inflammatory disease is asthma.

70. The method of claim 68, wherein the inflammatory disease is asthma, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, diabetes mellitus type 1, diabetic retinopathy, 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, acne vulgaris, celiac disease, chronic prostatitis, chronic obstructive pulmonary disease, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, graft-versus-host disease, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis.

71. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 66, or a pharmaceutically acceptable salt or tautomer thereof.

72. A method of inhibiting angiogenesis in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 66, or a pharmaceutically acceptable salt or tautomer thereof.

73. A method of reducing the level of activity of α5β1 integrin in a cell, said method comprising contacting the cell with an effective of a compound of one of claims 1 to 66, or a pharmaceutically acceptable salt or tautomer thereof.