Cap analogs and methods of use thereof

Abstract

Described herein are novel tetranucleotide and trinucleotide cap analogs and methods of making and using the same. Also described herein are RNA molecules comprising a 5'-cap, wherein the 5'-cap includes a tetranucleotide or trinucleotide cap analog as described herein. Methods of inducing a therapeutic effect in a subject are also described herein, the methods including a step of administering to the subject an RNA molecule including the tetranucleotide or trinucleotide cap analog. The tetranucleotide and trinucleotide cap analogs have formulas (I) and (II).

Description

CAP ANALOGS AND METHODS OF USE THEREOFCROSS-REFERENCE TO PRIORITY APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 536,844, filed September 6, 2023, the contents of which are incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The field of this invention relates to cap analogs and methods of making and using the same. Additionally, the invention relates to using the cap analogs for preparing 5 ’-capped RNAs.BACKGROUND

[0003] In vitro transcribed messenger RNAs (mRNAs) have numerous in vivo applications, such as vaccination, where mRNA encoding specific antigen(s) is administered to elicit protective immunity in a patient; cell therapy, where mRNA is transfected into cells ex vivo to alter cell phenotype or function prior to delivery of these altered cells to a patient: or replacement therapy, where mRNA encoding a therapeutic protein is administered to the patient.

[0004] A primary structural element of an mRNA molecule that is utilized in in vivo applications includes a Cap structure on the 5 ’-end of the mRNA. Naturally occurring Cap structures include a 7-methylguanosine (7mG orm7G) linked through a 5‘- to 5 ’-triphosphate chain at the 5 ’-end of the mRNA molecule. The Cap must be present for the mRNA to retain template activity for protein synthesis. The chemical structure of the Cap can modulate translation efficiency in a cell. Therefore, effective Cap structures are necessary. Described herein are new Cap structures, which can be used for preparing 5 ’-capped mRNAs.BRIEF SUMMARY OF THE INVENTION

[0005] In an aspect, provided herein is a compound of formula (I):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O. S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, 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; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary 1, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CCI3. -CBn, -CF3, -Ch, -CHCh. -CH Bn.-CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R19is independently hydrogen, halogen. -CCh, -CBrs. -CF3, -Cl3, -CHCl2, -CHBn. -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCh, -CBr3, -CF3, -Cl3 -CHCl2, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3. -OCBrs, -OCh, -OCHCl2, -OCH Bn. -OCHl2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo. halogen, -CCI3, -CBn. -CF3. -CI3, -CHCh, -CHBrs. -CHF2. -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2,-OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -Ns, -SF5, 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; n is an integer from 0 to 3; andX is -Cl, -Br, -I or -F; with the proviso that the compound of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0006] In embodiments, provided herein is a compound of formula (IA):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B ' is a natural nucleoside base;R4is independently hydrogen, -C(O)R4A, -C(O)OR4A, -OR4A, 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;R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR5A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBn.-CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR6A. -NR6AR6B, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr?. -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroarvl;R14is hydrogen, halogen, -CCb, -CBn. -CF3. -CI3. -CHCh, -CHBn.-CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R4A, R5A. R6A, R6B. R14A. and R14Bis independently hydrogen, -CX3, -CHX2, -CH2X. -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.R1, R2, R3, R7, R11, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, n, and Ring A are each as defined herein, including in embodiments.

[0007] In embodiments, provided herein is a compound of formula (IB):or an enantiomer. a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen. -CCI3, -CBrs, -CF3, -Ch. -CHCh, -CHBn, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2, -OCHBr2, -OCHI2. -OCHF2. -OCH2CI, -OQhBr. -OCH2I, -OCH2F, -N3. -SFs. 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;R8is independently hydrogen, halogen, -CCI3, -CBr . -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCIs, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R9is independently hydrogen, halogen, -CCI3, -CBr?. -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H. -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene:R10is hydrogen, halogen, -CCk, -CBn. -CF3. -Ch, -CHCh, -CHBr2. -CHF2. -CHI2, -CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR1OAR1OB, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H,-NHC(O)OH. -NHOH, -OCCI3, -OCF3, -OCBn. -OCI3, -OCHCl2. -OCHBn, -OCHI2. -OCHF2. -OCH2CI, -OCFBBr, -OCH2I, -OCH2F, -Ns, -SF5, 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; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R1, R2, R3, R4, R5. R6. R7, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3and n, are each as defined herein, including in embodiments.

[0008] In embodiments, provided herein is a compound of formula (IC):(IC); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.R1, R2, R3, R4, R5, R6, R7, R8, R8, R9, R10, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are as defined herein, including in embodiments.

[0009] In embodiments, provided herein is a compound of formula (ID):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptablesalt, solvate, or hydrate thereof; wherein.R12is independently hydrogen, -C(O)R12A, -C(O)OR12A, -OR12A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroary l;R13is independently hydrogen, -C(O)R1 JA, -C(O)OR13A, -OR13A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R12and R13together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; each R12Aand R13Ais independently hydrogen, -CX3. -CHX2, CH2X. -C(O)OH, -C(0)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, ONH2, NHC (0)NHNH2. NHC (O)NH2. -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2. -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR1, R2, R3, R4, R5, R6, R7, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, Ring A, X, and n, are each as defined herein, including in embodiments.

[0010] In embodiments, provided herein is a compound of formula (IE)or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptablesalt, solvate, or hydrate thereof; wherein: R1. R2. R3, R4, R5, R6, R7, R8, R8, R9, R10, R11. R12, R13.R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n, are each as defined herein, including in embodiments.

[0011] In embodiments, provided herein is a compound of formula (IF):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R8, R9, R10, R11, R12, R13, R14, R19, X1, X2, Y1. Y2, Y3, Y4, Y5, B3, and n, are each as defined herein, including in embodiments.

[0012] In embodiments, provided herein is a compound of formula (IG):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R15is hydrogen, halogen, -CCh, -CBn. -CF3. -CI3. -CHCh, -CHBn. -CHF2. -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR15A, -NR15AR15B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2. -OCHF2. -OCH2CI, -OCFBBr. -OCH2I, -OCH2F, -N3. -SFs. 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;R16is independently hydrogen, -C(O)R16A, -C(O)OR16A. -OR16A, 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; each R15A, R15B, and R,6Ais independently hydrogen. -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2. -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR15Aand R15Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroary l.R1, R2, R3. R4. R5, R6, R7, R11, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, Ring A, X, and n, are each as defined herein, including in embodiments.

[0013] In embodiments, provided herein is a compound of formula (IH):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R8, R9, R10, R11, R15, R16, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0014] In embodiments, provided herein is a compound of formula (I J) :or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof; wherein R1. R2, R3, R4, R5, R6, R7, R8, R8, R9, R10. R11, R15, R16. R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0015] In embodiments, provided herein is a compound of formula (IK):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R6, R7, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, Ring A, and n are each as defined herein, including in embodiments.

[0016] In embodiments, provided herein is a compound of formula (IL);or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein R1, R2, R1, R6, R7, R8, R8, R9, R10, R11, R14, R19, X1,X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0017] In embodiments, provided herein is a compound of formula (IM):(IM); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R6, R7, R8, R8, R9, R10, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0018] In embodiments, provided herein is a compound of formula (IN):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R6, R7, R11, R15, R16, R19, X1, X2, Y1, Y2, Y3,Y4, Y5, B3, Ring A. and n are each as defined herein, including in embodiments.

[0019] In embodiments, provided herein is a compound of formula (IO):(IO); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R6, R7, R8, R8, R9, R10, R11, R15, R16, R19, X1, X2, Y1, Y2, Y Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0020] In embodiments, provided herein is a compound of formula (IP):(IP); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R6, R7, R8, R8, R9, R10, R11, R15, R16, R19, X1,X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0021] In embodiments, provided herein is a compound of formula (IQ):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R6, R7, R11, R12, R13, R15, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, Ring A, and n are each as defined herein, including in embodiments.

[0022] In embodiments, provided herein is a compound of formula (IR):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R6, R7. R8, R8, R9, R10, R11, R12, R13,R15. R19. X1. X2. Y1. Y2, Y3, Y4, Y5, B3. and n are each as defined herein, including in embodiments.

[0023] In embodiments, provided herein is a compound of formula (IS):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R8, R9, R10, R11, R12, Rlj, R15, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, X, and n are each as defined herein, including in embodiments.

[0024] In embodiments, provided herein is a compound of formula (IT):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R17is hydrogen, halogen, -CCh, -CBn. -CF3. -CI3. -CHCh, -CHBn. -CHF2. -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR17A, -NR17AR17B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2. -OCHF2. -OCH2CI, -OCFBBr. -OCH2I, -OCH2F, -N3. -SFs. 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;R18is independently hydrogen, -C(O)R18A, -C(O)OR18A. -OR18A, 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; each R17A, R17B, and R18A, is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2. -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R17Aand R17Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalky 1 or substituted or unsubstituted heteroary l. and wherein: R1, R2, R3, R7, R11, R15. R16, R19, X1, X2, Y1, Y2, Y3, Y4. Y5. B3. Ring A, X. and n are each as defined herein, including in embodiments.

[0025] In embodiments, provided herein is a compound of formula (IU):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R7, R8, R8, R9, R10, R11, R15, R16, R17, R18, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0026] In embodiments, provided herein is a compound of formula (IV):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R7, R8, R8, R9, R10, R11, R15, R16, R17, R18, R19,X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0027] In embodiments, provided herein is a compound of formula (IW):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R7, R11, R14, R17, R18, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, Ring A, and n are each as defined herein, including in embodiments.

[0028] In embodiments, provided herein is a compound of formula (IX):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptablesalt, solvate, or hydrate thereof; wherein R1, R2, R3, R7, R8, R8, R9, R10, R11. R14, R17. R18, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0029] In embodiments, provided herein is a compound of formula (IY):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R7, R8, R8, R9, R10, R11, R14, R17, R18, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0030] In embodiments, provided herein is a compound of formula (IZ):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R7, R11, R14, R17, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, Ring A, and n are each as defined herein, including in embodiments.

[0031] In embodiments, provided herein is a compound of formula (IAA):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R7, R8, R8, R9, R10, R11, R14, R17, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0032] In embodiments, provided herein is a compound of formula (IBB):(IBB);or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R7, R8, R8, R9, R10, R11, R14, R17, R19, X1, X2, Y1, Y2, Y Y4, Y5, B3, and n are each as defined herein, including in embodiments.

[0033] In embodiments, provided herein is a compound of formula (II):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1and B2are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, and Y4are each independently O. S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary 1, or substituted or unsubstituted heteroaryl; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, 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;R7is independently hydrogen, halogen. -CCI3, -CBrs, -CF3, -Ch. -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; each R19is independently hydrogen, halogen. -CCI3, -CBr?. -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCI3, -CBn. -CF3. -Ch. -CHCh, -CHBn. -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently' hydrogen, -CX3,-CHX2, -CH2X. -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3. -OCHX2, -OCH2X, 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; or R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be j oined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each R101is independently hydrogen, oxo, halogen. -CCh, -CBrs, -CF3, -CI3, -CHCh, -CH Bn. -CHF2, -CHI2, -CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCk, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; n is an integer from 0 to 3; and each X is independently-Cl. -Br, -I or -F; with the proviso that R11is not OH.

[0034] In embodiments, provided herein is a compound of formula (IIA):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R4is independently hydrogen, -C(O)R4A. -C(O)OR4A, -OR4Asubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R5is independently hydrogen, -C(O)R5A. -C(O)OR5A, -OR5A. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary 1; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCI3. -CBrs, -CF3, -CI3, -CHCh. -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR6A, -NR6AR6B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R14is hydrogen, halogen, -CCI3, -CBn. -CF3. -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary l; each R4A, R5A, R6A, R6B. R14A. and R14Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH. -C(O)NH2. -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH. -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.R1, R2, R3, R7, R11, R19, X1, X2, Y1, Y2, Y3, Y4, Ring A, and n, are each as defined herein, including in embodiments.

[0035] In embodiments, provided herein is a compound of formula (IIB) :or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCI3, -CBn, -CFs, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBn, -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCI3, -CBr. -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2,-NHSO2H, -NHC(O)R8 A. -NHC(O)OH, -NHOH, -OCCI3. -OCF3. -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R9is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCH Bn. -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCls, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR1OAR1OB, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B. R8 A. R8’D, R9A, R9D, R1OA, and R10Dis independently hydrogen. -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, NHNH2, ONH2, NHC-(O)NHNH2. NHC~(O)NH2. -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.R1, R2, R3, R4. R5. R6, R7, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, and n, are each as defined herein, including in embodiments.

[0036] In embodiments, provided herein is a compound of formula (IIC):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R8, R9, R10, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, and n, are each as defined herein, including in embodiments.

[0037] In embodiments. Ring A is a substituted or unsubstituted heterocycloalkylene.

[0038] In embodiments, R1is independently hydrogen or substituted or unsubstituted alkyl.In embodiments, R1is independently hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t- butyl, pentyl, isopentyl, or hexyl. In embodiments, R1is independently hydrogen or methyl. In embodiments. R1is independently hydrogen.

[0039] In embodiments, R2is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R2is independently hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t- butyl, pentyl, isopentyl, or hexyl. In embodiments, R2is independently hydrogen or methyl. In embodiments. R2is independently hydrogen.

[0040] In embodiments. R3is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R3is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopentyl, or hexyl. In embodiments, R3is independently hydrogen or methyl. In embodiments, R3is independently methyl.

[0041] In embodiments. R4is independently hydrogen. -C(O)R4A. substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyd. In embodiments, R4is independently hydrogen, -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In embodiments, R4is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl. In embodiments, R4is independently hydrogen or methyl.

[0042] In embodiments, R5is independently hydrogen -C(O)R5A, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalk l. In embodiments, R3is independently hydrogen, -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In embodiments, R5is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl. In embodiments, R5is independently hydrogen or methyl.

[0043] In embodiments. R6is hydrogen, halogen, or -NR6AR6B. In embodiments, R6is hydrogen. -F, -NHMe, -NH2, or -NMe2. In embodiments, R6is hydrogen, -NH2. or -NHMe. In embodiments, R6is hydrogen.

[0044] In embodiments, (i) R4is independently hydrogen or methyl; or (ii) R5is independently hydrogen or methyl.

[0045] In embodiments. R7is independently hydrogen, halogen, or -OR7A. In embodiments. R7is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R7is independently methoxy.

[0046] In embodiments, R8is independently hydrogen, halogen, -OR8A, or -NHC(O)R8A. In embodiments, R8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t- butoxy. In embodiments, R8is independently hydrogen, hydroxy or methoxy. In embodiments, R8is independently hydrogen or hydroxy. In embodiments, R8is independently hydroxy.

[0047] In embodiments, R8Ais independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R8Ais independently hydrogen or methyl. In embodiments, R8Ais independently hydrogen. In embodiments, R8Ais independently methyl.

[0048] In embodiments, R8is independently hydrogen, halogen, -OR8 A, or -NHC(O)R8 A. In embodiments, R8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R8is independently hydrogen, hydroxy or methoxy. In embodiments. R8is independently hydrogen or hydroxy. In embodiments, R8is independently hydrogen.

[0049] In embodiments, R8 Ais independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R8 Ais independently hydrogen or methyl. In embodiments, R8 Ais independently hydrogen. In embodiments, R8 Ais independently methyl.

[0050] In embodiments, R9is independently hydrogen, halogen, -OR9A, or -NHC(O)R9A. In embodiments, R9is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t- butoxy. In embodiments, R9is independently methoxy.

[0051] In embodiments. R9Ais independently hydrogen or substituted or unsubstituted alkyl.

[0052] In embodiments, R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkydene.

[0053] In embodiments, R10is hydrogen.

[0054] In embodiments. R8and R10orR8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalky lene. In embodiments, R8and R10or R8and R10together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).

[0055] In embodiments. R19is independently hydrogen.

[0056] In embodiments. R7and R19together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).

[0057] In embodiments, R11is independently hydrogen, halogen, or -OR11A. In embodiments, R11is independently methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R11is independently methoxy.

[0058] In embodiments. R12is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R12is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopentyl, or hexyl. In embodiments, R12is independently hydrogen or methyl.

[0059] In embodiments. Rljis independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R13is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyd, or hexyl. In embodiments, R13is independently hydrogen or methyl.

[0060] In embodiments, R14is hydrogen, halogen, or -NR14AR14B. In embodiments, R14is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R14is hydrogen or -NH2. In embodiments. R14is -NH2.

[0061] In embodiments, R13is hydrogen, halogen, or -NR15AR13B. In embodiments, R13is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R13is hydrogen, -NHMe, or -NH2. Inembodiments. R15is hydrogen.

[0062] In embodiments, R16is hydrogen or substituted or unsubstituted alkyl. In embodiments, R16is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, penty l, isopentyl, or hexyl. In embodiments, R16is hydrogen.

[0063] In embodiments. R17is hydrogen, halogen, or -NR17AR17B. In embodiments, R17is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R17is hydrogen, -NHMe, or -NH2. In embodiments, R17is hydrogen.

[0064] In embodiments. R18is hydrogen or substituted or unsubstituted alkyl. In embodiments. R18is hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, R18is hydrogen.

[0065] In embodiments, X1is -O-, -CH2-, or -CX2-. In embodiments, X1is -O-, -CH2-, or - CF2-. In embodiments, X1is -O-.

[0066] In embodiments. X2is -O-, -CH2-, -CX2-, -N(R101)-, or -BH-. In embodiments. X2is -O-. -CH2-, -CF2-. -NH-, or -BH-. In embodiments. X2is -O-, -CH2-. or -NH-. In embodiments. X2is -O-. In embodiments, X2is -CH2- or -NH-.

[0067] In embodiments, Y1, Y2, Y3, and Y4are each independently O or S. In embodiments, Y’, Y2, Y3, and Y4are O.

[0068] In embodiments. Y5is O or S. In embodiments. Y5is O.

[0069] In embodiments, n is 1 or 2. In embodiments, n is 1.

[0070] In embodiments, B3is adenine, guanine, cytosine or uracil. In embodiments, B3is guanine.

[0071] In an aspect the compound provided herein has the structure:or an enantiomer. a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0072] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0073] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptablesalt, solvate, or hydrate thereof.

[0074] In an aspect the compound provided herein has the structure:or on enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, sob. ate. or hydrate thereof.

[0075] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0076] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0077] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hvdrate thereof.

[0078] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0079] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0080] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0081] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0082] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0083] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0084] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0085] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers. a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0086] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0087] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0088] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0089] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0090] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0091] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0092] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable sail; solvate, or hydrate thereof.

[0093] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0094] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0095] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0096] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salts, solvate, or hydrate thereof.

[0097] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0098] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0099] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hvdrate thereof

[0100] In an aspect the compound provided herein has the structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0101] In embodiments, the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt. In embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0102] In an aspect, provided herein is an RNA molecule comprising a 5 ’-cap, wherein the 5 ’-cap comprises any one of the compounds described herein, including in embodiments. In embodiments, the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.

[0103] In an aspect, provided herein is a pharmaceutical composition comprising any one of the compounds described herein, including in embodiments and a pharmaceutically acceptable excipient. In an aspect, provided herein is a pharmaceutical composition comprising an RNA molecule comprising a 5'-cap, wherein the 5'-cap comprises any one of the compounds described herein, including in embodiments, and a pharmaceutically acceptable excipient.

[0104] In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7GpppA2’0M6pG2’0M6pG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3'OMepppm6A2 OMepA2 OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3'OMepppm6A2 OMepG2 OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G 3'OMepppA2’OMepA2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3' 0Mepppm6A20Mepm6A20MepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMeppp(s)A2’OMepA2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppA2’OMepA2’OMepU. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppA2 OMepG2 OMepA. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppA2 OMepm6A2 OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppA2’OMepm6A2’OMepU. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppA2’OMep(s)A2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppA2 OMepU2 OMepA. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppA2 OMepU2 OMepC. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppA2’OMepU2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of forrnulam7G3’OMepppC2’OMepG2’OMepG. Inan aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppG2’OMepG2’OMepC. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppG2’OMepG2’OMepU. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppG2 OMepU2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of forrnulam7G3’OMepppm6A2’OMepA2’OMepU. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMCpppm6A2 OMcpG2 OMcpA. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppm6A2 OMepm6A2 OMepU. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppm6A2 OMepU2’OMepA. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppU2’OMepG2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppU2 OMepU2 OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppm6A2’onpA2 OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OMepppN6‘1Pr6A2’OMepA2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3’OM6pppN6'cyclopropylA2’OMepA2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3 OMepppN6'ethylureaA2-oMepA2 OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7GpppA2 OMepG2 OMe. In an aspect, provided herein is an initiating capped oligonucleotide primer of formulam7G3'OMePPpA2’OMepG2’OMe.

[0105] In an aspect, provided herein is an RNA molecule comprising any one of the initiating capped oligonucleotide primers, stereoisomer, or a pharmaceutically acceptable salt thereof, as described herein including in embodiments. In embodiments, the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt. In embodiments, the pharmaceutically acceptable salt is a sodium salt. In embodiments, the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.

[0106] In an aspect, provided herein is a pharmaceutical composition comprising an RNA molecule comprising any one of the initiating capped oligonucleotide primers, stereoisomers, or a pharmaceutically acceptable salt thereof, as described herein, including in embodiments, and a pharmaceutically acceptable excipient.

[0107] In an aspect, provided herein is a method of inducing a therapeutic effect in a subject, comprising administering to the subject any one of RNA molecules described herein, including in embodiments. In an aspect, provided herein is a method of administering to a subject atherapeutic dose unit of an mRNA molecule comprising a 5 ’-cap, wherein the 5 ’-cap comprises anyone of the compounds described herein, including in embodiments.

[0108] In an aspect, provided herein is a method of synthesizing capped RNA transcripts, comprising:(i) forming a reaction mixture comprising a compound as described herein, a DNA template, an RNA polymerase, and nucleotide triphosphates (NTPs); and(ii) incubating the reaction mixture under conditions that allow transcription of the DNA template to produce capped RNA transcripts.

[0109] In an aspect, provided herein is a method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (I)or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A. -C(O)OR2A. -OR2Asubstituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, 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;R7is hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I, -OCH2F. -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R19is independently hydrogen, halogen. -CCh, -CBrs, -CF3, -CI3, -CHCh, -CHBn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCh, -CB13. -CF3, -Ch, -CHCh, -CHB12. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBrs. -OCh. -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R2A. R3A, R7A, R7D, R11A, R11D, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHC12,-OCHBr2. -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; andX is -Cl. -Br, -I or -F; with the proviso that the compound of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; into a mixture comprising a polynucleotide template, an RNA polymerase, and nucleotide triphosphates (NTPs), under conditions conducive to transcription by the RNA polymerase of the polynucleotide template and incubating said mixture for a time sufficient to allow for transcription of said template.

[0110] In an aspect, provided herein is a method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (II)or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable sail, solvate, or hydrate thereof; wherein:B1and B2are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, and Y4are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A. -C(O)OR1A, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, 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; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is independently hydrogen, halogen, -CCI3, -CBn. -CF3, -CI3. -CHCh, -CH Bn. -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR7A. -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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; each R19is independently hydrogen, halogen, -CCI3, -CBrs, -CFs, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCB , -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R7and R19together with the carbon atoms to which they are connected form a substitutedor unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCI2, -C'HBn.-CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2. -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBry -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may7optionally be joined to form a substituted or unsubstituted heterocycloalky7! or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCk, -CBr3, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2. -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2.-OCHBr2. -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky7!, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; andX is -Cl. -Br, -I or -F; with the proviso that R11is not OH;into a mixture comprising a polynucleotide template, an RNA polymerase, and nucleotide triphosphates (NTPs), under conditions conducive to transcription by the RNA polymerase of the polynucleotide template and incubating said mixture for a time sufficient to allow for transcription of said template.BRIEF DESCRIPTION OF THE DRAWINGS

[0111] FIG. 1A-B show hEPO protein production with IFNa pretreatment relative to no IFNa pretreatment, using wildtype uridine triphosphates (FIG. 1A) or N1 -methylpseudouridine triphosphates (FIG. IB) for hEPO mRNA synthesis.

[0112] FIG. 2 shows LC-MS trace of a fragment cleaved from the 5’ end of the mRNA to determine capping efficiency of A- 12 cap.

[0113] FIG. 3A-B show total hEPO protein expression after 72 hours in A-549 cells, using wildtype uridine triphosphates (FIG. 3A) or N1 -methylpseudouridine triphosphates (FIG. 3B) for hEPO mRNA synthesis.

[0114] FIG. 4A-D show total hEPO protein expression after 72 hours in A-549 cells, using wildtype uridine triphosphates for hEPO mRNA synthesis, without IFNa pretreatment (FIG. 4A) or with IFNa pretreatment (FIG. 4B); using N 1 -methylpseudouridine triphosphates for hEPO mRNA synthesis, without IFNa pretreatment (FIG. 4C) or with IFNa pretreatment (FIG. 4D).

[0115] FIG. 5A-B show RIG-I induction of innate immune response in HEK293-Lucia RIG-I cells (after overnight incubation), using wildtype uridine triphosphates (FIG. 5A) or N 1 - methylpseudouridine triphosphates (FIG. 5B) for hEPO mRNA synthesis.DETAILED DESCRIPTION OF THE INVENTIONDefinitions:

[0116] Unless defined otherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0117] As used herein, “a” or '‘an’’ means “at least one" or “one or more’’. For example.reference to “a transcript” may include a plurality of transcripts.

[0118] “Or” is used in the inclusive sense, i.e., equivalent to “and / or”, unless the context clearly indicates otherwise.

[0119] The use of any and all examples or exemplary language (e.g., “such as”) provided herein, is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0120] The terms “may,” “may be,” “can,” and “can be,” and related terms are intended to convey that the subject matter involved is optional (that is, the subject matter is present in some examples and is not present in other examples), not a reference to a capability’ of the subject matter or to a probability, unless the context clearly indicates otherwise.

[0121] The terms “optional” and “optionally” mean that the subsequently described event, circumstance, or material may or may not occur or be present, and that the description includes instances where the event, circumstance, or material occurs or is present as well as instances where it does not occur or is not present.

[0122] 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.

[0123] 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.

[0124] Ranges include the endpoints of the range. For example, “between 0 and 2” includes 0, 1, 2, and (unless the context requires otherwise) fractional values greater than 0 and less than 2.

[0125] 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-.

[0126] The term “alky l,” 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). 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, 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, croty l, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl. 3-(l,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 alky l moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and / or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and / or one or more double bonds in addition to the one or more triple bonds.

[0127] The term “alky lene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alky l, 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.

[0128] 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 quatemized. The heteroatom(s) (e.g., O, 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, -CH2-S-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 differentheteroatoms (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.

[0129] 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", -OR1, -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.

[0130] 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 heterocycloalkyd 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, l-(l,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 “cycloalkydene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0131] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or amulticyclic 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. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CIEjw . where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one nng system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin- 1-yl, and perhydrophenoxazin- 1-yl.

[0132] 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. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CEtyty, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbomenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.

[0133] In embodiments, a heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” asused herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, P, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N, P, and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N, P, and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N, P, and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl. isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl. oxazolinyl. oxazolidinyl, piperazinyl, piperidinyl. pyranyl, pyrazolinyl. pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl. indolin-3-yl. 2.3- dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro- IH-indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ringsystems independently selected from the group consisting of a phenyl, a bicychc aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to lOH-phenothiazin- 10- yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, lOH-phenoxazin-10-yl, 10,11-dihydro- 5H-dibenzo[b,f|azepin-5-yl, l,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H- benzo[b]phenoxazin-12-yl, and dodecahydro-lH-carbazol-9-yl.

[0134] 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(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl. 4-chlorobutyl, 3-bromopropyl. and the like.

[0135] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0136] 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 ary l) 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. 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 quatemized. 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). A5.6-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, a6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 membersand 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.

[0137] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.

[0138] 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 maybe 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 havingall 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.

[0139] The symboldenotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0140] The term "oxo." as used herein, means an oxygen that is double bonded to a carbon atom.

[0141] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alk l group as defined above. R' may have a specified number of carbons (e.g.„ “C1-C4 alkylsulfonyl”).

[0142] 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:

[0143] An alkylaiylene 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, - CCh, -CBn. -Ch, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, , - OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyd or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0144] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryd”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0145] Substituents for the alkyl and heteroalkyd radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkeny 1, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-0R', -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, -NR'SO2R", -NR'C(O)R", - NR'C(O)-OR", -NR'OR", in a number ranging from zero to (2m'+l), 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 heteroal \ 1, 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 alky l, 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 -C hCFs) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0146] 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", -SR1, -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(NRR")=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', -Ns, - CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-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.

[0147] 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 chemicalvalency) 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.

[0148] 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 ringforming substituents are attached to adjacent members of the base structure. For example, two ringforming 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, tw o 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.

[0149] Tw o 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 singlebonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adj acent 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.

[0150] As used herein, the terms ’heteroalom" or ‘Ting heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0151] A ‘‘substituent group,” as used herein, means a group selected from the following moieties:

[0152] (A) oxo, halogen, -CC13. -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2.-CH Bn. -CHF2. -CHI2, -CN, -OH, -NH2. -COOH, -CONH2, -NO2. -SH. -SO3H.-SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCI3, -OCF3, -OCBn, -OCI3,-OCHC12.-OCHBn, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g.. Ci-Cs alkyl, Ci-Ce 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., Ci-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce 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

[0153] (B) alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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 Cs-Ce cycloalkyl), heterocycloalkyl (e.g.. 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered hcteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:

[0154] (1) oxo, halogen. -CCh, -CBr3, -CF3, -CI3. -CH2CI, -CH2Br, -CH2F, -CH2I. -CHCh,-CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H,-NHC(O)H. -NHC(O)OH, -NHOH, -OCCl3. -OCFs, -OCBrs, -OCI3.-OCHCI2.-OCHBn, -OCHI2, -OCHF2, -Ns, unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyd, or C1-C4 alkyd), unsubstituted heteroalky l (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalky l (e.g., Cs-Cs 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., Ce-Cio aryl, C10 ary l, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0155] (ii) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd), cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyd, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio 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:

[0156] (a) oxo, halogen, -CCI3, -CBrs, -CF3, -Cis, -CH2CI, -CH2Br, -CH2F, -CH2I,-CHCh, -CHB12. -CHF2, -CHI2, -CN. -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2. -NHC(0)NHNH2. -NHC(O)NH2.-NHSO2H, -NHC(0)H, -NHC(O)OH, -NHOH, -OCCI3, -OCFs, -OCBr3, -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -Ns, unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci-Ce 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, Cs- Ce cycloalkyl, or Cs-Ce cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalky 1, or 5 to 6 membered heterocycloalkyd), unsubstituted ary l (e.g., Ce-Cio ary l, C10 ary l, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryd. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0157] (b) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyd, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd), cycloalkyl (e.g., Cs-Cs cycloalkyl, Cs-Ce cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). aryl (e.g., Ce-Cio 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, -CCI3, -CBrs, -CF3, -Cis, -CH2CI, -CH2Br,-CH2F, -CH2I. -CHCh, -CHBr2, -CHF2, -CHI2. -CN. -OH. -NH2. -COOH. -CONH2. -NO2, -SH. -S OsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2,-NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3,-OCBn. -OCl3,-OCHCl2, -OCHBn, -OCHI2. -OCHF2. -N3, unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyd), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted and (e.g., Cs-Cio and, 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).

[0158] 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 Cg-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0159] 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 Ci-Cs 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.

[0160] 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, substitutedcycloalkylene, 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 w ith at least one sizelimited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0161] In other embodiments of the compounds herein, each substituted or unsubstituted alkyd 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 Ce-Cio aryl, and / or each substituted or unsubstituted heteroary l 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 Ce- C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0162] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs 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 Ce-Cio 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 Ci-Cs 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 Ce-Cio arylene, and / or each substituted or unsubstituted heteroaryleneis 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.

[0163] 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 ary lene, 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 alkydene, substituted or unsubstituted heteroalky dene, 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 heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryd, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0164] In embodiments, a substituted moiety (e.g.. substituted alkyl, substituted heteroalkyl, substituted cycloalky 1, substituted heterocycloalkyl, substituted aryl, substituted heteroaryd, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted ary lene, 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.

[0165] 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, substitutedheterocycloalkylene, 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 plurality7of 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.

[0166] 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.

[0167] 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 ary lene, 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.

[0168] 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 containolefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. In certain embodiments, "optically active” and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%. no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the racemate in question.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0174] 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.

[0175] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each nucleoside base position that contains more than one possiblenucleoside base. 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.

[0176] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0177] The term “solvate"’ refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0178] The term “salt thereof’ means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable.the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0179] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a patient, such as a mammal, such as human (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and when the molecule contains a basic functionality, salts of organic or inorganic acids. The pharmaceutically acceptable salts of the compounds described herein are suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible, of the compounds described herein. These salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and lauryl sulphonate salts, and the like. Salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See S.M. Barge et al., J. Pharm. Sci. (1977) 66, 1; and Remington: The Science and Practice of Pharmacy, 23d Edition. Adejare et al. eds., Academic Press (2020); which are incorporated herein by reference in their entireties.)

[0180] As used herein, the term “cap analog” means a structural derivative of an RNA cap.

[0181] As used herein, the term “complement,” “complementary ,” or “complementarity ” refers to specific base pairing between nucleotides or nucleic acids. Complementary nucleotides are, generally. A and T (or A and U), and G and C. Complementarity, for example, between a capped oligonucleotide primer and a single stranded DNA template or one strand of dsDNA template, may be “complete” or "total" where all of the nucleotide bases of two nucleic acid strands are matched according to recognized base pairing rules, it may be “partial” in which only some of the nucleotide bases of an initiating capped oligonucleotide primer and a DNA template are matched according to recognized base pairing rules, or it may be “absent” where none of the nucleotide bases of two nucleic acid strands are matched according to recognized base pairing rules. Complementarity7can also be “substantial complementarity7” where the nucleotide bases of two nucleic acids are matched according to recognized base pairing rules, but include one or more mismatches (e.g., 1, 2, 3, 4) from total complementarity.

[0182] As used herein, a “deoxyribonuclease (DNase)” is an enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA.

[0183] As used herein, the term “hybridize” or “specifically hybridize” refers to a process where initiating trinucleotide primer anneals to a DNA template under appropriately stringent conditions during a transcription reaction. Hybridizations to DNA are conducted with an initiating capped oligonucleotide primer which, in certain embodiments, is 3-10 nucleotides in lengthincluding the 5 ’-5’ inverted cap structure. Nucleic acid hybridization techniques are well known in the art (e.g., Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Press, Plainview, N.Y.(1989); Ausubel, F.M., et al., Current Protocols in Molecular Biology, John Wiley & Sons, Secaucus, N.J. (1994)).

[0184] As used herein, the term “impurities” refers to substances which differ from the chemical composition of the target material (e g., mRNA transcripts). Impurities are also referred to as contaminants.

[0185] “Inorganic pyrophosphatase” refers to an enzy me that catalyzes the conversion of one ion of pyrophosphate to two phosphate ions, thus inhibiting aggregation and in some instances preventing interaction of pyrophosphate with magnesium ions during T7 transcription reactions.

[0186] As used herein, the term “intemucleotide linkage” refers to the bond or bonds that connect two nucleosides of an oligonucleotide or nucleic acid and may be a natural phosphodiester linkage or modified linkage (any linkage that is not a phosphodiester linkage).

[0187] As used herein, “phosphorothioate linkage” refers to a linkage between nucleosides in which the phosphorodiester linkage is modified by replacing one of the oxygen atoms, connected to a phosphorus atom, with a sulfur atom.

[0188] As used herein, the term “in vitro'" refers to a process that takes place outside a living organism (e.g., a multi-cellular organism, such as a human or a non-human animal), for example, in a test tube, culture dish, or elsewhere outside a living organism.

[0189] As used herein, the term “in vivo” refers to events that occur within a living organism.

[0190] As used herein the term “in vivo assays” refer to methods used to detect and / or measure capacity of one or more of the compounds or molecules including the compounds (e.g., mRNA molecules in, for example, a therapeutic dose) to increase or decrease a property relative to a control (e.g., biomarker levels). Optionally, in vivo assays as described herein can be used to determine a subject's tolerability levels to a given compound or molecule. Exemplary measurements for assessing tolerability include one or more of body weight, organ weight, aspartate aminotransferase (AST) levels, alanine transaminase (ALT) levels, C-reactive protein (CRP) levels, procalcitonin (PCT) levels, interleukin-6 (IL-6) levels, ery throcyte sedimentation rate (ESR), serum amyloid A levels, and serum ferritin levels.

[0191] As used herein, “locked nucleic acid” (LNA) means a ribonucleotide having a bridge between the 2’0 and 4’C methylene bicyclonucleotide monomers. An LNA moiety can have the following structure:

[0192] As used herein, ‘"messenger RNA transcript,” or “mRNA transcript,” is a transcript transcribed from a DNA template encoding a desired polypeptide. The mRNA transcript may contain coding and non-coding regions. For example, the DNA template can comprise an RNA polymerase promoter sequence, a 5’ UTR sequence, an open reading frame, and a 3’ UTR sequence. In some examples, the DNA template also comprises a nucleic acid sequence encoding a poly (A) tail.

[0193] As used herein, the term “nucleoside” refers to a nitrogenous base linked to a 5- carbon sugar (e.g., ribose or deoxyribose). The term includes all nucleosides, including all forms of nucleoside bases and furanoses. The term “natural nucleoside” refers to adenosine, guanosine, cytidine, uridine and thymidine.

[0194] According to Aduri et al (Adun, R. el al.. Journal of Chemical Theory and Computation. 2006 3(4): 1464-75) there are 107 naturally occurring “modified” nucleosides, including 1 -methyladenosine, 2-methylthio-N6-hydroxynorvalyl carbamoyladenosine, 2- methyladenosine, 2-0-ribosy {phosphate adenosine. N6-metbyl-N6-threonylcarbamoyladenosine, N6-acetyl adenosine, N6-glyciny1carbamoyladenosine, N6-isopentenyladenosine, N6- methyladenosine, N6-threonylcarbamoyladenosine, N6,N6-dimethyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, N6-hydroxynorvalylcarbamoy (adenosine, 1,2-0- dimethyladenosine, N6,2-0-dimethyladenosine, 2-O-methyladenosine, N6,N6,O-2- trimethyl adenosine, 2-meihyIthio-N6-(cis-hydroxyisopentenyl) adenosine, 2-methylthio-N6- methyladenosme, 2-methylthio-N6-isopentenyladenosme, 2-methylthio~N6-threonyl carbamoyladenosine, 2-thiocytidine, 3-methylcytidine, N4-acetylcytidine, 5-formylcytidine, N4- methylcytidine, 5-methylcytidine, 5-hydroxymethylcytidine, lysidine, N4-aceiyl-2-O- methykytidme, 5-formyl-2-O-methylcytidine, 5.2~O~dmiethylcytidme. 2-O-methylcytidine, N4,2~ O-dimethy (cytidine, N4,N4.2-O-trimethy(cytidine, 1 -methylguanosine, N2,7-dimethy (guanosine, N2-methy [guanosine, 2-0-ribosy] phosphate guanosine, 7-raethylguanosine, under modified hydroxy wybutosine, 7-aminomethyl-7-deazaguanosine, 7-cyano-7-deazaguanosine, N2,N2- dimethylguanosine, 4-deniethylwyosine, epoxyqueuosine, hydroxy wybutosine, isowyosine. N2,7,2-()-trimethy (guanosine, N2,2-O-dimethy [guanosine, 1 ,2-O-di methylguanosine, 2-O-methylguanosine, N2,N2.2-0-trimethylguanosine. N2.N2.7-trimethylguanosine. peroxy wybutosme. galactosyl-queuosine, mannosyl-queuosine, queuosine. arcbaeosine, wybtrtosine, methyhvyosine, wyosine, 2-thiouridine, 3-(3-amino-3-carboxypropyl)uridine, 3- niethyiuridme, 4-thio«ridine, 5-methyl-2-thiouridine. 5-methylaminomethyluridine, 5- carboxymethylnridine, 5-carboxymethylaminometliyluridine, 5 -hydroxy uridme, 5-methyluridine, 5-taurinomethyluridine, 5-carbamoylmetbyluridine, 5-(carboxyhYdroxymethyl)uridine methyl ester, dihydrouridine, 5-methyldihydrouridine, 5-methylaminomethyl-2-thiouridine, 5- (carboxyhydroxyniethyl)uridine, 5-(isopentenylaminomethyl)uridine, 5-(isopenteiiylandnometiiyl)- 2-thiouridme. 3,2-O-dimethyluridine, 5-carboxymethylaminomethyl-2-O-methy[uridine, 5- carbamoyhnethyl-2-O-methyluridine, 5-methoxycarbonylmethy]-2-O-methyluridine, 5- (isopentenylaminomethyl)-2-O-methyluridine, 5,2-O-dimethyluridine, 2-O-methyluridine, 2-thio- 2-O-methyluridine, uridine 5-oxyacetic acid, 5-metfioxycarbonyimethyluridine, uridine 5 -oxy acetic acid methyl ester, 5-methoxy uridine, 5-aminomediy1-2-thiouridine, 5-carboxymeihylaminomelhyl- 2-thiouridine, 5-meihylaminomelhyl-2-selenouridine, 5-methoxx'carbonylmethyl-2-ihiouridine, 5- taurinomethyl-2-thiouridine, pseudouridine. l-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, 1 -methylpseudouridine, 3-methylpseudouridine, 2-O-methylpseudouridine, inosine, 1- methylinosine, 1,2-O-dimethylinosine and 2-O-methylinosine. Each of these or the modified nucleobase thereof may be components of nucleic acids of the present invention.

[0195] All other nucleosides (not including the ones described above as natural nucleosides or modified natural nucleosides) are unnatural nucleosides AU unnatural nucleosides are considered modified. Modified nucleosides (whether natural or unnatural) have, independently, a modified sugar moiety and / or modified nucleobase. Modified nucleotides (whether natural or unnatural) have, independently, a modified sugar moiety, a modified intemucleotide linkage, and / or modified nucleobase

[0196] As used herein, the terms “nucleoside base” or “nucleobase” refer to a nitrogenous base. A “natural nucleoside base” includes purine and pyrimidine rings. Purine rings include, for example, adenine and guanine. Pyrimidine rings include, for example, cytosine, thymine, and uracil.

[0197] As used herein, the term “modified nucleoside base” describes natural modified nucleoside bases, including but is not limited to, for example, pseudouracil, 5 -methylcytosine, N6- methyladenine, hypoxanthine, 5-hydroxymethylcytosine, 5-carboxylcytosine, N4-acetylcytosine, N4-methylcytosine, N1 -methyladenine, N2, N2-dimethylguanine and the like. Also, see naturally occurring modified nucleosides above.

[0198] As used herein, the term "unnatural nucleoside base” refers to all nucleoside bases that are not natural (whether modified or not; see naturally occurring modified nucleosides above) including but is not limited to, for example, N1 -methylpseudouracil, 7-deazaadenine, 2- aminoadenine, 5-methylisocytosine, 5 -fluorouracil, 5 -bromouracil, 5-iodouracil, 2- methylthioadenine, 2-thio-5-methyluracil, 2-amino-6-methylthiopurine and the like. Natural nucleosides are described above.

[0199] As used herein, the term “modified sugar” means substitution and / or any change from a natural sugar moiety.

[0200] As used herein, the terms “nucleoside analogs,” “modified nucleosides,” or “nucleoside derivatives” include synthetic nucleosides as described herein. Nucleoside derivatives also include nucleosides having modified base or / and sugar moi eties, with or without protecting groups and include, for example, 2'-deoxy-2’-fluorouridine, 5 -fluorouridine and the like. The compounds and methods provided herein include such base rings and synthetic analogs thereof, as well as unnatural heterocycle-substituted base sugars, and acyclic substituted base sugars. Other nucleoside derivatives that may be utilized with the present disclosure include, for example, LNA nucleosides, halogen-substituted purines (e.g., 6-fluoropurine), halogen-substituted pyrimidines, N6-ethyladenine, N4-(alkyl)-cytosines, 5-ethylcytosine. and the like (U.S. Patent No. 6,762,298).

[0201] As used herein, the term “nucleoside triphosphate,” “nucleoside 5’ triphosphate” or “NTP” refers to a nucleoside linked to three phosphate groups. The term encompasses natural NTPs (for example, adenosine triphosphate (ATP), uridine triphosphate (UTP), guanine triphosphate (GTP), and cytosine triphosphate (CTP)) as well as modified NTPs.

[0202] As used herein, the term “modified NTP” refers to a nucleoside 5 ’-triphosphate having a chemical moiety group bound at any position or substituted at any position, including the sugar, base, triphosphate chain, or any combination of these three locations. Optionally, the chemical moiety' group may be a group of any nature compatible w ith the process of transcription. Examples of such NTPs include inosine triphosphate, dihydrouridine triphosphate, 2’-fluoro-2’- deoxy cytidine triphosphate, pseudouridine triphosphate, N 1 -methylpseudouridine triphosphate, and 5-methyluridine triphosphate, and can be found, for example in “Nucleoside Triphosphates and Their Analogs: Chemistry, Biotechnology and Biological Applications,” Vaghefi, M., ed., Taylor and Francis, Boca Raton (2005).

[0203] As used herein, the term “modified oligonucleotide” or “modified trinucleotide” includes, for example, an oligonucleotide containing a modified nucleoside, a modified intemucleotide linkage, or having any combination of modified nucleosides and intemucleotidelinkages. Non-limiting examples of intemucleotide linkage modifications include, but are not limited to, phosphorothioate, phosphotriester and methylphosphonate derivatives (Stec, W.J., et al., Chem. Int. Ed. Engl., 33:709-722 (1994); Lebedev, A.V., et al., E., Perspect. Drug Discov. Des., 4: 17-40 (1996); and Zon, et al., U.S. Patent Application No. 20070281308). Other examples of intemucleotide linkage modifications may be found in Waldner, et al.. Bloor g. Med. Chem. Letters 6:2363-2366 (1996).

[0204] As used herein, “oligo dT purification” is an affinity chromatography method for purification of mRNA comprising or including a poly-A tail.

[0205] A “primary’ RNA” or “primary’ RNA transcript” means the RNA molecule that is newly synthesized by an RNA polymerase in vitro and which RNA molecule has a triphosphate on the 5 '-end.

[0206] As used herein, the term “prematurely aborted RNA transcript” refers to incomplete products of an in vitro transcription reaction. Prematurely aborted RNA sequences may be any length that is less than the intended length of the desired transcriptional product.

[0207] The term “promoter” as used herein refers to a nucleotide sequence in a DNA template that directs and controls the initiation of transcription of a particular DNA sequence. Promoters are typically immediately adjacent to (or partially overlap with) the DNA sequence to be transcribed. Promoter sequences are typically located directly upstream or at the 5' end of the transcription initiation site. Nucleotide positions in the promoter are designated relative to the transcriptional start site, where transcription of DNA begins (position +1).

[0208] As used herein, the term “purified” or “purify” refers to separating a substance from at least some of the components (e.g., impurities or contaminants) with which it was associated when initially produced. For example, RNA transcripts are purified by removal of contaminating proteins or other undesired nucleic acid species (e g., double-stranded RNA, DNA, and / or incomplete or aborted RNA transcripts). Purified substances (e.g., capped mRNA transcripts) can be separated from 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%. 90%. 91%. 92%. 93%. 94%. 95%. 96%, 97%, 98%, 99%, or more than 99% of the other components with which they were initially associated.

[0209] As used herein, the term “RNase inhibitor” or “ribonuclease inhibitor” refers to a protein that inhibits RNAse activity for example, during an in vitro transcription reaction.

[0210] As used herein, the term “RNA polymerase” refers to an enzyme that synthesizes RNA using a DNA template. For in vitro transcription methods, single subunit phage RNA polymerases derived from T7, T3, SP6, KI -5, K1E, K1F or KI 1 bacteriophages, or variantsthereof, are typically used. This family of polymerases has simple, minimal promoter sequences of about 17 nucleotides which require no accessory proteins and have minimal constraints of the initiating nucleotide sequence.

[0211] As used herein, ‘‘self-amplifying RNA,” or “saRNA,” is a linear, single-stranded RNA molecule that encodes the gene of interest. saRNA is a type of mRNA, but also includes non- structural proteins that encode a viral replicase. The viral replicase enables the RNA to selfreplicate once delivered into the cell.

[0212] As used herein, the term “specific” when used in reference to an initiating trinucleotide primer sequence and its ability to hybridize to a DNA template is a sequence that has at least 50% sequence identity with a portion of the DNA template when the initiating trinucleotide primer and DNA strand are aligned. Higher levels of sequence identity include at least 66%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, and optionally 100% sequence identity.

[0213] As used herein, the term “substantially free” refers to a state in which relatively little or no amount of an undesired substance (e.g., prematurely aborted RNA sequences, DNA, and / or double-stranded RNA) is present in a sample. “Substantially free of impurities” means impurities are present at a level less than approximately 5%, 4%, 3%, 2%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%. 0.3%, 0.2%, 0.1% or less (w / w) in a sample. For example, “substantially free of double-stranded RNA” means double-stranded RNA is present at a level less than approximately 5%, 4%, 3%, 2%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less (w / w) in a sample.

[0214] As used herein, “tangential flow filtration (TFF)” is a type of filtration wherein the material to be filtered is passed tangentially across a filter rather than through it. In TFF, undesired permeate passes through the filter, while the desired retentate passes along the filter and is collected downstream. In TFF, the desired material is typically contained in the retentate, which is the opposite of what is encountered when performing traditional membrane or dead-end filtration.

[0215] As used herein, the term “transcription” refers to enzymatically making or synthesizing RNA that is complementary to a noncoding strand of the DNA template, thereby producing a number of RNA copies of a DNA sequence. The RNA molecule synthesized in a transcription reaction is an “RNA transcript,” “primary transcript,” or “transcript.” Transcription reactions involving the compositions and methods provided herein employ initiating capped oligonucleotide primers described herein. Transcription of a DNA template may be exponential, nonlinear or linear. A DNA template may be a double-stranded linear DNA, a partially double-stranded linear DNA. circular double-stranded DNA. DNA plasmid. PCR amplified product, or a modified nucleic acid template that is compatible with RNA polymerase.

[0216] As used herein, the terms “universal base,” “degenerate base,” “universal base analog” and “degenerate base analog” include, for example, a nucleoside analog with an artificial base which is. in certain embodiments, recognizable by RNA polymerase as a substitute for one of the natural NTPs (e.g. ATP, UTP, CTP and GTP) or other specific NTP. Universal bases or degenerate bases are disclosed in Loakes, D., Nucleic Acids Res., 29:2437-2447 (2001); Crey- Desbiolles, C., et. al., Nucleic Acids Res 33:1532-1543 (2005); Kincaid, K., et. al., Nucleic Acids Res., 33:2620-2628 (2005); Preparata, FP, Oliver, JS, J. Comput. Biol. 753-765 (2004); and Hill, F„ et. al., Proc Natl Acad. Sci. USA, 95:4258-4263 (1998)).

[0217] As used herein, the term “unsubstituted” or “unmodified” in the context of the initiating capped oligonucleotide primer and NTPs refers to an initiating capped oligonucleotide primer and NTPs that have not been modified.

[0218] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0219] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0220] As used herein, the term “subject” or “patient” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0221] The term "immunization" or "vaccination" describes the process of treating a subject for therapeutic or prophylactic reasons.

[0222] The terms "effective amount", “therapeutically effective amount” or “effective dose” or related terms may be used interchangeably and refer to an amount of the therapeutic agentthat when administered to a subject, is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. Therapeutically effective amounts of the therapeutic agents provided herein, will vary' depending upon the relative activity of the therapeutic agent, and depending upon the subject and disease condition being treated, the weight and age and sex of the subject, the severity of the disease condition in the subject, the manner of administration, drugs used in combination or coincidental with the specific compound employed and the like, which can readily be determined by one of ordinary skill in the art. In one embodiment, a therapeutically effective amount will depend on certain aspects of the subject to be treated and the disorder to be treated and may be ascertained by one skilled in the art using known techniques. In addition, as is known in the art, adjustments for age as well as the body weight, general health, sex, diet, time of administration, drug interaction, and the severity of the disease may be necessary7. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0223] As used herein, ‘‘dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alphatocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, poly oxy ethylene9-10 nonyl phenol, sodium deoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g.. benzoic acid, phenol, gentamicin), antifoaming agents (e g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g.. glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0224] As used herein, ‘‘kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0225] The term “administering”, “administered” and grammatical variants refers to the physical introduction of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary' routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional. intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation. In one embodiment, the formulation is administered via a non-parenteral route, e.g., orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally. vaginally, rectally, sublingually or topically.Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0226] “Treating” is to be understood broadly and encompasses any beneficial effect,including, e.g., delaying, slowing, or arresting the worsening of symptoms associated with a viral disease or remedying such symptoms, at least in part. The term is intended to include the cure or elimination of the disease, disorder or condition. Those in need of treatment include those who already have the disease or disorder, as well as those who should prevent the disease or disorder. The patient to be treated is preferably a mammal, in particular a human being.

[0227] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0228] As used herein, the term “therapeutic agent” includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to. adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, antiinflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone grow th stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants;psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g, doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzy mes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0229] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, andN-oxides of a parent compound.

[0230] “Analog,” or “analogue” 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.

[0231] “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 disclosure 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 (suchas Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethy cellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary7agents 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 disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0232] The term a “sub-therapeutic amount” of an agent or therapy is an amount less than the effective amount for that agent or therapy as a single agent, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.

[0233] Combination therapy or “in combination with” refer to the use of more than one therapeutic agent to treat a particular disorder or condition. By “in combination with,” it is not intended to imply that the therapeutic agents must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. A therapeutic agent can be administered concurrently with, prior to (e.g., 5 minutes, 15 minutes. 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours. 1 week, 2 weeks, 3 weeks. 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after), one or more other additional agents. The therapeutic agents in a combination therapy can also be administered on an alternating dosing schedule, with or without a resting period (e.g, no therapeutic agent is administered on certain days of the schedule). The administration of a therapeutic agent “in combination with" another therapeutic agent includes, but is not limited to, sequential administration and concomitant administration of the two agents. In general, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent.

[0234] In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “ includes,” “including,” and the like. “Consisting essentially of or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0235] Described herein are novel tnnucleotide cap analogs and compositions, and methods of using the same. Also described herein is an RNA molecule comprising a 5:-cap, wherein the 5’- cap includes a trinucleotide cap analog as described herein. Methods of inducing a therapeutic effect in a subject are also described herein, the methods including a step of administering to the subject a trinucleotide cap analog or RNA molecule including the trinucleotide cap analog.Compounds

[0236] In an aspect, provided herein is a compound of formula (I):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene:X1and X2are each independently -O-, -CH2-, -CX2-. -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CCk, -CBn, -CF3, -CI3, -CHCh, -CHBn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R19is independently hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCI2, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCls, -CBrs, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H. -SO2NH2, -NHNH2, -ONH2. -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCb, -OCHB12. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHO(0)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH. -OCX3. -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCls, -CBrs, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2. -ONH2, -NHC(O)NHNH2. -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH. -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2.-OCHBn. -OCHI2, -OCHF2, -OCH2C1, -OCThBr, -OCHH, -OCH2F, -Ns, -SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; andX is -Cl, -Br, -I or -F; with the proviso that the compound of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0237] In embodiments, provided herein is a complex comprising a compound and a DNA template, wherein the compound is of formula (I):or an enantiomer, a mixture of enantiomers. a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1, B2. and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted ary lene, or substituted or unsubstitutedheteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A. -C(O)OR1A, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, 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; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR7A. -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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; each R19is independently hydrogen, halogen, -CCk, -CBrs, -CFs, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCk, -OCF3, -OCB , -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R7and R19together with the carbon atoms to which they are connected form a substitutedor unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCI2, -CHBn.-CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2. -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13. -OCF3. -OCBrs, -OCI3, -OCHCl2, -OCHBry -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkyd ene; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCI3, -CBrs. -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br. -CH2F. -CH2I, -CN, -OH, -NHy -COOH, -CONH2, -NOy -SH. -SO3H. -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCIs, -OCHCl2, -OCHBry -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; and X is -Cl, -Br, -I or -F;with the proviso that the compound of formula (1) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0238] In embodiments, provided herein is a complex comprising an initiating capped oligonucleotide primer and a DNA template, wherein the initiating capped oligonucleotide primer comprises a structure of formula (I):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A. -C(O)OR1A, -OR1Asubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A. -C(O)OR2A, -OR2A. 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; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, 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;R7is hydrogen, halogen, -CCh. -CBrs, -CF3, -CI3, -CHCh. -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; each R19is independently hydrogen, halogen. -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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;or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCI2, -CHBr2,-CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2. -SH, -SO3H. -SO4H. -SO2NH2, -NHNH2, -ONH2. -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCI3, -OCHCb, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R2A. R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X. -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SOiH, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo. halogen, -CCh, -CBn. -CF3. -Ch, -CHCh, -CHB . -CHF2. -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2,-OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -Ns, -SFs, substituted or unsubstituted allyd. substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; andX is -Cl. -Br, -I or -F; with the proviso that the compound of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more di stereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0239] In embodiments, a complex formation as described above is a prerequisite for the initiation of an in vitro transcription. In embodiments, a complex as described herein contains any one of the compounds (formulas or structures) or initiating capped oligonucleotide primers described below, including in embodiments, and a DNA template.

[0240] In embodiments. R1is independently hydrogen, substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., Cs-Cio aryl, C10 ary l, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0241] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1is independently substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1is independently substituted, it is substituted with at least one substituent group. In embodiments, when R1is independently substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1is independently substituted, it is substituted with at least one lower substituent group.

[0242] In embodiments, R1is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R1is independently hydrogen or substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci- Ce alkyl, or C1-C4 alkyl). In embodiments, R1is independently hydrogen. In embodiments, R1is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R1is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0243] In embodiments. R1is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

[0244] In embodiments, R1is independently hydrogen or methyl.

[0245] In embodiments. R1is independently hydrogen. In embodiments. R1is independently methyl. In embodiments, R1is independently ethyl. In embodiments. R1is independently propyl. In embodiments, R1is independently isopropyl. In embodiments, R1is independently butyl. In embodiments, R1is independently isobutyl. In embodiments, R1is independently t-butyl. In embodiments, R1is independently pentyl. In embodiments, R1is independently isopentyl. In embodiments, R1is independently hexyl.

[0246] In embodiments, R2is independently hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cscycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloal ky l. or 5 to 6 membered heterocycloalkyl). substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted and (e.g., Cs-Cio and. C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroa 1 (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0247] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2is independently 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 optionally7be different. In embodiments, when R2is independently substituted, it is substituted with at least one substituent group. In embodiments, when R2is independently substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2is independently substituted, it is substituted with at least one lower substituent group.

[0248] In embodiments, R2is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R2is independently hydrogen or substituted (e.g. with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci- Ce alkyl, or C1-C4 alkyl). In embodiments. R2is independently hydrogen. In embodiments, R2is independently7unsubstituted alkyl (e g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R2is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0249] In embodiments. R2is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopenty l, or hexyl.

[0250] In embodiments, R2is independently hydrogen or methyl.

[0251] In embodiments, R2is independently hy drogen. In embodiments, R2is independently methyl. In embodiments, R2is independently ethyl. In embodiments, R2is independently propyl. In embodiments, R2is independently isopropyl. In embodiments, R2is independently7butyl. In embodiments, R2is independently isobutyl. In embodiments, R2is independently t-butyl. In embodiments, R2is independently penty l. In embodiments, R2isindependently isopentyl. In embodiments, R2is independently hexyl.

[0252] In embodiments, R1is hydrogen and R2is hydrogen.

[0253] In embodiments, R3is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e g., C?-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g.. Ce-Cio aryl, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0254] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0255] In embodiments, R3is hydrogen or substituted or unsubstituted alkyl. In embodiments, R3is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R3is hydrogen. In embodiments, R3is unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R3is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Csalkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0256] In embodiments, R3is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopentyl, or hexyl.

[0257] In embodiments. R3is hydrogen. In embodiments, R-' is methyl. In embodiments, R is ethyl. In embodiments, R3is propyl. In embodiments, R3is isopropyl. In embodiments. R3is butyl. In embodiments, R3is isobutyl. In embodiments, R3is t-butyl. In embodiments, R3is pentyl. In embodiments, R3is isopentyd. In embodiments, R3is hexyl.

[0258] In embodiments. R7is independently hydrogen, halogen, -CCI3, -CBrs. -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2. -CN, -OR7A, -NR7AR7B, -NO2.-SH, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyd (e.g., Cs-Cs cy cloalkyl, Cs-Ce cy cloalkyd, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or low er substituent group) or unsubstituted heterocycloalkyd (e.g., 3 to 8 membered heterocycloalkyd. 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or low er substituent group) or unsubstituted aryl (e.g., Cs-Cio ary l, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroary 1, or 5 to 6 membered heteroaryl).

[0259] In embodiments, a substituted R7(e.g., substituted alkyd, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyd, substituted ary l, and / or substituted heteroary !) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wdierein if the substituted R7is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or low er substituent group may optionally be different. In embodiments, when R7is substituted, it is substituted with at least one substituent group. In embodiments, when R7is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7is substituted, it is substituted with at least one lower substituent group.

[0260] In embodiments. R7is independently hydrogen, halogen, or -OR7A. In embodiments. R7is independently hydrogen. In embodiments, R7is independently halogen. In embodiments, R7is independently -OR7A. In embodiments, R7is independently chloro. In embodiments, R7is independently bromo. In embodiments, R7is independently iodo. In embodiments, R7is independently fluoro.

[0261] In embodiments, R7is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R7is independently hydroxy. In embodiments, R7is independently methoxy. In embodiments, R7is independently ethoxy. In embodiments. R7is independently propoxy. In embodiments, R7is independently butoxy. In embodiments. R7is independently t- butoxy.

[0262] In embodiments, R7Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R7Ais hydrogen. In embodiments, R7Ais substituted alkyl. In embodiments, R7Ais an unsubstituted alkyl.

[0263] In embodiments. R7Ais hydrogen, substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-C6alkyl, or C1-C4 alkyl).

[0264] In embodiments, a substituted R7A(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 R7Ais 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 R7Ais substituted, it is substituted with at least one substituent group. In embodiments, when R7Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7Ais substituted, it is substituted with at least one lower substituent group.

[0265] In embodiments, R7Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R7Ais hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R7Ais hydrogen. In embodiments, R7Ais unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R7Ais substituted (e.g.. with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e g., Ci-Cs alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0266] In embodiments. R7Ais hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexyl. In embodiments, R7Ais hydrogen. In embodiments, R7Ais methyl. In embodiments, R7Ais ethyl. In embodiments, R7Ais propyl. In embodiments, R7Ais isopropyl. In embodiments, R7Ais butyl. In embodiments, R7Ais isobutyl. In embodiments, R7Ais t-butyl. In embodiments. R7Ais pentyl. In embodiments, R7Ais hexyl.

[0267] In embodiments, R11is independently hydrogen, halogen, -CCh, -CBr-. -CF3, -Cis, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCb, -CH B . -CHF2, -CHI2, -CN, -OR11A, -NR11AR11B, -NO2, -SH, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyd (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroai 4, or 5 to 6 membered heteroary l).

[0268] In embodiments, a substituted R11(e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R11is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R11is substituted, it is substituted with at least one substituent group. In embodiments, when R11is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11is substituted, it is substituted with at least one lower substituent group.

[0269] In embodiments, R11is independently hydrogen, halogen, or -OR11A. Inembodiments. R11is independently hydrogen. In embodiments, R11is independently halogen. In embodiments, R11is independently -OR11A. In embodiments, R11is independently chloro. In embodiments, R11is independently bromo. In embodiments, R11is independently iodo. In embodiments, Rnis independently fluoro.

[0270] In embodiments. R11is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R11is independently hydroxy. In embodiments, R11is independently methoxy. In embodiments, R11is independently ethoxy. In embodiments, R11is independently propoxy. In embodiments, R11is independently butoxy. In embodiments, R11is independently t- butoxy.

[0271] In embodiments, R11Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R11Ais hydrogen. In embodiments, R11Ais substituted alkyl. In embodiments, R11Ais an unsubstituted alkyd.

[0272] In embodiments. R11Ais hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cs alkyl, or C1-C4 alkyl).

[0273] In embodiments, a substituted R11A(e.g., substituted alky 1, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R11Ais 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 R11Ais substituted, it is substituted with at least one substituent group. In embodiments, when R11Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11Ais substituted, it is substituted with at least one lower substituent group.

[0274] In embodiments. R11Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R11Ais hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alky l, or C1-C4 alky l). In embodiments, R11Ais hydrogen. In embodiments, R11Ais unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R11Ais substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0275] In embodiments, R11Ais hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobuty l,t-butyl, pentyl, isopentyl, hexyl. In embodiments, R11Ais hydrogen. In embodiments, R11Ais methyl. In embodiments, R11Ais ethyl. In embodiments, R11Ais propyl. In embodiments, R11Ais isopropyl. In embodiments, R11Ais butyl. In embodiments, R11Ais isobutyl. In embodiments, R11Ais t-butyl. In embodiments, R11Ais pentyl. In embodiments, R11Ais hexyl.

[0276] In embodiments, each R19is hydrogen, halogen, -CCI3. -CBrs, -CFs, -CI3, -CH2CI. -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBrz -CHF2, -CHI2, -CN, -OR19A, -NR19AR19B, -CONH2, -COOH, -NHC(O)OH, -NO2, -SH, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g.. Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0277] In embodiments, a substituted R19(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 R19is 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 R19is substituted, it is substituted with at least one substituent group. In embodiments, when R19is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R19is substituted, it is substituted with at least one lower substituent group.

[0278] In embodiments, each R19is hydrogen.

[0279] In embodiments, R7and R19together with the carbon atoms to which they areconnected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene. In embodiments, R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene. In embodiments, R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.

[0280] In embodiments, R7and R19together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, R7and R19together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., Cs-Cs cycloalkylene, C3-C6 cycloalkylene, or Cs-Ce cycloalkylene).

[0281] In embodiments, a substituted heterocycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkylene is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, sizelimited substituent group, and / or lower substituent group may optionally be different. In embodiments, when heterocycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one substituent group. In embodiments, when heterocycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when heterocycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.

[0282] In embodiments, a substituted cycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted cycloalkylene 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 cycloalkylene formed by the joining of R7and R19together with the carbon atoms to whichthey are connected is substituted, it is substituted with at least one substituent group. In embodiments, when cycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when cycloalkylene formed by the joining of R7and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.

[0283] In embodiments, R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments. R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted 4 membered heterocycloalkylene.

[0284] In embodiments, R7and R19together with the carbon atoms to which they are connected form a substituted 4 membered heterocycloalkylene. In embodiments, R7and R19together with the carbon atoms to which they are connected form an unsubstituted 4 membered heterocycloalkylene.

[0285] In embodiments, R7and R19together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).

[0286] In embodiments. R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene. In embodiments, R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene. In embodiments, R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.

[0287] In embodiments, R11and R19together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, R11and R19together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., Cs-Cs cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).

[0288] In embodiments, a substituted heterocycloalkylene formed by the joining of R11and R19together with the carbon atoms to w hich they are connected is substituted with at least one substituent group, size-limited substituent group, or low er substituent group; wherein if thesubstituted heterocycloalkylene is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, sizelimited substituent group, and / or low er substituent group may optionally be different. In embodiments, when heterocycloalkylene formed by the joining of R11and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one substituent group. In embodiments, when heterocycloalkylene formed by the joining of R11and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when heterocycloalkylene formed by the joining of R11and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.

[0289] In embodiments, a substituted cycloalkylene formed by the joining of R11and R19together with the carbon atoms to which they are connected is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted cycloalkylene 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 cycloalkylene formed by thejoining of R11and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one substituent group. In embodiments, when cycloalkylene formed by thejoining of R11and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when cycloalkylene formed by the joining of R11and R19together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.

[0290] In embodiments, R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments. R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted 4 membered heterocycloalkylene.

[0291] In embodiments, R11and R19together w ith the carbon atoms to which they are connected form a substituted 4 membered heterocycloalkylene. In embodiments, R11and R19together with the carbon atoms to which they are connected form an unsubstituted 4 membered heterocycloalkylene.

[0292] In embodiments, R11and R19together with the carbon atoms to w hich they are connected form a locked nucleic acid (LNA).

[0293] In embodiments, each R1A, R2A. R3A, R7AR11AR11B. R19Aand R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHO(0)NHNH2, -NHO(0)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g.. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted aryl (e.g., Cs-Cio aryl, C10 aryl, or phenyl), or substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted heteroar l (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0294] In embodiments, each R1A, R2A. R3A, R7A. R11A. R11B. R19A. and R19Bis independently substituted with one or more substituent groups. In embodiments, each R1A, R2A, R3A, R7A, R11A, R11B, R19A, and R19Bis independently substituted with one or more size-limited substituent groups. In embodiments, each R1A, R2A, R3A, R7A, R11A, R11B, R19A, and R19Bis independently substituted with one or more lower substituent groups.

[0295] In embodiments. R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when a heterocycloalkyl formed by the joining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one low er substituent group. In embodiments, when a heteroaryl formed by the joining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heteroaryl formed by the joining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heteroaryl formed by the j oining of R7Aand R7Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.

[0296] In embodiments, R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a low er substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality7of 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 a heterocycloalkyl formed by the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formedI l lby the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heteroaryl formed by the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heteroaryl formed by the joining of R11Aand R11Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.

[0297] In embodiments, R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R19Aand R19Bsubstituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl 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 a heterocycloalkyl formed by the joining of R19Aand R19Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R197Aand R19Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R19Aand R19Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one low er substituent group. In embodiments, when a heteroary l formed by the joining of R19Aand R19Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heteroaryl formed by the joining of R19Aand R19Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heteroaryl formed by the joining of R19Aand R19Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.

[0298] In embodiments, B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base. In embodiments, B1, B2, and B3are each independently a naturalnucleoside base. In embodiments, B1. B2. and B3are each independently a modified nucleoside base. In embodiments, B1, B2, and B3are each independently an unnatural nucleoside base.

[0299] In embodiments, B1, B2, and B3are each independently adenine, guanine, cytosine, uracil, or thymine. In embodiments, B1is adenine. In embodiments, B1is guanine. In embodiments, B1is cytosine. In embodiments. B1is uracil. In embodiments, B1is thymine. In embodiments, B2is adenine. In embodiments, B2is guanine. In embodiments, B2is cytosine. In embodiments, B2is uracil. In embodiments, B2is thymine. In embodiments, B' is adenine. In embodiments, B3is guanine. In embodiments. B3is cytosine. In embodiments, B3is uracil. In embodiments, B3is thymine.

[0300] In embodiments, B1and B2are each independently 5-methylcytosine. pseudouracil. hypoxanthine, Nl-methylpseudouracil, N6-meihyiadenine. N6-ethyladenine, 7-deazaadenine, N - (alkyl)-cytosines, or 5-ethylcytosine, and the like (U.S. Patent No. 6,762,298).

[0301] In embodiments. B1includes, but is not limited to, pyrazolo[3,4-d]pyrimidines, 5- methylcytosine (5-me-C). 5-hydroxymethyl cytosine, xanthine, hypoxanthine. 2-aminoadenine. 6- methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 1 -methylpseudouracil, 5-uracil (pseudouracil). 4- thiouracil. 8-halo (e.g., 8-bromo). 8-amino. 8-thiol. 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5 -trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, deazaguanine, 7-deazaguanine, 3-deazaguanine, deazaadenine, 7-deazaadenine, 3- deazaadenine, pyrazolo[3,4-d]pyrimidine, imidazo[l,5-a]1.3.5 triazinones. 9-deazapurines, imidazo[4,5- d]pyrazines. thiazolo[4.5-d]pyrimidines, pyrazin-2-ones. 1 ,2,4-tnazine. pyridazine; and 1 ,3,5 tri azine.

[0302] In embodiments, B2includes, but is not limited to, pyrazolo[3,4-d]pyrimidines, 5- methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6- methyl and other alkyl derivatives of adenine and guanine. 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, N I -methylpseudouracil, 5-uracil (pseudouracil), 4- thiouracil, 8-halo (e g., 8-bromo), 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8- azaadenine, deazaguanine, 7-deazaguanine, 3-deazaguanine, deazaadenine, 7-deazaadenine, 3 -deazaadenine,pyrazolo[3,4-d]pyrimidine. irmdazo[l,5-a]1.3.5 triazinones. 9-deazapurines, imidazo[4,5- d]pyrazines, thiazolo[4,5-d]pyrimidines, pyrazin-2-ones, 1,2,4-triazine, pyridazine; and 1,3,5 triazine.

[0303] In embodiments. B3includes, but is not limited to, adenine, guanine, cytosine, uracil, pseudouracil, Nl-meihylpseudouracd, 5-methylcytosine, N6-methyladenine. hypoxanthine, 5-hydroxymethylcytosine, 5 -carboxylcytosine, N4-acetylcytosine, N4-methylcytosine, Nl- methyladenine, N2, N2-dimethylguanine and the like.

[0304] Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0305] In embodiments, Ring A is a substituted or unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted heterocycloalkylene. In embodiments, Ring A is an unsubstituted heterocycloalkylene.

[0306] In embodiments. Ring A is a substituted or unsubstituted heteroarylene. In embodiments, Ring A is a substituted heteroarylene. In embodiments, Ring A is an unsubstituted heteroarylene.

[0307] In embodiments. Ring A is a 3 to 10 membered substituted heterocycloalkylene. In embodiments. Ring A is a 3 membered substituted heterocycloalkylene. In embodiments, Ring A is a 4 membered substituted heterocycloalkylene. In embodiments, Ring A is a 5 membered substituted heterocycloalkylene. In embodiments, Ring A is a 6 membered substituted heterocycloalkylene. In embodiments, Ring A is a 7 membered substituted heterocycloalkylene. In embodiments. Ring A is a 8 membered substituted heterocycloalkylene. In embodiments, Ring A is a 9 membered substituted heterocycloalkylene. In embodiments. Ring A is a 10 membered substituted heterocycloalkylene.

[0308] In embodiments, Ring A is a 3 to 10 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 3 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 4 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 5 membered unsubstituted heterocycloalkylene. In embodiments. Ring A is a 6 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 7 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 8 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 9 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 10 membered unsubstituted heterocycloalkylene.

[0309] In embodiments, Ring A is a substituted or unsubstituted tetrahydrofuranylene. Inembodiments. Ring A is a substituted tetrahydrofuranylene. In embodiments, Ring A is an unsubstituted tetrahydrofuranylene. In embodiments, Ring A is a substituted or unsubstituted morpholinylene. In embodiments, Ring A is a substituted morpholinylene. In embodiments, Ring A is an unsubstituted morpholinylene.

[0310] In embodiments. Ringembodiments. Ringembodiments, Ring

[0311] In embodiments, X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-,-BH-, or -S-.

[0312] In embodiments. X1is -O-, -CH2-, or -CX2-. In embodiments, X1is -O-, -CH2-, or - CF2-. In embodiments, X1is -O-. In embodiments, X1is -CH2-. In embodiments, X1is -CX2-. In embodiments, XHs -CF2-. In embodiments, XHs -N(R101)-. In embodiments, X' is -NH-. In embodiments, X1is -BH-. In embodiments, X1is -S-.

[0313] In embodiments, X2is -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-. In embodiments, X2is -O-, -CH2-, -CF2-, -NH-, -BH-, or -S-. In embodiments, X2is -O-, -CH2-, or -NH-. In embodiments. X2is -CH2- or -NH-.

[0314] In embodiments, X2is -O-. In embodiments, X2is -CH2-. In embodiments, X2is -CX2-. In embodiments, X2is -CF2-. In embodiments, X2is -N(R101)-. In embodiments, X2is -NH-. In embodiments, X2is -BH-. In embodiments, X2is -S-.

[0315] In embodiments. Y1, Y2, Y3, Y4, and Y5, are each independently O, S, or Se. In embodiments, Y1, Y2, Y3, and Y4, are each independently O, S, or Se. In embodiments, Y1, Y2, Y3, Y4, and Y5, are each independently O or S. In embodiments, Y1, Y2, Y3, and Y4, are each independently O or S. In embodiments, Y1, Y2, Y3, Y4, and Y5, are each independently O. In embodiments. Y1. Y2. Y3. and Y4, are each independently O. In embodiments. Y1is O. In embodiments, Y1is S. In embodiments, Y1is Se. In embodiments, Y2is O. In embodiments, Y2is S. In embodiments, Y2is Se. In embodiments, Y3is O. In embodiments, Y3is S. In embodiments, Y3is Se. In embodiments, Y4is O. In embodiments, Y4is S. In embodiments, Y4is Se. In embodiments, Y5is O or S. In embodiments, Y5is O. In embodiments, Y5is S. In embodiments, Y5is Se.

[0316] In embodiments, R101is hydrogen, oxo, halogen, -CCk, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, NHC(O)NH2. -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3. -OCF3. -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd), substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalky 1, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted ary l (e.g., Ce-Cio ary 1, C10 ary l, or phenyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R101is substituted with one or more substituent groups. In embodiments, R101is substituted with one or more size-limited substituent groups. In embodiments, R101is substituted with one or more lower substituent groups.

[0317] In embodiments, X is -Cl, -Br, -I or -F. In embodiments, X is -Cl. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is F.

[0318] In embodiments, n is an integer from 0 to 3. In embodiments, n is 1 or 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0319] In embodiments, the compound of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0320] In embodiments, provided herein is a compound of formula (IA)or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: wherein:B' is a natural nucleoside base;R4is independently hydrogen, -C(O)R4A. -C(O)OR4A. -OR4A. substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R5is independently hydrogen, -C(O)R5A. -C(O)OR5A, -OR5A, 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; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR6A, -NR6AR6B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R14is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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; each R4A, R5A, R6A, R6B, R14A, and R14Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH. -SO3H, -SO4H, -SO2NH2, -NHNH2. -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2. -NHSO2H. -NHC=(O)H, -NHC(O)OH. -NHOH, -OCXs, -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andR14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.R1, R2, R3, R7, R11, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, n, and Ring A are each as defined herein, including in embodiments.

[0321] In embodiments. R4is independently hydrogen. -C(O)R4A. -C(O)OR4A, -OR4A. substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g.. 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl. 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted ary l (e.g., Ce-Cio ary l, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl)-

[0322] In embodiments, a substituted R4(e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l, and / or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4is independently substituted with a plurality' of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4is independently substituted, it is substituted with at least one substituent group. In embodiments, when R4is independently substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4is independently substituted, it is substituted with at least one lower substituent group-

[0323] In embodiments. R4is independently hydrogen. -C(O)R4A, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In embodiments, R4is independently hydrogen, -C(O)R4A, substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), orsubstituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl). In embodiments, R4is independently hydrogen. In embodiments, R4is independently -C(O)R4A. In embodiments, R4is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R4is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R4is independently unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl). In embodiments, R4is independently substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl).

[0324] In embodiments, R4is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R4is independently hydrogen or substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci- Ce alkyl, or C1-C4 alkyl). In embodiments, R4is independently hydrogen. In embodiments, R4is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R4is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0325] In embodiments, R4is independently hydrogen, -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In embodiments, R4is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl.

[0326] In embodiments. R4is independently hydrogen or methyl.

[0327] In embodiments, R4is independently hydrogen. In embodiments, R4is independently -C(O)NHCH2CHs. In embodiments, R4is independently methyl. In embodiments, R4is independently ethyl. In embodiments, R4is independently propyl. In embodiments, R4is independently isopropyl. In embodiments, R4is independently butyl. In embodiments, R4is independently isobutyl. In embodiments, R4is independently t-butyl. In embodiments, R4is independently penty l. In embodiments, R4is independently hexyl. In embodiments, R4is independently cyclopropyl. In embodiments, R4is independently cyclobutyl. In embodiments, R4is independently cyclopentyl. In embodiments, R4is independently cyclohexyl.

[0328] In embodiments, R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR3A, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, orlower substituent group) or unsubstituted alkyl (e.g.. Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e g., Ca-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0329] In embodiments, a substituted R5(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5is independently substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5is independently substituted, it is substituted with at least one substituent group. In embodiments, when R5is independently substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5is independently substituted, it is substituted with at least one lower substituent group.

[0330] In embodiments, R5is independently hydrogen, -C(O)R5A, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In embodiments, R5is independently hydrogen. -C(O)R5A, substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalky l (e g., Ca-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5is independently hydrogen. In embodiments, R5is independently -C(O)R5A. In embodiments, R5is independently unsubstituted alkyl (e.g., Ci-Cs alkyd, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R5is independently7substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Csalkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R5is independently unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5is independently substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0331] In embodiments, R3is independently hydrogen or substituted or unsubstituted alky l. In embodiments, R5is independently hydrogen or substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci- Ce alkyl, or C1-C4 alkyl). In embodiments, R5is independently hydrogen. In embodiments, R5is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R5is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0332] In embodiments. R5is independently hydrogen. -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl. pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In embodiments, R3is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl.

[0333] In embodiments. R5is independently hydrogen or methyl.

[0334] In embodiments. R5is independently hydrogen. In embodiments. R5is independently -C(O)NHCH2CH3. In embodiments, R5is independently methyl. In embodiments, R5is independently ethyl. In embodiments, R5is independently propyl. In embodiments, R5is independently isopropyl. In embodiments, R5is independently buty l. In embodiments, R5is independently isobutyl. In embodiments, R5is independently t-butyl. In embodiments, R5is independently pentyl. In embodiments. R5is independently hexyl. In embodiments. R5is independently cyclopropyl. In embodiments, R3is independently cyclobutyl. In embodiments, R5is independently cyclopentyl. In embodiments, R5is independently cyclohexyl.

[0335] In embodiments, (i) R4is independently hydrogen or methyl; or (ii) R5is independently hydrogen or methyl.

[0336] In embodiments, R6is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCb, -CH Bn. -CHF2, -CHI2, -CN, -OR6A, -NR6AR6B, -NO2, -SH, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyd (e.g., Cs-Cs cycloalkyl, Cs-Ce cycloalkyl, or Cs-Ce cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl. 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted ary 1 (e.g., Ce-Cio ary 1, Cio aryl, or pheny l), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroary 1, 5 to 9 membered heteroary 1, or 5 to 6 membered heteroaryl).

[0337] In embodiments, a substituted R6(e.g., substituted alkyl, substituted heteroalky 1, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary 1, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6is substituted, it is substituted with at least one substituent group. In embodiments, when R6is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6is substituted, it is substituted with at least one lower substituent group.

[0338] In embodiments. R6is hydrogen, halogen, or -NR6AR6B. In embodiments, R6is hydrogen. In embodiments. R6is halogen. In embodiments, R6is -NR6AR6B. In embodiments. R6is -Cl. In embodiments, R6is -Br. In embodiments, R6is -I. In embodiments, R6is -F. In embodiments, R6is -NHMe. In embodiments, R6is -NH2. In embodiments, R6is -NMe2.

[0339] In embodiments. R6is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R6is hydrogen. -NH2, or -NHMe. In embodiments, R6is hydrogen or -NHMe.

[0340] In embodiments, R6Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R6Ais hydrogen. In embodiments, R6Ais substituted alkyd. In embodiments, R6Ais an unsubstituted alkyl. In embodiments, R6Bis hydrogen or substituted or unsubstituted alky 1. In embodiments. R6Bis hydrogen. In embodiments, R6Bis substituted alkyl. In embodiments, R6Bis an unsubstituted alkyl.

[0341] In embodiments, R6Ais hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl(e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl). In embodiments. R6Bis hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0342] In embodiments, a substituted R6A(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 R6Ais 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 R6Ais substituted, it is substituted with at least one substituent group. In embodiments, when R6Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Ais substituted, it is substituted with at least one lower substituent group. In embodiments, a substituted R6B(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 R6Bis 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 R6Bis substituted, it is substituted with at least one substituent group. In embodiments, when R6Bis substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R6Bis substituted, it is substituted with at least one lower substituent group.

[0343] In embodiments, R6Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R6Ais hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R6Ais hydrogen. In embodiments, R6Ais unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R6Ais substituted (e g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R6Bis hydrogen or substituted or unsubstituted alkyl. In embodiments, R6Bis hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cg alkyd, or C1-C4 alkyl). In embodiments, R6Bis hydrogen. In embodiments, R6Bis unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l). In embodiments, R6Bis substituted (e.g., witha substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyd, Ci-Ce alkyl, or C1-C4 alkyl).

[0344] In embodiments, R6Ais hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexyl. In embodiments, R6Ais hydrogen. In embodiments, R6Ais methyl. In embodiments, R6Ais ethyl. In embodiments. R6Ais propyl. In embodiments, R6Ais isopropyl. In embodiments, R6Ais butyl. In embodiments, R6Ais isobuty 1. In embodiments, R6Ais t-butyl. In embodiments, R6Ais pentyl. In embodiments, R6Ais hexyl. In embodiments, R6Bis hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. In embodiments, R6Bis hydrogen. In embodiments, R6Bis methyl. In embodiments, R6Bis ethyl. In embodiments, R6Bis propyl. In embodiments, R6Bis isopropyl. In embodiments, R6Bis butyl. In embodiments, R6Bis isobutyl. In embodiments, R6Bis t-butyl. In embodiments, R6Bis pentyl. In embodiments, R6Bis hexyl.

[0345] In embodiments. R14is hydrogen, halogen, -CCh, -CBra. -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I. -CHCh, -CHBr2. -CHF2, -CHI2. -CN, -OR14A. -NR14AR14B. -NO2. -SH. substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g.. 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl. 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., Ce-Cio ary l. C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0346] In embodiments, a substituted R14(e.g., substituted alkyd, substituted heteroalky 1, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary 1. and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R14is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; eachsubstituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R14is substituted, it is substituted with at least one substituent group. In embodiments, when R14is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14is substituted, it is substituted with at least one lower substituent group.

[0347] In embodiments, R14is hydrogen, halogen, or -NR14AR14B. In embodiments, R14is hydrogen. In embodiments, R14is halogen. In embodiments, R14is -NR14AR14B. In embodiments, R14is -Cl. In embodiments, R14is -Br. In embodiments, R14is -I. In embodiments, R14is -F. In embodiments. R14is -NHMe. In embodiments. R14is -NFb. In embodiments, R14is -NMe2.

[0348] In embodiments, R14is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R14is hydrogen or -NH2. In embodiments, R14is hydrogen.

[0349] In embodiments. R14Ais hydrogen or substituted or unsubstituted alkyl. In embodiments. R14Ais hydrogen. In embodiments, R14Ais substituted alkyl. In embodiments, R14Ais an unsubstituted alkyl. In embodiments, R14Bis hydrogen or substituted or unsubstituted alkyl. In embodiments, R14Bis hydrogen. In embodiments, R14Bis substituted alkyl. In embodiments, R6Bis an unsubstituted alkyd.

[0350] In embodiments. R14Ais hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cs alkyl, or C1-C4 alkyl). In embodiments, R14Bis hydrogen, substituted (e g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky 1 (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0351] In embodiments, a substituted R14A(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 R14Ais 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 R14Ais substituted, it is substituted with at least one substituent group. In embodiments, when R14Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14Ais substituted, it is substituted with at least one lower substituent group. In embodiments, a substituted R14B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R14Bis 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 R14Bis substituted, it is substituted with at least one substituent group. In embodiments, when R14Bis substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R14Bis substituted, it is substituted with at least one lower substituent group.

[0352] In embodiments. R14Ais hydrogen or substituted or unsubstituted alkyl. In embodiments. R14Ais hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alky l, or C1-C4 alkyd). In embodiments, R14Ais hydrogen. In embodiments, R14Ais unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R14Ais substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R14Bis hydrogen or substituted or unsubstituted alky l. In embodiments, R14Bis hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R14Bis hydrogen. In embodiments, R14Bis unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Ce alkyl, or C1-C4 alkyl). In embodiments. R14Bis substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd).

[0353] In embodiments. R,4Ais hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. In embodiments, R14Ais hydrogen. In embodiments, R14Ais methyl. In embodiments, R14Ais ethyl. In embodiments, R14Ais propyl. In embodiments, R14Ais isopropyl. In embodiments, R14Ais butyl. In embodiments, R14Ais isobuty 1. In embodiments, R14Ais t-butyl. In embodiments, R14Ais pentyl. In embodiments, R146Ais hexyl. In embodiments, R14Bis hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. In embodiments, R14Bis hydrogen. In embodiments, R14Bis methyl. In embodiments, R14Bis ethyl. In embodiments, R14Bis propyl. In embodiments, R14Bis isopropyl. In embodiments, R14Bis butyl. In embodiments, R14Bis isobutyl. In embodiments, R14Bis t-butyl. In embodiments, R14Bis pentyd. In embodiments, R14Bis hexyl.

[0354] In embodiments, each R4A, R5A. R6A, R6B. R14A. and R14Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2,-NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH. -OCXs. -OCHX2, -OCH2X, substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd), substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd), substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyd, C3-C6 cycloalkyd, or C5-C6 cycloalkyd), substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted aryl (e.g., Ce-Cio aryl, C10 ary 1, or phenyl), or substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryd, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0355] In embodiments, each R4A, R5A, R6A, R6B, R14A, and R14Bis independently substituted with one or more substituent groups. In embodiments, each R4A, R5A, R6A, R6B, R14A, and R14Bis independently substituted with one or more size-limited substituent groups. In embodiments, each R4A, R5A, R6A, R6B, R14A, and R14Bis independently substituted with one or more lower substituent groups.

[0356] In embodiments, R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g. with a substituent group, a size-limited substituent group or a low er substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryd 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 a heterocycloalkyl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with atleast one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heteroaryl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heteroaryl formed by the joining of R6Aand R6Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.

[0357] In embodiments, R14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl 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 a heterocycloalkyl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heteroaryl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when a heteroaryl formed by the joining of R14Aand R14Bsubstituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.

[0358] In embodiments. X is -Cl, -Br, -I or -F. In embodiments. X is -Cl. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is -F.

[0359] In embodiments, provided herein is a compound of formula (IB)or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B, -COOH, -CONH2, -NO2. -SH,-OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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;R8is independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NCh, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2,-NHSO2H, -NHC(O)R8 A. -NHC(O)OH, -NHOH, -OCCI3. -OCF3. -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2L -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCI2, -CHBrc, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H. -NHC(O)R9A, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCls, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN. -OR10A, -NR10AR,0B. -COOH, -CONH2, -NO2, -SH. -SO3H, -SO4H, -SO2NH2. -NHNH2. -ONH2, -NHC(O)NHNH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn. -OCIs, -OCHCb, -OCHBr2, -OCHb, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -Ns, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC~(O)H. -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, andR1, R2, R3, R4, R5, R6, R7, R11, R14, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, B3and n, are each as defined herein, including in embodiments.

[0360] In embodiments, R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2. -CHBr2, -CHF2, -CHI2, -CN, -OR8A, -NR8AR8B, -CONH2. -COOH. -NHC(O)R8A, -NO2. -SH, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C -C6 cycloalkyl, or Cs-Ce cycloalkyl), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0361] In embodiments, a substituted R8(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; eachsubstituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R8is substituted, it is substituted with at least one substituent group. In embodiments, when R8is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8is substituted, it is substituted with at least one lower substituent group.

[0362] In embodiments, R8is independently hydrogen, halogen, -OR8A, or -NHC(O)R8A. In embodiments, R8is independently hydrogen. In embodiments, R8is independently halogen. In embodiments, R8is independently -OR8A. In embodiments, R8is independently -NHC(O)R8A. In embodiments. R8is independently chloro. In embodiments, R8is independently bromo. In embodiments, R8is independently iodo. In embodiments, R8is independently fluoro.

[0363] In embodiments, R8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

[0364] In embodiments. R8is independently hydrogen, hydroxy, or methoxy. In embodiments, R8is independently hydroxy or methoxy. In embodiments, R8is independently hydrogen or hydroxy.

[0365] In embodiments, R8is independently hydrogen. In embodiments, R8is independently hydroxy. In embodiments, R8is independently methoxy. In embodiments, R8is independently ethoxy. In embodiments, R8is independently propoxy. In embodiments, R8is independently butoxy. In embodiments, R8is independently t-butoxy.

[0366] In embodiments, R8Ais independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R8Ais hydrogen. In embodiments, R8Ais a substituted alkyl. In embodiments. R8Ais an unsubstituted alkyl.

[0367] In embodiments, R8Ais hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-C6alkyl, or Ci-C4alkyl).

[0368] In embodiments, a substituted R8A(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 R8Ais 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 R8Ais substituted, it is substituted with at least one substituent group. In embodiments, when R8Ais substituted, it is substituted with at least one size-limitedsubstituent group. In embodiments, when R8Ais substituted, it is substituted with at least one lower substituent group.

[0369] In embodiments, R8Ais hydrogen or substituted or unsubstituted alkyl. In embodiments. R8Ais hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cg alkyd, or C1-C4 alkyl). In embodiments, R8Ais hydrogen. In embodiments, R8Ais unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd). In embodiments, R8Ais substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0370] In embodiments, R8Ais hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyd, isopent d, or hexyl. In embodiments, R8Ais hydrogen. In embodiments, R8Ais methyl. In embodiments, R8Ais ethyl. In embodiments, R8Ais propyl. In embodiments, R8Ais isopropyl. In embodiments, R8Ais butyl. In embodiments, R8Ais isobutyl. In embodiments, R8Ais t-butyl. In embodiments, R8Ais pentyl. In embodiments, R8Ais isopentyl. In embodiments, R8Ais hexyl.

[0371] In embodiments, R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2. -CHBn, -CHF2, -CHI2, -CN, -OR8 A, -NR8 AR8 B, -CONH2, -COOH, -NHC(O)R8 A. -NO2, -SH, substituted (e.g.. substituted wi th at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyd. 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalky l), or substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyd, or 5 to 6 membered heterocycloalkyd), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted ary l (e.g., Ce-Cio ary l, C10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0372] In embodiments, a substituted R8(e.g., substituted alkyd, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R8is substituted, it is substituted with at least one substituent group. In embodiments, when R8is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8is substituted, it is substituted with at least one lower substituent group.

[0373] In embodiments, R8is independently hydrogen, halogen, -OR8 A, or -NHC(O)R8 A. In embodiments, R8is independently hydrogen. In embodiments, R8is independently halogen. In embodiments, R8is independently -OR8 A. In embodiments, R8is independently -NHC(O)R8 A. In embodiments. R8is independently chloro. In embodiments, R8is independently bromo. In embodiments, R8is independently iodo. In embodiments, R8is independently fluoro.

[0374] In embodiments, R8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

[0375] In embodiments. R8is independently hydrogen, hydroxy, or methoxy. In embodiments. R8is independently hydroxy or methoxy. In embodiments, R8is independently hydrogen or hydroxy.

[0376] In embodiments, R8is independently hydrogen. In embodiments, R8is independently hydroxy. In embodiments, R8is independently methoxy. In embodiments, R8is independently ethoxy. In embodiments, R8is independently propoxy. In embodiments, R8is independently butoxy. In embodiments, R8is independently t-butoxy.

[0377] In embodiments, R8 Ais independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R8 Ais hydrogen. In embodiments, R8 Ais a substituted alkyl. In embodiments. R8 Ais an unsubstituted alkyl.

[0378] In embodiments, R8 Ais hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-C6alkyl, or C1-C4 alkyl).

[0379] In embodiments, a substituted R8 A(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 Ais substituted with a plurality’ of groups selectedfrom 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 Ais substituted, it is substituted with at least one substituent group. In embodiments, when R8 Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8 Ais substituted, it is substituted with at least one lower substituent group.

[0380] In embodiments, R8 Ais hydrogen or substituted or unsubstituted alkyl. In embodiments, R8 Ais hydrogen or substituted (e.g.. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl). In embodiments, R8 Ais hydrogen. In embodiments, R8 Ais unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd). In embodiments, R8 Ais substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).

[0381] In embodiments, R8 Ais hydroge...

Claims

What is claimed is:

1. A compound of formula (I):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-. -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, 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;R7is hydrogen, halogen, -CCI3. -CBrs, -CF3, -CI3, -CHCh. -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; each R19is independently hydrogen, halogen. -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCI3, -CBn. -CF3. -CI3. -CHCh, -CHBn. -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;each R1A, R2A. R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(0)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroaiy 1; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCI3, -CB13. -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2. -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHC12,-OCHBr2. -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ar l, or substituted or unsubstituted heteroaiy 1; n is an integer from 0 to 3; andX is -Cl. -Br, -I or -F; with the proviso that the compound of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. The compound of claim I. which is a compound of formula (LA):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B3is a natural nucleoside base;R4is independently hydrogen, -C(O)R4A, -C(O)OR4A, -OR4A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR5A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCh, -CBn, -CF3, -Cis, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR6A, -NR6AR6B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2,-NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R14is hydrogen, halogen, -CCI3, -CB13. -CF3, -Ch, -CHCb, -CHB12.-CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; each R4A, R5A. R6A, R6B. R14B. and R14Bis independently hydrogen, -CX3, -CHX2, -CH2X. -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

3. The compound of claim 1 or 2, which is a compound of formula (IB):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof: wherein.R8is independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3. -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBT2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn,-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R9A. -NR9AR9B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and. or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

4. The compound of claim 1 or 2, which is a compound of formula (IC):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein.R8is independently hydrogen, halogen. -CCI3, -CBr?. -CF3, -CI3. -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -0CF3, -OCBn, -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCI3, -CBr. -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A-NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs. -OCR, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R9is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2,-OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted hctcrocycloalkylene:R10is hydrogen, halogen, -CCh, -CBr,. -CF3. -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. - CH2C1. -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH. -OCH2F. -N3, -SFs, 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; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

5. The compound of chum I . which is a compound of formula (ID):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R4is independently hydrogen, -C(O)R4A, -C(O)OR4A, -OR4A, 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;R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR5A, 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; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCl3-CBn, -CF3, -CI3, -CHCl2, -CHBn, -CHF2, -CHI2, -CH2CI. -CH2Br, -CH2F, -CH2I, -CN. -OR6A. -NR6AR6D, -COOH, -CONH2, -NO2. -SH, -SO3H.-SO4H, -SO2NH2. -NHNH2. -ONH2, -NHC(O)NHNH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCIs, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCFbBr, -OCH2I, -OCH2F, -Ns, -SFs, 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;R12is independently hydrogen, -C(O)R12A, -C(O)OR12A, -OR12A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R13is independently hydrogen, -C(O)R13A, -C(O)OR13A, -OR13A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; or R12and R13together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R14is hydrogen, halogen, -CCls, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN. -OR14A, -NR14AR,4B-COOH, -CONH2, -NO2, -SH. -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCR, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -Ns, -SFs, 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; each R4A, R5A. R6A, R6B. R12A. R13A. R14Aand R14Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky 1, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R14Aand R14Bsubstituents bonded to the same nitrogen atom may' optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroary 1.

6. The compound of claim 1 or 5, which is a compound of formula (IE):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein.R8is independently hydrogen, halogen, -CCh, -CBrs. -CF3, -Ch. -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CEEBr, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CI IBn. -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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;each R9is independently hydrogen, halogen, -CCI3, -CBn. -CF3. -CI3. -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBn, -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCls, -CBrs, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR1OAR1OB, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B. R8 A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X. -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

7. The compound of claim 1 or 5, which is a compound of formula (IF):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CH Bn. -CHF2, -CHl2. - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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;R8is independently hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8’A. -NHC(O)OH, -NHOH, -OCCl3. -OCF3. -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R9is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2,-OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted hctcrocycloalkylene:R10is hydrogen, halogen, -CCh, -CBr,. -CF3. -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. - CH2C1. -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH. -OCH2F. -N3, -SFs, 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; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

8. The compound of claim 1 , which is a compound of formula (IG):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof:R4is independently hydrogen, -C(O)R4A. -C(O)OR4A, -OR4A, 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;R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR5A, 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; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBn,-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R6A. -NR6AR6B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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;R15is hydrogen, halogen, -CCh, -CBrs. -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR15A, -NR15AR15B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, 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;R16is independently hydrogen, -C(O)R16A, -C(O)OR16A, -OR16A, 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; each R4A, R5A, R6A, R6B, R15A, R15B, and R16Ais independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R15Aand R15Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroary 1.

9. The compound of claim 1 or 8, which is a compound of formula (IH):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:R8is independently hydrogen, halogen, -CCI3, -CBrs. -CF3, -CI3. -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO.iH, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs. -OCI3, -OCHCk, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCIs, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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;each R9is independently hydrogen, halogen, -CCI3, -CBn. -CF3. -CI3. -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBn, -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCls, -CBrs, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR1OAR1OB, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B. R8 A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X. -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

10. The compound of claim 1 or 8, which is a compound of formula (IJ):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCh, -CBrs. -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch, -CHCh, -CHBrs. -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A-NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2,-OCHBn. -OCHb, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R9is independently hydrogen, halogen, -CCh, -CBn. -CF3. -CI3, -CHCI2, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs. -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CHCI2, -CHB12. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCh. -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3.-CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC~(O)H. -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined toform a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; Rlt)Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

11. The compound of claim 1, which is a compound of formula (IK):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hvdrate thereof; wherein;R6is hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn. -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN. -OR6A, -NR6AR6B, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2. -ONH2, -NHC(O)NHNH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCI3, -OCHCb, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCFbBr, -OCH2I, -OCH2F, -Ns, -SFs, 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;R14is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH, -CONH2, -NO2, -SH, -SO3H,-SO4H, -SO2NH2. -NHNH2. -ONH2, -NHC(O)NHNH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH, -NHOH, -OCCls, -OCFs, -OCBn, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -NS, -SFS, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R6A, R6B, R14A, and R14Bis independently hydrogen, -CXs, -CHX2, -CH2X,-C(0)0H, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2,-ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH. -OCX3, -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroary l.

12. The compound of claim 1 or 11, which is a compound of formula (IL):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCI3, -CBn, -CFs, -Ch, -CHCh, -CH Bn.-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R8A. -NR8AR8B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 a, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CHH, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkyd ene;R10is hydrogen, halogen, -CCh, -CBrs. -CF3. -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CHH, -CN, -OR10A, -NR10AR10B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH. -OCH2F, -N3, -SFs, 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;or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3.-CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC~(O)H. -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocvcloalkvl. substituted or unsubstituted arvl. or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

13. The compound of claim 1 or 11 , which is a compound of formula (IM):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptablesalt, solvate, or hydrate thereof: wherein:R8is independently hydrogen, halogen, -CCIs, -CBn, -CF3, -Ch. -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBn. -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A-NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBry -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkydene;R10is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

14. The compound of claim 1 , which is a compound of formula (IN):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R6is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, -CH2CI. -CH2Br, -CH2F, -CH2I, -CN. -OR6A. -NR6AR6B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCk, -OCF3, -OCBn, -OCIs, -OCHCk, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCFbBr, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R15is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR15A, -NR15AR15B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R16is independently hydrogen, -C(O)R16A, -C(O)OR16A, -OR16A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted ay?cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R6A, R6B, R15A, R15B, and R16Ais independently hydrogen, -CX3, -CHX2,-CH2X, -C(0)0H, -C(0)NH2, -CN. -OH, -NH2, -C00H. -CONH2, -NO2, -SH, -SO3H, -SO4H,-SO2NH2. -NHNH2, -ONH2. -NHC=(0)NHNH2. -NHC=(0)NH2, -NHSO2H, -NHC=(0)H. -NHC(0)0H, -NH0H, -OCX3, -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R15Aand R15Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

15. The compound of claim 1 or 14, which is a compound of formula (10):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof: wherein:R8is independently hydrogen, halogen, -CCI3, -CBn. -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -0R8A. -NR8AR8B, -C00H, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)R8A, -NHC(0)0H, -NH0H, -0CC13, -0CF3, -OCBr3, -OCI3, -OCHCI2,-OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCh, -CBr . -CF3, -CI3, -CHCh. -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A. -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2, -OCH Bn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; each R9is independently hydrogen, halogen, -CCh, -CBr?. -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR9A. -NR9AR9B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCH Bn. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F. -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkydene;R10is hydrogen, halogen, -CCh, -CBrs. -CF3. -Ch. -CHCh, -CHBn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;each R8A, R8B. R8 a. R8 b, R9A, R9B. RIOA. and R10Bis independently hydrogen. -CX3. -CHX2, -CH2X, -C(O)OH, -C(0)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyL substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hcteroarykR8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

16. The compound of claim 1 or 14, which is a compound of formula (IP):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:R8is independently hydrogen, halogen. -CCI3, -CBr?. -CF3, -Ch. -CHCh, -CH Bn.-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R8A. -NR8AR8B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 a, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CHH, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkyd ene;R10is hydrogen, halogen, -CCh, -CBrs. -CF3. -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CHH, -CN, -OR10A, -NR10AR10B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH. -OCH2F, -N3, -SFs, 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;or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHO(0)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroary l; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

17. The compound of claim I. which is a compound of formula (IQ):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R4is independently hydrogen, -C(O)R4A. -C(O)OR4A, -OR4A, 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;R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR5A, 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; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, -CH2CI. -CH2Br, -CH2F, -CH2I, -CN. -OR6A. -NR6AR6B, -COOH, -CONH2, -NO2. -SH, -SO3H. -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCls, -OCFs, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCFbBr, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is independently hydrogen, -C(O)R12A, -C(O)OR12A, -OR12A, 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;R13is independently hydrogen, -C(O)R13A, -C(O)OR13A, -OR13A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R12and R13together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R15is hydrogen, halogen, -CCh, -CBrs. -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR15A, -NR15AR15B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCh, -OCHCl2,-OCHBn. -OCHb, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R4A, R5A. R6A, R6B. R12A. R13A. R15A.and R15Dis independently hydrogen. -CX3, -CHX2, -CH2X,-C(O)OH, -C(0)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroaryl; and R15Aand R15Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

18. The compound of claim 1 or 17, which is a compound of formula (IR):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof: wherein:R8is independently hydrogen, halogen. -CCI3, -CBr?. -CF3, -CI3. -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBn, -OCI3, -OCHCk, -OCH Bn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCI3, -CBn. -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A-NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn. -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCk, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCh, -CBn. -CF3. -Ch. -CHCh, -CHBn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -Ns, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryk or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B. R8 A. R8’D, R9A, R9D, R1OA, and R10Dis independently hydrogen. -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H,-SChH. -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCXs. -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

19. The compound of claim 1 or 17, which is a compound of formula (IS):or an enantiomer. a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCI3, -CBn. -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBn, -OCI3. -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCh. -CBn. -CF3, -Ch, -CHCh. -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A. -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn. -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R9is independently hydrogen, halogen, -CCh, -CBn. -CF3, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2,-NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B. R8’A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCXs. -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

20. The compound of claim 1, which is a compound of formula (IT):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof: wherein:R15is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCb, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR15A, -NR15AR15B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCh, -OCHCk, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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;R16is independently hydrogen, -C(O)R16A, -C(O)OR16A, -OR16A, 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;R17is hydrogen, halogen, -CCh, -CBr?. -CF3, -Ch, -CHCb, -CHBr?. -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR17A, -NR17AR17B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCh. -OCHCl2,-OCHBrr. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH21. -OCH2F. -N3, -SF5, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R18is independently hydrogen, -C(O)R18A. -C(O)OR18A. -OR18A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalky 1, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15A, R15B, R16A, R17A, R17B, and R18A. is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H,-SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R15Aand R15Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R17Aand R17Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

21. The compound of claim 1 or 20, which is a compound of formula (IU):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen. -CCI3, -CBrs, -CF3, -Ch. -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -0CF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCI3, -CBr. -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCIs, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary l; each R9is independently hy drogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CHH, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCh, -CBn. -CF3. -Ch, -CHCh, -CHBr2. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CHH, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2,-OCHBn. -OCHb, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they’ are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

22. The compound of claim 1 or 20, which is a compound of formula (IV):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:R8is independently hydrogen, halogen, -CCI3, -CBn, -CFs, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -OCF3, -OCBrv. -OCI3, -OCHCl2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I, -OCH2F. -N3, -SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCI3, -CBr. -CF3, -CI3, -CHCh, -CHBn. -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A-NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs. -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary 1; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBr2,-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R9A. -NR9AR9B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted helerocycloalkylene;R10is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituentsbonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

23. The compound of claim 1, which is a compound of formula (IW):or an enantiomer. a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:R14is hydrogen, halogen, -CCh, -CBrs. -CF3. -CI3. -CHCh, -CHBri. -CHF2. -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2L -CN, -OR14A, -NR14AR14B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn. -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCFbBr, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl;R17is hydrogen, halogen, -CCh, -CBn. -CF3, -Ch, -CHCb, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR17A, -NR17AR17B, -COOH, -CONH2. -NO2. -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroarykR18is independently hydrogen, -C(O)R18A, -C(O)OR18A, -OR18A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R14A, R14B, R17A, R17B, and R18Ais independently hydrogen, -CX3, -CHX2,-CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHO(0)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH. -NHOH, -OCX3. -OCHX2. -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl;R14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R17Aand R17Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

24. The compound of claim 1 or 23, which is a compound of formula (IX):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomer: a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCk, -CBrv -CF3, -Ch, -CHCh, -CHBrc,-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R8A. -NR8AR8B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 a, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CHH, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkyd ene;R10is hydrogen, halogen, -CCh, -CBrs. -CF3. -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CHH, -CN, -OR10A, -NR10AR10B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH. -OCH2F, -N3, -SFs, 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;or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R1OA, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHO(0)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

25. The compound of claim 1 or 23, which is a compound of formula (IY):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptablesalt, solvate, or hydrate thereof: wherein:R8is independently hydrogen, halogen, -CCIs, -CBn, -CF3, -Ch. -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBn. -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A-NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR9A, -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBry -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkydene;R10is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, 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;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

26. The compound of claim 1, which is a compound of formula (IZ):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R4is independently hydrogen, -C(O)R4A, -C(O)OR4A, -OR4A, 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;R5is independently hydrogen, -C(O)R5A, -C(O)OR5A, -OR5A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R14is hydrogen, halogen, -CCls, -CBr3, -CF3, -CI3, -CHCk, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2. -ONH2, -NHC(O)NHNH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH, -NHOH, -OCCls, -OCFs, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -Ns, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky 1, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R17is hydrogen, halogen, -CCI3, -CBn. -CF3, -CI3. -CHCh, -CHBr2.-CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR17A, -NR17AR17B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBn. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R4A, R5A. R14A. R14B. R17A. and R17Bis independently hydrogen. -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,-NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH,-NHOH, -OCX3, -OCHX2, -OCH2X, 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; andR14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R17Aand R17Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

27. The compound of claim 1 or 26, which is a compound of formula (IAA):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen. -CCI3, -CBrs, -CF3, -Ch. -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH. -OCC13, -0CF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SF5, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is independently hydrogen, halogen, -CCI3, -CBr. -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCIs, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary l; each R9is independently hy drogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CHH, -CN, -OR9A. -NR9AR9B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCHH, -OCH2F, -N3, -SFs, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCh, -CBn. -CF3. -Ch, -CHCh, -CHBr2. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CHH, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2,-OCHBn. -OCHb, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they’ are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8’A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

28. The compound of claim 1 or 26, which is a compound of formula (IBB):(IBB); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt solvate, or hydrate thereof; wherein:R8is independently hydrogen, halogen, -CCh, -CBr?. -CF3, -Ch. -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn,-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -0R9A. -NR9AR9B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and. or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituentsbonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

29. A compound of formula (II):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixlure of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. wherein:B1and B2are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, and Y4are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, 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; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is independently hydrogen, halogen, -CCI3, -CBrs, -CFs, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A. -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCI2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; each R19is independently hydrogen, halogen, -CCls, -CBrs, -CFs, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBrs, -OCh. -OCHCk, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2. -SH. -SO3H. -SO4H. -SO2NH2, -NHNH2, -ONH2. -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalky 1, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo. halogen, -CCI3, -CBn. -CF3. -CI3, -CHCh, -CHBrr. -CHF2. -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2,-OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -Ns, -SF5, 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; n is an integer from 0 to 3; andX is -Cl, -Br, -I or -F; with the proviso that R11is not OH.

30. The compound of claim 29, which is a compound of formula (II A):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:R4is independently hydrogen, -C(O)R4A. -C(O)OR4A, -OR4A, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R5is independently hydrogen, -C(O)R5A. -C(O)OR5A, -OR5A, 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; or R4and R5together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R6is hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR6A, -NR6AR6B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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;R14is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR14A, -NR14AR14B, -COOH. -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F, -N3, -SFs, 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; each R4A, R5A, R6A, R6B, R14A, and R14Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH. -SO3H, -SO4H, -SO2NH2, -NHNH2. -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2. -NHSO2H. -NHC=(O)H, -NHC(O)OH. -NHOH, -OCXs, -OCHX2, -OCH2X, 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;R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andR14Aand R14Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

31. The compound of claim 29 or 30, which is a compound of formula (IIB):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:R8is independently hydrogen, halogen, -CCh, -CBrs, -CF3, -Ch. -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A, -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SFs, 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;R8is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CI IBn. -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8’AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A, -NHC(O)OH, -NHOH, -OCCk, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; each R9is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBn,-CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR9A. -NR9AR9B. -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3. -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituentsbonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

32. The compound of claim 29 or 30, which is a compound of formula (IIC):or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof: wherein:R8is independently hydrogen, halogen, -CCI3, -CBrs, -CFs, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8A. -NR8AR8B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8A, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrr, -OCh, -OCHCI2, -OCHBrs. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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;R8is independently hydrogen, halogen, -CCI3, -CBrs, -CFs, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR8 A, -NR8 AR8 B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R8 A. -NHC(O)OH, -NHOH, -OCCl3. -OCF3. -OCBn, -OCh, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R9is independently hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CHBrs.-NO2. -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R9A, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; or R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene;R10is hydrogen, halogen, -CCI3, -CBr?. -CF3. -Ch, -CHCI2, -CHBre.-CHF2, -CHI2, - CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OR10A, -NR10AR10B, -COOH, -CONH2, -NO2, -SH, -SChH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, 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; or R8and R10or R8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R8A, R8B, R8 A, R8’B, R9A, R9B, R10A, and R10Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8 Aand R8 Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalky l or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

33. The compound of any one of claims 1, 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, or 30, wherein Ring A is a substituted or unsubstituted heterocycloalkylene.

34. The compound of any one of claims 1-33, wherein R1is independently hydrogen or substituted or unsubstituted alkyl.

35. The compound of claim 34, wherein R1is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

36. The compound of claim 35, wherein R1is independently hydrogen or methyl.

37. The compound of claim 36, wherein R1is independently hydrogen.

38. The compound of any one of claims 1-37, wherein R2is independently hydrogen or substituted or unsubstituted alkyl.

39. The compound of claim 38, wherein R2is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

40. The compound of claim 39, wherein R2is independently hydrogen or methyl.

41. The compound of claim 40. wherein R2is independently hydrogen.

42. The compound of claim 19, wherein R1is hydrogen and R2is hydrogen.

43. The compound of any one of claims 1-42, wherein R3is independently hydrogen or substituted or unsubstituted alkyl.

44. The compound of claim 43, wherein R3is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

45. The compound of claim 44, wherein R3is methyl.

46. The compound of any one of claims 2-10, 17-19, 26-28, or 30-45, wherein R4is independently hydrogen, -C(O)R4A, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

47. The compound of claim 46, wherein R4is independently hydrogen, -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cy clopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

48. The compound of claim 47, wherein R4is independently hydrogen, -C(O)NHCH2CHs, methyl, isopropyl, or cyclopropyl.

49. The compound of claim 48, wherein R4is independently hydrogen or methyl.

50. The compound of any one of claims 2-10, 17-19, 26-28, or 30-49, wherein R5is independently hydrogen -C(O)R5A. substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

51. The compound of claim 50. wherein R5is hydrogen, -C(O)NHCH2CH3. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

52. The compound of claim 51, wherein R5is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl.

53. The compound of claim 52, wherein R5is independently hydrogen or methyl.

54. The compound of any one of claims 2-19 or 30-53, wherein R6is hydrogen, halogen, or -NR6AR6B.

55. The compound of claim 54, wherein R6is hydrogen, -F, -NHMe. -NH2, or -NMe2.

56. The compound of claim 55, wherein R6is hydrogen, -NH2, or -NHMe.

57. The compound of claim 56, wherein R6is a hydrogen.

58. The compound of any one of claims 2-10, 17-19, 26-28, or 30-57, wherein (i) R4is independently hydrogen or methyl; or (ii) R5is independently hydrogen or methyl.

59. The compound of any one of claims 1-58, wherein R7is independently hydrogen, halogen, or -OR7A.

60. The compound of claim 59, wherein R7is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

61. The compound of claim 60, wherein R7is independently methoxy.

62. The compound of any one of claims 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22, 24, 25, 27, 28, or 31-61, wherein R8is independently hydrogen, halogen, -OR8A, or -NHC(O)R8A.

63. The compound of claim 62, wherein R8Ais independently hydrogen or substituted or unsubstituted alkyl.

64. The compound of claim 62 or 63. wherein R8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

65. The compound of claim 64, wherein R8is independently hydrogen, hydroxy or methoxy.

66. The compound of claim 65, wherein R8is independently hydrogen or hydroxy.

67. The compound of claim 66. wherein R8is independently hydroxy.

68. The compound of any one of claims 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22, 24, 25,27, 28, or 31-67, wherein R8is independently hydrogen, halogen, -OR8 A, or -NHC(O)R8 A.

69. The compound of claim 68, wherein R8 Ais independently hydrogen or substituted or unsubstituted alkyl.

70. The compound of claim 68 or 69, wherein R8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

71. The compound of claim 70. wherein R8is independently hydrogen, hydroxy or methoxy.

72. The compound of claim 71, wherein R8is independently hydrogen or hydroxy.

73. The compound of claim 72, wherein R8is independently hydrogen.

74. The compound of any one of claims 3, 4, 6. 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22. 24, 25,27, 28, or 31-73, wherein R9is independently hydrogen, halogen, -OR9A, or -NHC(O)R9A.

75. The compound of claim 74, wherein R9Ais independently hydrogen or substituted or unsubstituted alky l.

76. The compound of claim 74 or 75, wherein R9is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

77. The compound of claim 76, wherein R9is independently methoxy.

78. The compound of any one of claims 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22, 24, 25,27, 28, or 31-61, wherein R8and R9or R8and R9together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.

79. The compound of any one of claims 3, 4, 6. 7, 9, 10, 12, 13, 15, 16, 18, 19, 21.

22.

24. 25.27, 28, or 31-78, wherein R10is hydrogen.

80. The compound of any one of claims 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22, 24, 25, 27, 28, 31-61, or 74-77 wherein R8and R10orR8and R10together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.

81. The compound of claim 80, w herein R8and R10or R8and R10together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).

82. The compound of any one of claims 1-81, wherein each R19is independently hydrogen.

83. The compound of any one of claims 1-58 or 62-81, wherein R7and R19together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).

84. The compound of any one of claims 1-83, wherein R11is independently hydrogen, halogen, or -OR11A.

85. The compound of claim 84, wherein R11is independently methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

86. The compound of claim 85, w herein R11is independently methoxy.

87. The compound of any one of claims 5-7, 17-19, or 33-86, wherein R12is independently hydrogen or substituted or unsubstituted alkyl.

88. The compound of claim 87, wherein R12is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

89. The compound of claim 88, w herein R12is independently hydrogen or methyl.

90. The compound of any one of claims 5-7, 17-19, or 33-89, wherein R13is independently hydrogen or substituted or unsubstituted alkyl.

91. The compound of claim 90, wherein R13is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl. pentyl, isopentyl, or hexyl.

92. The compound of claim 91. wherein R13is independently hydrogen or methyl.

93. The compound of any one of claims 2-7, 11-13, 23-28, or 30-92, wherein R14is hydrogen, halogen, or -NR14AR14B.

94. The compound of claim 93, wherein R14is hydrogen, -F, -NHMe, -NH2, or -NMe2.

95. The compound of claim 94, wherein R14is hydrogen or -NH2.

96. The compound of claim 95, wherein R14is -NH2.

97. The compound of any one of claims 8-10, 14-22, or 33-96, wherein R15is hydrogen, halogen, or -NR15AR15B.

98. The compound of claim 97, wherein R15is hydrogen. -F, -NHMe, -NH2, or -NMe2.

99. The compound of claim 98. wherein R15is hydrogen. -NHMe. or -NH2.

100. The compound of claim 99, wherein R15is hydrogen.

101. The compound of any one of claims 8-10, 14-16, 20-22, or 33-100, wherein R16is hydrogen or substituted or unsubstituted alkyl.

102. The compound of claim 101, wherein R16is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

103. The compound of claim 102, wherein R16is hydrogen.

104. The compound of any one of claims 20-28 or 33-103, wherein R17is hydrogen, halogen, or -NR17AR17B.

105. The compound of claim 104, wherein R17is hydrogen. -F, -NHMe, -NH2, or -NMe2.

106. The compound of claim 105, wherein R17is hydrogen, -NHMe, or -NH2.

107. The compound of claim 106, wherein R17is hydrogen.

108. The compound of any one of claims 20-25 or 33-107, wherein R18is hydrogen or substituted or unsubstituted alkyl.

109. The compound of claim 108, wherein R18is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

110. The compound of claim 109, wherein R18is hydrogen.

111. The compound of any one of claims 1-110, wherein X1is -O-, -CH2-, or -CX2-.

112. The compound of claim 1 11, wherein X1is -O-, -CH2-, or -CF2-.

113. The compound of claim 1 12, wherein X1is -O-.

114. The compound of any one of claims 1-113. wherein X2is -O-, -CH2-, -CX2-. -N(R101)-, or -BH-.

115. The compound of claim 114, wherein X2is -O-, -CH2-, -CF2-, -NH-, or -BH-.

116. The compound of claim 115, wherein X2is -O-, -CH2-, or -NH-.

117. The compound of claim 116, wherein X2is -O-.

118. The compound of claim 1 16, wherein X2is -CH2- or -NH-.

119. The compound of any one of claims 1-118, wherein Y1, Y2, Y3, and Y4are each independently O or S.

120. The compound of claim 119, wherein Y1. Y2. Y3. and Y4are O.

121. The compound of any one of claims 1-28 or 33-120, wherein Y5is O or S.

122. The compound of claim 121, wherein Y5is O.

123. The compound of any one of claims 1-122, wherein n is 1 or 2.

124. The compound of claim 123, wherein n is 1.

125. The compound of any one of claims 1-28 or 33-124, wherein B3is an adenine, guanine, cytosine or uracil.

126. The compound of claim 125, wherein B3is guanine.

127. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof'; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

128. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof129. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

130. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof131. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

132. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof133. A compound of the follow ing structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hvdrate thereof.

134. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof135. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

136. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

137. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

138. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof139. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

140. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof141. A compound of the following structure:or an enantiomer, a mixture of enantiomers. a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

142. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof143. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

144. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

145. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

146. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt; solvate, or hydrate thereof.

147. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof148. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

149. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof150. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof151. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof152. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

153. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

154. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof155. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

156. A compound of the following structure:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

157. The compound of any one of claims 1-156, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt.

158. The compound of claim 157, wherein the pharmaceutically acceptable salt is a sodium salt.

159. An RNA molecule comprising a 5 ’-cap, wherein the 5 ’-cap comprises a compound of any one of claims 1-158.

160. The RNA molecule of claim 159, wherein the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.

161. A pharmaceutical composition comprising a compound of any one of claims 1-158 and a pharmaceutically acceptable excipient.

162. A pharmaceutical composition comprising an RNA molecule of claim 159 and a pharmaceutically acceptable excipient.

163. An initiating capped oligonucleotide primer of the following formula:m7GpppA2’OMepG2’OMepG.

164. An initiating capped oligonucleotide primer of the follow ing formula:m7G3'OMepppm6A2’OMepA2’OMepG.

165. An initiating capped oligonucleotide primer of the following formula:m7G3'OMepppm6A2’OMepG2’OMepG.

166. An initiating capped oligonucleotide primer of the following formula:m7G 3'OMePPpA2’OMepA2’OMepG.

167. An initiating capped oligonucleotide primer of the follow ing formula:m7G 3' OMePPp"16A2’OMepm6A2’OMepG.

168. An initiating capped oligonucleotide primer of the following formula:m7G3’OMeppp(s)A2’OMepA2’OMepG.

169. An initiating capped oligonucleotide primer of the following formula:m7G3’0MePPpA2’0MepA2’0MepU.

170. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpA2’OMepG2‘OMepA.

171. An initiating capped oligonucleotide primer of the following formula:m7G3’0MePPpA2’0Mepm6A2’0MepG.

172. An initiating capped oligonucleotide primer of the following formula:m7G3'OMepppA2’OMepm6A2’OMepU.

173. An initiating capped oligonucleotide primer of the following formula:m7G3’OMepppA2’OMep(s)A2’OMepG174. An initiating capped oligonucleotide primer of the following formula:m7G3’0MePPpA2’0MepU2’0MepA.

175. An initiating capped oligonucleotide primer of the following formula:m7G3’0MepppA2’0MepU2’0MepC.

176. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpA2’OM6pU2‘OMepG.

177. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpC2’OMepG2’OMepG.

178. An initiating capped oligonucleotide primer of the following formula:m7G3’0MePPpG2’0MepG2’0MepC.

179. An initiating capped oligonucleotide primer of the following formula:m7G3'OMepppG2’OMepG2’OMepU.

180. An initiating capped oligonucleotide primer of the following formula:m7G3’OMepppG2’OMepU2’OMepG.

181. An initiating capped oligonucleotide primer of the following formula:m7G3’0MePPpm6A2’0MeP A2’OMeP U .

182. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpm6A2’OMepG2’OMepA.

183. An initiating capped oligonucleotide primer of the following formula:m7G3’OMepppm6A2-OMepm6A2-OMepU.

184. An initiating capped oligonucleotide primer of the following formula:m7G3’OMepppm6A2’OMepU2’OMepA.

185. An initiating capped oligonucleotide primer of the following formula:m7G3’0MePPpU2’0MepG2’0MepG.

186. An initiating capped oligonucleotide primer of the following formula:m7G3'OMepppU2’OMepU2’OMepG.

187. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpm6A2’OHpA2’OMepG.

188. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpN6'iPr6A2’OMepA2’C)MepG.

189. An initiating capped oligonucleotide primer of the following formula:m7G3’OMepppN6-Cyclopr0PylA2’OMepA2’OMepG.

190. An initiating capped oligonucleotide primer of the following formula:m7G3’OMePPpN6-CthylurCaA2’OMepA2’OMepG.

191. An initiating capped oligonucleotide primer of the following formula:m7GpppA2’OMepG2’OMe.

192. An initiating capped oligonucleotide primer of the following formula:m7G3'OMepppA2’OMepG2’OMe.

193. An RNA molecule comprising the initiating capped oligonucleotide primer, stereoisomer, or a pharmaceutically acceptable salt thereof, of any one of claims 158-192.

194. The RNA molecule of claim 193, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt.

195. The RNA molecule of claim 194. wherein the pharmaceutically acceptable salt is a sodium salt.

196. The RNA molecule of claim 195, wherein the RNA molecule is a messenger RNA (rnRNA) molecule or a self-amplifying RNA (saRNA) molecule.

197. A pharmaceutical composition comprising an RNA molecule comprising the initiating capped oligonucleotide primer, stereoisomer, or a pharmaceutically acceptable salt thereof, of any one of claims 158-192, and a pharmaceutically acceptable excipient.

198. A method of inducing a therapeutic effect in a subject, comprising administering to the subject an RNA molecule according to claim 159 or 193.

199. A method of administering to a subject a therapeutic dose unit of an rnRNA molecule comprising a 5’-cap, wherein the 5’-cap comprises a compound of any one of claims 1-158.

200. The RNA molecule of claim 159 or 193, for use in therapy.

201. An rnRNA molecule comprising a 5’-cap, wherein the 5'-cap comprises a compound of any one of claims 1-158, for use in therapy.

202. A method of synthesizing capped RNA transcripts, comprising:(iii) forming a reaction mixture comprising a compound of any one of claims 1-158, a DNA template, an RNA polymerase, and nucleotide triphosphates (NTPs); and(iv) incubating the reaction mixture under conditions that allow transcription of the DNA template to produce capped RNA transcripts.

203. A method for preparing a fully templated RNA molecule comprising: introducing an initiating capped oligonucleotide primer of formula (I)or an enantiomer, a mixture of enantiomers, a mixture of two or more di stereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein :B1, B2, and B3are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, Y4, and Y5are each independently O. S, or Se;R1is independently hydrogen, -C(O)R1A, -C(O)OR1A, -OR1A, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A, -C(O)OR2A, -OR2A, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R7is hydrogen, halogen, -CCh, -CBrs, -CFs, -Cis, -CHCh, -C'HBn. -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR7A, -NR7AR7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R19is independently hydrogen, halogen, -CCh, -CBr3, -CF3, -Ch, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCh, -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI. -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCh, -CBr3, -CF3, -Ch, -CHCI2, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR11A, -NR11AR11B, -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH. -OCCl3, -OCF3, -OCBr3, -OCh. -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R11and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkydene; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(0)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2,-OCHBr2. -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; andX is -Cl. -Br, -I or -F; with the proviso that the initiating capped oligonucleotide primer of formula (I) is not:or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof; into a mixture comprising a polynucleotide template, an RNA polymerase, and nucleotide triphosphates (NTPs). under conditions conducive to transcription by the RNA polymerase of thepolynucleotide template and incubating said mixture for a time sufficient to allow for transcription of said template.

204. A method for preparing a fully templated RNA molecule comprising: introducing an initiating capped oligonucleotide primer of formula (II)or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:B1and B2are each independently a natural, modified, or unnatural nucleoside base;Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;X1and X2are each independently -O-, -CH2-, -CX2-, -N(R101)-, -BH-, or -S-;Y1, Y2, Y3, and Y4are each independently O, S, or Se;R1is independently hydrogen, -C(O)R1A. -C(O)OR1A, -OR1A. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2is independently hydrogen, -C(O)R2A. -C(O)OR2A, -OR2A, 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; or R1and R2together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;R3is hydrogen, -C(O)R3A, -C(O)OR3A, -OR3A, 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;R7is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -Ch. -CHCh, -CHBr2, -CHF2, -CHI2. - CH2CI. -CH2Br, -CH2F, -CH2I, -CN, -OR7A. -NR7AR7B. -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -N3, -SFs, 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; each R19is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHC12, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OR19A, -NR19AR19B, -COOH, -CONH2. -NO2, -SH, -SO3H, -SO4H, -SO2NH2. -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -Ns, -SFs, 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; or R7and R19together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;R11is hydrogen, halogen, -CCh, -CBn. -CF3. -Ch, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br. -CH2F. -CH2I, -CN, -OR11A. -NR11AR11B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBrs, -OCh, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I. -OCH2F. -Ns, -SFs, 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; each R1A, R2A, R3A, R7A, R7B, R11A, R11B, R19A,and R19Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCXs, -OCHX2, -OCH2X, 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;R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R19Aand R19Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R101is hydrogen, oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBn, -OCI3, -OCHCl2,-OCHBr2. -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I. -OCH2F. -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; andX is -Cl. -Br, -I or -F; with the proviso that R11is not OH; into a mixture comprising a polynucleotide template, an RNA polymerase, and nucleotide triphosphates (NTPs), under conditions conducive to transcription by the RNA polymerase of the polynucleotide template and incubating said mixture for a time sufficient to allow for transcription of said template.

205. The method of claim 203 or 204, wherein Ring A, B1, B2, B3, R1, R2, R3, R7, R11, R19, X1, X2, Y1, Y2, Y3, Y4, Y5, and n are as defined in any one of claims 1-126.

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