Lipid compounds, lipid nanoparticles and pharmaceutical compositions

Abstract

The present application provides lipid compounds, e.g., compounds of Formula (I). Also provided are lipid nanoparticles and pharmaceutical compositions, each of which comprises a lipid compound, e.g., a compound of Formula (I).

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to International Application PCT / CN2022 / 129490 filed November 3, 2022, PCT / CN203 / 083169 filed March 22, 2023, and PCT / CN2023 / 102918 filed June 27, 2023, the disclosures of each of which are incorporated by reference herein in their entirety. 2. RELATED SEQUENCE LISTING

[0002] The sequence listing submitted herewith is filed in XML file format as an ASCII text file entitled “TFG00919PCT Sequence Listing.XML” created on November 2, 2023, having a size of 75,000 bytes. 3. TECHNICAL FIELD

[0003] Provided herein are lipid compounds, lipid nanoparticles, and pharmaceutical compositions thereof. 4. BACKGROUND

[0004] Lipid nanoparticles (LNPs) are promising delivery vehicles for a variety of therapeutic agents, including small molecule drugs, proteins, and nucleic acids. See, Akinc et al., Nat. Nanotechnol. 2019, 14, 1084-87; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. Two FDA-approved COVID-19 mRNA vaccines (mRNA-1273 and BNT162b) employ lipid nanoparticles for antigen mRNA delivery. See, Polack et al., N. Engl. J. Med. 2020, 383, 2603-15; Baden et al., N. Engl. J. Med. 2021, 384, 403-16. However, it remains challenging to effectively deliver highly charged nucleic acids as therapeutic agents. See, Weng et al., Biotechnol. Adv. 2020, 40, 107534; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. To achieve therapeutic effects, for example, highly charged nucleic acids must reach their intracellular targets. See, Torres-Canegas et al., Pharmaceutics 2021, 13, 428; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. Thus, there is a need for lipid compounds for effective delivery of therapeutic agents. 5. SUMMARY

[0005] The present application provides a compound of Formula (I): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopologues thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R 1 and R 2 each independently is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a-OS(O)NR 1b R 1c -OS(O)2NR 1b R 1c -NR 1b R 1c -NR 1a C(O)R 1d -NR 1a C(O)OR 1d -NR 1a C(O)NR 1b R 1c -NR 1a C(O)SR 1d -NR 1a C(NR 1d )NR 1b R 1c -NR 1a C(S)R 1d -NR 1a C(S)OR 1d -NR 1a C(S)NR 1b R 1c -NR 1a S(O)R 1d -NR 1a S(O)2R 1d -NR 1a S(O)NR 1b R 1c -NR 1a S(O)2NR 1b R 1c -S(O)R 1a -S(O)2R 1a -S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ; or R 1 and R 2 Together with the N atoms they are attached to, they form heteroaryl or heterocyclic groups; R 3 and R 4 Each independently is C 1-40 Alkyl, C 1-40 Heteroalkyl, C 2-40 alkenyl, C 2-40 Heterene, C 2-40 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-30 Aryl, heteroaryl, or heterocyclic groups; L1 and L 2 each independently C 1-6 alkylene or C 1-6 heteroalkylene; L 3 and L 4 each independently C 1-20 alkylene, C 1-20 heteroalkylene, C 2-20 alkenylene or C 2-20 alkynylene; A is -O- or -N(R 1a )-; E is -UC(O)N(R 1a )-, wherein U is -O- or -N(R 1b )-; X and Z are each independently a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; and each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15heteroaryl and heterocyclyl, each of which is optionally further substituted by one or more, in one embodiment, one, two, three, or four, substituents Q a substituted; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b )OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR aC(S)OR d C(S)NR a R b R c S(O)R a S(O)2R d S(O)NR a R d S(O)2NR a R b R c R a R b R c R a R a R a R a R b R c R b R c wherein each R a , R b , R c and R d is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c , together with the N atom to which they are attached, form a heterocyclyl group, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; wherein each Q a is independently selected from: (a) deuterium, cyano, halogen, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NRf R g 、-C(O)SR e 、-C(NR e )NR f R g 、-C(S)R e 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OP(O)(OR f )OR g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR eS(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , =NOR e , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g ; wherein each R e , R f , R g , and R h is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g , together with the N atom to which they are attached, form heterocyclyl.

[0006] The present application also provides a compound of Formula (I): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R 1 and R 2 are each independently: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R1d -NR 1a S(O)2R 1d -NR 1a S(O)NR 1b R 1c -NR 1a S(O)2NR 1b R 1c -S(O)R 1a -S(O)2R 1a -S(O)NR 1b R 1c -S(O)2NR 1b R 1c ; or R 1 and R 2 , together with the N atom to which they are attached, form a heteroaryl or heterocyclyl group; R 3 and R 4 are each independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene; L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene; A is -O- or -N(R 1a )-; E is -UC(O)N(R 1a )-, wherein U is -O- or -N(R 1b )-; X and Z are each independently a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; and each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(S)Ra, -C(S)ORa, -C(S)NRaRb, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRaRb, -OC(S)Ra, -OC(S)ORa, -OC(S)NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -NRaRb, -N=C(NRaRb)2, -N3, and -S(O)2NRaRb; a ; a ; b ; c ; a ; a ; b ; c ; a ; a ; b ; c ; a ; a ; a ; b ; c ; a ; a ; b ; c ; a ; a ; b ; c, -OP(O)(OR b )OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , =NOR a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c wherein each R a , R b , R c and R d is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 cycloalkyl, C 6-14 aryl, C 7-15 heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a substituted; or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a substituted; wherein each Q a is independently selected from the group consisting of: (a) deuterium, cyano, halogen, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f )OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g, -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , =NOR e , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g ; wherein each R e , R f , R g , and R h is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

[0007] Also provided herein are lipid nanoparticles comprising: a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0008] Further provided herein are lipid nanoparticles comprising: (i) a nucleic acid, and (ii) a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0009] Provided herein are pharmaceutical compositions comprising a lipid nanoparticle, the lipid nanoparticle comprising: (i) a nucleic acid, and (ii) a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, 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. 6. Exemplary Embodiments

[0010] a compound of Formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, 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: R 1 and R 2 each independently is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R1d -NR 1a S(O)NR 1b R 1c -NR 1a S(O)2NR 1b R 1c -S(O)R 1a -S(O)2R 1a -S(O)NR 1b R 1c -S(O)2NR 1b R 1c ; or R 1 and R 2 , together with the N atom to which they are attached, form a heteroaryl or heterocyclyl group; R 3 and R 4 are each independently C 1-40 alkyl, C 1-40 heteroalkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene; L 3 and L 4 are each independently C 1-20 alkylene, C 1-20 heteroalkylene, C 2-20 alkenylene, C 2-20 heteroalkenylene, or C 2-20 alkynylene; A is -O- or -N(R 1a )-; E is -UC(O)N(R 1a )-, wherein U is -O- or -N(R 1b )-; X and Z are each independently a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; and each R 1aR 1b R 1c and R 1d Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups; Each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenyl, ynyl, alkenylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic group is optionally substituted by one or more substituents Q in one embodiment, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituented by one or more, in one embodiment, one, two, three, or four substituents. a Substitution; and (c)-C(O)R a -C(O)OR a -C(O)NR b R c -C(O)SR a -C(NR) a )NR b R c -C(S)R a -C(S)OR a -C(S)NR b R c -OR a -OC(O)R a -OC(O)OR a -OC(O)NR b R c -OC(O)SR a -OC(NR) a )NR b R c -OC(S)R a -OC(S)OR a -OC(S)NR b R c -OP(O)(OR)b )OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , =NOR a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c wherein each R a , R b , R c , and R d is independently: (i) hydrogen or deuterium; (ii) a C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a substituted; or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a substituted; wherein each Q a is independently selected from the group consisting of: (a) deuterium, cyano, halogen, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f )OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NRf R g -NR f R g -NR e C(O)R h -NR e C(O)OR f -NR e C(O)NR f R g -NR e C(O)SR f -NR e C(NR h )NR f R g -NR e C(S)R h -NR e C(S)OR f -NR e C(S)NR f R g -NR e S(O)R h -NR e S(O)2R h -NR e S(O)NR f R g -NR e S(O)2NR f R g =NOR e -SR e -S(O)R e -S(O)2R e -S(O)NR f R g and -S(O)2NR f R g ; where each R e R f R g and R h Independently: (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii)R f and R g Together with the N atoms they are attached to, they form heterocyclic groups.

[0011] In the compounds of paragraph

[0010] , R 1 and R 2 are each independently: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)2NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ; or R 1 and R 2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl group; R 3 and R 4 are each independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene; L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10alkenylene or C 2-10 alkynylene; A is -O- or -N(R 1a )-; E is -UC(O)N(R 1a )-, wherein U is -O- or -N(R 1b )-; X and Z are each independently a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; and each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from the group consisting of: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c-C(S)R a -C(S)OR a -C(S)NR b R c -OR a -OC(O)R a -OC(O)OR a -OC(O)NR b R c -OC(O)SR a -OC(NR a )NR b R c -OC(S)R a -OC(S)OR a -OC(S)NR b R c -OP(O)(OR b )OR c -OS(O)R a -OS(O)2R a -OS(O)NR b R c -OS(O)2NR b R c -NR b R c -NR a C(O)R d -NR a C(O)OR d -NR a C(O)NR b R c -NR a C(O)SR d -NR a C(NR d )NR b R c -NR a C(S)R d -NR a C(S)OR d -NR a C(S)NR b R c -NR a S(O)R d -NR a S(O)2R d -NR a S(O)NR b R c -NR a S(O)2NRb R c , =NOR a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c , wherein each R a , R b , R c , and R d is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c , together with the N atom to which they are attached, form a heterocyclyl group, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; wherein each Q a is independently selected from: (a) deuterium, cyano, halogen, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e-OC(O)OR e -OC(O)NR f R g -OC(O)SR e -OC(NR e )NR f R g -OC(S)R e -OC(S)OR e -OC(S)NR f R g -OP(O)(OR f )OR g -OS(O)R e -OS(O)2R e -OS(O)NR f R g -OS(O)2NR f R g -NR f R g -NR e C(O)R h -NR e C(O)OR f -NR e C(O)NR f R g -NR e C(O)SR f -NR e C(NR h )NR f R g -NR e C(S)R h -NR e C(S)OR f -NR e C(S)NR f R g -NR e S(O)R h -NR e S(O)2R h -NR e S(O)NR f R g -NR e S(O)2NR f R g =NOR e -SR e -S(O)R e -S(O)2R e -S(O)NRf R g and -S(O)2NR f R g ; wherein each R e , R f , R g and R h is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl group.

[0012] In the compounds of paragraph

[0010] , L 1 is C 1-6 alkylene optionally substituted with one or more substituents Q.

[0013] In the compounds of paragraph

[0010] or

[0012] , L 1 is -(CR 2a R 2b ) a -, each R 2a and R 2b is independently: (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form a C 3-10 cycloalkyl group optionally substituted with one or more substituents Q; and a is an integer 1, 2, 3, 4, 5 or 6.

[0014] In the compounds of any one of paragraphs

[0010] to

[0013] , L 1 is -(CH2) a -.

[0015] In the compounds of any one of paragraphs

[0010] to

[0014] , L 2 is C 1-6 alkylene optionally substituted with one or more substituents Q.

[0016] In the compounds of any one of paragraphs

[0010] to

[0015] , L 2 is -(CR 2a R 2b ) b -, wherein each R2a and R 2b are independently: (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form a C 3-10 cycloalkyl optionally substituted with one or more substituents Q; and b is an integer 1, 2, 3, 4, 5 or 6.

[0017] In the compound of any one of paragraphs

[0010] to

[0016] , L 2 is -(CH2) b -.

[0018] In the compound of any one of paragraphs

[0010] to

[0017] , L 3 is C 1-10 alkylene optionally substituted with one or more substituents Q.

[0019] In the compound of any one of paragraphs

[0010] to

[0018] , L 3 is -(CR 2a R 2b ) c - wherein each R 2a and R 2b are independently: (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form a C 3-10 cycloalkyl optionally substituted with one or more substituents Q; and c is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0020] In the compound of any one of paragraphs

[0010] to

[0019] , L 3 is -(CH2) c -.

[0021] In the compound of any one of paragraphs

[0010] to

[0020] , L 4 is C 1-10 alkylene optionally substituted with one or more substituents Q.

[0022] In the compound of any one of paragraphs

[0010] to

[0021] , L 4 is -(CR 2a R 2b ) d - wherein each R 2a and R 2bindependently: (i) hydrogen; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form a C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and d is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0023] In the compound of any one of paragraphs

[0010] to

[0022] , L 4 is -(CH2) d -.

[0024] The compound of any one of paragraphs

[0010] to

[0023] has the structure of Formula (II): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein a and b are each independently an integer 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0025] In the compound of any one of paragraphs

[0010] to

[0024] , E is -OC(O)N(R 1a )-.

[0026] In the compound of any one of paragraphs

[0010] to

[0025] , E is -OC(O)N(H)-.

[0027] In the compound of any one of paragraphs

[0010] to

[0024] , E is -NR 1a C(O)N(R 1b )-.

[0028] In the compound of any one of paragraphs

[0010] to

[0024] and

[0027] , E is -NHC(O)N(H)-.

[0029] The compound of paragraph

[0024] has the structure of Formula (III): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U is -O- or -N(R1a )-.

[0030] In the compound of any one of paragraphs

[0010] to

[0029] , A is -O-.

[0031] In the compound of any one of paragraphs

[0010] to

[0029] , A is -N(R 1a )-.

[0032] In the compound of any one of paragraphs

[0010] to

[0029] and

[0031] , A is -N(H)-.

[0033] In the compound of any one of paragraphs

[0024] to

[0032] , U is -O-.

[0034] In the compound of any one of paragraphs

[0024] to

[0032] , U is -N(R 1a )-.

[0035] In the compound of any one of paragraphs

[0024] to

[0032] and

[0034] , U is -N(H)-.

[0036] The compound of paragraph

[0024] or

[0029] has the structure of Formula (IV): or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0037] The compound of paragraph

[0024] or

[0029] has the structure of Formula (V): or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0038] The compound of paragraph

[0024] or

[0029] has the structure of Formula (VI): or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0039] ​The compound of paragraph

[0024] or

[0029] has the structure of Formula (VII): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0040] In the compound of any one of paragraphs

[0013] to

[0039] , a is an integer of 2.

[0041] In the compound of any one of paragraphs

[0016] to

[0040] , b is an integer of 2.

[0042] In the compound of any one of paragraphs

[0010] to

[0041] , R 1 is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)2NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c or -S(O)2NR 1b R 1c .

[0043] In the compounds of any one of paragraphs

[0010] to

[0042] , R 1 is: (i) C 1-6 alkyl, C 2-6 alkenyl, C3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)NR 1b R 1c , -OR 1a , or -S(O)2R 1a .

[0044] In the compounds of any one of paragraphs

[0010] to

[0043] , R 1methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxy-ethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethyl-ureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxy-propyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxy-imino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4-dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, formamidinyl, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylformamidinyl, (Z)-N'-cyano-N,N-dimethylformamidinyl, (E)-N'-methoxy-N,N-dimethylformamidinyl, (Z)-N'-methoxy-N,N-dimethylformamidinyl, (E)-N'-methylsulfonyl-N,N-dimethylformamidinyl, (Z)-N'-methylsulfonyl-N,N-dimethylformamidinyl, hydroxy, methoxy, or methylsulfonyl.

[0045] In the compounds of any one of paragraphs

[0010] to

[0043] , R 1 is C 1-6 alkyl, optionally substituted with one or more substituents Q.

[0046] In the compounds of any one of paragraphs

[0010] to

[0043] and

[0045] , R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0047] In the compounds of any one of paragraphs

[0010] to

[0046] , R 2 is: (i) hydrogen; (ii) C1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more substituents Q; or (iii)-C(O)R 1a -C(O)OR 1a -C(O)NR 1b R 1c -C(O)SR 1a -C(NR) 1a )NR 1b R 1c -C(NCN)NR 1b R 1c -C(NOR) 1a )NR 1b R 1c -C(NS(O2)R 1a )NR 1b R 1c -C(S)R 1a -C(S)OR 1a -C(S)NR 1b R 1c -OR 1a -OC(O)R 1a -OC(O)OR 1a -OC(O)NR 1b R 1c -OC(O)SR 1a -OC(NR) 1a )NR 1b R 1c -OC(S)R 1a -OC(S)OR 1a -OC(S)NR 1b R 1c -OS(O)R 1a -OS(O)2R 1a -OS(O)NR 1b R 1c -OS(O)2NR 1b R 1c -NR 1b R 1c -NR 1a C(O)R 1d -NR 1a C(O)OR 1d -NR 1aC(O)SR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)2NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c or -S(O)2NR 1b R 1c .

[0048] In the compound of any one of paragraphs

[0010] to

[0047] , R 2 is: (i) hydrogen; (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a or -C(O)OR 1a .

[0049] In the compound of any one of paragraphs

[0010] to

[0048] , R 2 is hydrogen, methyl, ethyl, isopropyl, acetyl, or methoxycarbonyl.

[0050] In the compound of any one of paragraphs

[0010] to

[0049] , R 2 is hydrogen, methyl, ethyl, or isopropyl.

[0051] In the compound of any one of paragraphs

[0010] to

[0041] , R 1 and R 2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0052] In the compounds of any one of paragraphs

[0010] to

[0041] , and

[0051] , R 1 and R 2 together with the N atom to which they are attached form a heteroaryl group, which is optionally substituted with one or more substituents Q.

[0053] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] , and

[0052] , R 1 and R 2 together with the N atom to which they are attached form a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q.

[0054] In the compounds of any one of paragraphs

[0010] to

[0041] , and

[0051] to

[0053] , R 1 and R 2 together with the N atom to which they are attached form a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q.

[0055] In the compounds of any one of paragraphs

[0010] to

[0041] , and

[0051] to

[0054] , R 1 and R 2 together with the N atom to which they are attached form a 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2,4-dioxo-3,4-dihydro-pyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl group.

[0056] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] , and

[0052] , R 1 and R 2 together with the N atom to which they are attached form a bicyclic heteroaryl group, which is optionally substituted with one or more substituents Q.

[0057] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] ,

[0052] , and

[0056] , R 1 and R 2 together with the N atom to which they are attached form a 5,5-, 5,6-, or 6,6-fused heteroaryl group, each of which is optionally substituted with one or more substituents Q.

[0058] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] ,

[0052] ,

[0056] , and

[0057] , R 1 and R 2together with the N atom to which they are attached form a 6-aminopurin-9-yl group, or a 2-amino-6-oxo-1,9-dihydropurin-9-yl group.

[0059] In the compounds of any one of paragraphs

[0010] to

[0041] , and

[0051] , R 1 and R 2 together with the N atom to which they are attached form a heterocyclyl group, optionally substituted with one or more substituents Q.

[0060] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] , and

[0059] , R 1 and R 2 together with the N atom to which they are attached form a monocyclic heterocyclyl group, optionally substituted with one or more substituents Q.

[0061] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] ,

[0059] , and

[0056] , R 1 and R 2 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl group, each optionally substituted with one or more substituents Q.

[0062] In the compounds of any one of paragraphs

[0010] to

[0041] ,

[0051] , and

[0059] to

[0061] , R 1 and R 2 together with the N atom to which they are attached form a 2-methylaziridin-1-yl group, azetidin-1-yl group, pyrrolidin-1-yl group, 2-oxopyrrolidin-1-yl group, 2,5-dioxopyrrolidin-1-yl group, 2-oxo-oxazolidinon-3-yl group, 2,5-dioximidazolidin-1-yl group, piperidin-1-yl group, azepan-1-yl group, morpholin-4-yl group, 3,5-dioxomorpholin-4-yl group, piperazinyl-1-yl group, 4-methylpiperazinyl-1-yl group, 4-(4-methoxybenzyl)piperazinyl-1-yl group, 4-(2-hydroxyethyl)piperazinyl-1-yl group, or 1,3-dioxoisoindolinyl-2-yl group.

[0063] In the compounds of any one of paragraphs

[0010] to

[0062] , R 3 is C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 3-10 cycloalkyl, or C 6-14 aryl, each optionally substituted with one or more substituents Q.

[0064] In the compounds of any one of paragraphs

[0010] to

[0063] , R3 is C 1-25 alkyl, optionally substituted with one or more substituents Q.

[0065] In the compounds of any one of paragraphs

[0010] to

[0064] , R 3 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0066] In the compounds of any one of paragraphs

[0010] to

[0063] , R 3 is C 1-25 alkenyl, optionally substituted with one or more substituents Q.

[0067] In the compounds of any one of paragraphs

[0010] to

[0063] and

[0066] , R 3 is: (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3- octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

[0068] In the compounds of any one of paragraphs

[0010] to

[0063] , R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.

[0069] In the compounds of any one of paragraphs

[0010] to

[0063] and

[0068] , R 3 is 4-pentylcyclohexyl, or 4-cyclohexylcyclohexyl.

[0070] In the compounds of any one of paragraphs

[0010] to

[0063] and

[0068] , R 3 is C 6-14 aryl, each optionally substituted with one or more substituents Q.

[0071] In the compounds of any one of paragraphs

[0010] to

[0063] and

[0070] , R 3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0072] In the compounds of any one of paragraphs

[0010] to

[0071] , R 4 is C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 3-10 cycloalkyl, or C 6-14 aryl, each optionally substituted with one or more substituents Q.

[0073] In the compounds of any one of paragraphs

[0010] to

[0072] , R 4 is C 1-25 alkyl, optionally substituted with one or more substituents Q.

[0074] In the compounds of any one of paragraphs

[0010] to

[0073] , R 4 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0075] In the compounds of any one of paragraphs

[0010] to

[0072] , R 4 is C 1-25 alkenyl, optionally substituted with one or more substituents Q.

[0076] In the compounds of any one of paragraphs

[0010] to

[0072] and

[0075] , R4 (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3- octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

[0077] In the compounds of any one of paragraphs

[0010] to

[0072] , R 4 is C 3-10 cycloalkyl optionally substituted with one or more substituents Q.

[0078] In the compounds of any one of paragraphs

[0010] to

[0072] and

[0077] , R 4 is 4-pentylcyclohexyl, or 4-cyclohexylcyclohexyl.

[0079] In the compounds of any one of paragraphs

[0010] to

[0072] , R 4 is C 6-14 aryl optionally substituted with one or more substituents Q.

[0080] In the compounds of any one of paragraphs

[0010] to

[0072] and

[0079] , R 4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0081] The compound of paragraph

[0010] has the following structure: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of e and f is independently an integer 0, 1, 2, 3, 4, or 5; each of g and h is independently an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; each of i and j is independently an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; each of k and m is independently an integer 0, 1, 2, 3, 4, or 5; and each n is independently an integer 1, 2, 3, 4, 5, or 6.

[0082] In the compound of any one of paragraphs

[0019] to

[0081] , c is an integer 2, 3, 4, 5, or 6.

[0083] In the compound of any one of paragraphs

[0022] to

[0082] , b is an integer 2, 3, 4, 5, or 6.

[0084] In the compound of any one of paragraphs

[0010] to

[0083] , X is a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-.

[0085] In the compound of any one of paragraphs

[0010] to

[0084] , X is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-.

[0086] In the compound of any one of paragraphs

[0010] to

[0085] , Z is a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-.

[0087] In any of the compounds in paragraphs

[0010] to

[0086] , Z is a chemical bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -SS-.

[0088] The compound in paragraph

[0010] has the following structure: or an enantiomer, a mixture of enantiomers, a diastereomer, 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] The compound is 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyl- bis(hexanoate) 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyl-bis(hexanoate) 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)-carbamoyl)oxy)heptane-1,7-diyl-bis(hexanoate) 3; 4-(3-(2-((2-(dimethylamino)ethyl)amino)ethyl)-ureido)heptane-1,7-diyl-bis(hexanoate) 4; or 7-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)tridecane-1,13-diyl-bis(2-hexyldecanoate) 5; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0090] The compound has the following structure: or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0091] The lipid nanoparticle comprises the compound of any one of paragraphs

[0010] to

[0089] , or an enantiomer, a mixture of enantiomers, a diastereomer, 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] The pharmaceutical composition comprises a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a nucleic acid; (ii) the compound of any one of paragraphs

[0010] to

[0089] , or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol.

[0093] The pharmaceutical composition of paragraph

[0092] further comprises a conjugated lipid.

[0094] In the pharmaceutical composition of paragraph

[0093] , the conjugated lipid comprises a polyethylene glycol-conjugated lipid.

[0095] In the pharmaceutical composition of any one of paragraphs

[0092] to

[0094] , the nucleic acid is mRNA.

[0096] In the pharmaceutical composition of any one of paragraphs

[0092] to

[0095] , the nucleic acid is circular RNA.

[0097] In the pharmaceutical composition of any one of paragraphs

[0092] to

[0096] , the pharmaceutical composition preferentially distributes into a target organ of a subject in need thereof.

[0098] In the pharmaceutical composition of paragraph

[0097] , the target organ is an eye, heart, lung, kidney, liver, or spleen of the subject.

[0099] In the pharmaceutical composition of any one of paragraphs

[0092] to

[0096] , the pharmaceutical composition preferentially distributes into a liver cell.

[0100] In the pharmaceutical composition of paragraph

[0099] , the liver cell is a hepatocyte.

[0101] In the pharmaceutical composition of any one of paragraphs

[0092] to

[0096] , the pharmaceutical composition preferentially distributes into a spleen cell.

[0102] In the pharmaceutical composition of paragraph

[00101] , wherein the spleen cell is a splenocyte.

[0103] In the pharmaceutical composition of any one of paragraphs

[0092] to

[00102] , the nucleic acid encodes a biologically active protein or enzyme.

[0104] In the pharmaceutical composition of paragraph

[00103] , the biologically active protein or enzyme is produced or systematically secreted from a liver cell.

[0105] In the pharmaceutical composition of paragraph

[00103] , the biologically active protein or enzyme is produced or systemically secreted from cells of the lung, heart or eye, or central nervous system. 7. BRIEF DESCRIPTION OF DRAWINGS

[0106] Figure 1 In vitro evaluation of luciferase expression from circular RNAs encoding luciferase is shown. Human embryonic kidney 293T cells (HEK 293T cells), non-small cell lung cancer cell line (A549), human hepatocarcinoma cell line (HepG2), and mouse myoblast cell line (c2c12) were used in this experiment. The graph was processed by calculating the average of the respective expression of LNP. The relative values of expression of LNP were divided by the average of expression of reference 1 to obtain consistency of data.

[0107] Further reference is made to Figure 1 , Figure 2 In vitro expression of cationic liposomes of different tail types is shown.

[0108] Figure 3 In vivo expression of cationic liposomes of different tail types is shown. LNP-encapsulated circular RNAs encoding luciferase were administered systemically to 6-8 week old female BALB / cJ mice by tail vein injection or intramuscular injection. 2 mice / group were injected by tail vein injection at the predetermined dose. 1 mouse / group was injected by intramuscular injection in the left and right legs at the predetermined dose. At 6 hours and 24 hours, mice were placed on the imaging platform. Bioluminescence imaging was performed with IVIS Spectrum and data were obtained. The graph was processed by calculating the average of the respective expression of LNP.

[0109] Further reference is made to Figure 3 , Figure 4 Expression with five cationic liposomes is shown. 8. DETAILED DESCRIPTION 8.1 Definitions

[0110] To facilitate the understanding of the disclosure described herein, a number of terms are defined below.

[0111] Generally, the nomenclature used herein, and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology and pharmacology described herein follow those that are well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0112] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. The terms "subject" and "patient" are used interchangeably herein, for example, with reference to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0113] The terms "treat," "treating," and "treatment" are intended to include alleviating or abrogating a condition, disease, or disorder, or one or more symptoms associated with the condition, disease, or disorder; or alleviating or eradicating the cause of the condition, disease, or disorder itself.

[0114] The terms "prevent," "preventing," and "prevention" are intended to include a method of delaying and / or precluding the onset of a condition, disease, or disorder, and / or its attendant symptoms; barring a subject from acquiring a condition, disease, or disorder; or reducing the risk of a subject acquiring a condition, disease, or disorder.

[0115] The terms "alleviate" and "alleviating" refer to the mitigation or lessening of one or more symptoms (e.g., pain) of a condition, disease, or disorder. These terms can also refer to the reduction of adverse effects associated with an active ingredient. At times, the beneficial effects that a subject derives from a prophylactic or therapeutic drug do not cure the condition, disease, or disorder.

[0116] The terms "contacting" and "contact" refer to bringing a therapeutic agent and a biomolecule (e.g., a protein, an enzyme, RNA, or DNA), a cell, or a tissue together such that the contact produces a physiological and / or chemical effect. The contacting can be performed in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, a therapeutic agent is contacted with a cell in a cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biomolecule, a cell, or a tissue includes administering the therapeutic agent to a subject having the biomolecule, cell, or tissue to be contacted.

[0117] The terms "therapeutically effective amount" or "effective amount" refer to the amount of a compound that, upon administration, is sufficient to prevent the development of or to alleviate to some extent one or more symptoms associated with the condition, disease, or disorder being treated. The terms "therapeutically effective amount" or "effective amount" also refer to the amount of a compound that a researcher, veterinarian, doctor, or clinician is seeking to elicit a biological or medical response of a biomolecule (e.g., a protein, an enzyme, RNA, or DNA), a cell, a tissue, a system, an animal, or a human.

[0118] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, solvent, or encapsulation material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015.

[0119] The term “about” or “approximately” refers to an acceptable error for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the term “about” or “approximately” refers to within 1, 2, or 3 standard deviations. In some embodiments, the term “about” or “approximately” refers to within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0120] As used herein, the singular forms “a,” “an,” and “the” can refer to one or more than one. As used in the claims, the term “comprising” or “including,” when used, means “including one or more of.”

[0121] The term “alkyl” refers to a straight or branched chain saturated monovalent hydrocarbon radical, wherein the alkyl group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6Alkyl groups refer to straight-chain saturated monovalent hydrocarbon groups having 1-6 carbon atoms, or branched saturated monovalent hydrocarbon groups having 3-6 carbon atoms. In some embodiments, alkyl groups are those having 1-20 carbon atoms. 1-20 ), 1-15 (C) 1-15 ), 1-10 (C) 1-10 ) or 1-6 (C 1-6 A straight-chain saturated monovalent hydrocarbon group with 3-20 carbon atoms, or a hydrocarbon group with 3-20 carbon atoms. 3-20 ), 3-15 (C) 3-15 ), 3-10 (C) 3-10 ) or 3-6 (C 3-6 A branched, saturated monovalent hydrocarbon group of a carbon atom. As used in this article, a straight-chain C 1-6 and branch C 3-6 Alkyl groups are also known as "lower alkyl groups". Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl (including all isomers, such as n-propyl and isopropyl), butyl (including all isomers, such as n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including all isomers, such as n-pentyl, isopentyl, sec-pentyl, neopentyl and tert-pentyl), and hexyl (including all isomers, such as n-hexyl, isohexyl and sec-hexyl).

[0122] The terms “alkylene” and “alkidine” are used interchangeably herein, referring to a straight-chain or branched saturated divalent hydrocarbon group, wherein the alkidine is optionally substituted by one or more substituents Q as described herein. For example, C 1-6 Alkidine refers to a straight-chain saturated divalent hydrocarbon group with 1-6 carbon atoms, or a branched saturated divalent hydrocarbon group with 3-6 carbon atoms. In some embodiments, the alkidine group has 1-30 carbon atoms. 1-30 ), 1-20 (C) 1-20 ), 1-15 (C) 1-15 ), 1-10 (C) 1-1 0) or 1-6 (C) 1-6 A straight-chain saturated divalent hydrocarbon group of carbon atoms, or having 3-30 carbon atoms. 3-30 ), 3-20 (C) 3-20 ), 3-15 (C) 3-1 5) 3-10 (C) 3-10 ) or 3-6 (C 3-6 Branched saturated divalent hydrocarbon groups of carbon atoms. As used in this article, straight-chain C 1-6 and branch C 3-6Alkanediyl groups are also referred to as "lower alkanediyl groups." Examples of alkanediyl groups include, but are not limited to: methanediyl, ethanediyl (including all isomeric forms, such as ethane- 1, 1-diyl and ethane- 1, 2-diyl), propanediyl (including all isomeric forms, such as propane- 1, 1-diyl, propane- 1, 2-diyl, and propane- 1, 3-diyl), butanediyl (including all isomeric forms, such as, butane- 1, 1-diyl, butane- 1, 2-diyl, butane- 1, 3-diyl, and butane- 1, 4-diyl), pentanediyl (including all isomeric forms, such as, pentane- 1, 1-diyl, pentane- 1, 2-diyl, pentane 1, 3-diyl, and pentane- 1, 5-diyl), and hexanediyl (including all isomeric forms, such as, hexane- 1, 1-diyl, hexane- 1, 2-diyl, hexane- 1, 3-diyl, and hexane- 1, 6-diyl). Examples of substituted alkanediyl groups include, but are not limited to: -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, -C(O)(CH2) 10 - -C(O)CH2C(O)-, -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.

[0123] The term "heteroalkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon radical containing one or more heteroatoms in its backbone, each heteroatom being independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6heteroalkyl refers to a straight-chain saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms, or a branched-chain saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In some embodiments, the heteroalkyl is a straight-chain saturated monovalent hydrocarbon radical having 1-20 (C1-20heteroalkyl), 1-15 (C1-15heteroalkyl), 1-10 (C1-10heteroalkyl), or 1-6 (C1-6heteroalkyl) carbon atoms, or a branched-chain saturated monovalent hydrocarbon radical having 3-20 (C3-20heteroalkyl), 3-15 (C3-15heteroalkyl), 3-10 (C3-10heteroalkyl), or 3-6 (C3-6heteroalkyl) carbon atoms. As used herein, straight-chain C1-6heteroalkyl and straight-chain C1-10heteroalkyl refer to a straight-chain saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or 1 to 10 carbon atoms, respectively, and branched-chain C3-6heteroalkyl and branched-chain C3-10heteroalkyl refer to a branched-chain saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms or 3 to 10 carbon atoms, respectively. 1-20 1-15 1-10 1-6 3-20 3-15 3-10 3-6 1-6 3-6 ​​​​​​​​​Heteroalkyl also refers to "lower heteroalkyl." Examples of heteroalkyl groups include, but are not limited to: -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to: -CH2NHC(O)CH3and -NHC(O)CH2CH3.

[0124] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein to refer to a straight-chain or branched saturated divalent hydrocarbon radical containing one or more heteroatoms in its backbone, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a straight-chain saturated divalent hydrocarbon radical of 1-6 carbon atoms, or a branched saturated divalent hydrocarbon radical of 3-6 carbon atoms. In some embodiments, the heteroalkylene is a straight-chain saturated divalent hydrocarbon radical having 1-20 (C 1-20 ), 1-15 (C 1-15 ), 1-10 (C 1-10 ), or 1-6 (C 1-6 ) carbon atoms, or a branched saturated divalent hydrocarbon radical having 3-20 (C 3-20 ), 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 and branched C 3-6 Heteroalkylene also refers to "lower heteroalkylene." Examples of heteroalkylene groups include, but are not limited to: -CH2O-, -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -(CH2)5O-, -(CH2)6O-, -(CH2)7O-, -(CH2)8O-, -(CH2)9O-, -(CH2) 10O-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups include, but are not limited to: -C(O)CH2O-, -C(O)(CH2)2O-, -C(O)(CH2)3O-, -C(O)(CH2)4O-, -C(O)(CH2)5O-, -C(O)(CH2)6O-, -C(O)(CH2)7O-, -C(O)(CH2)8O-, -C(O)(CH2)9O-, -C(O)(CH2) 10 O-, -C(O)CH2OCH2CH2O-, -C(O)CH2O(CH2CH2O)2-, -C(O)CH2O(CH2CH2O)3-, -C(O)CH2O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5-, -CH2NHC(O)CH2-, or -CH2CH2C(O)NH-.

[0125] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical containing one or more, in one embodiment, one, two, three, or four, in another embodiment, one carbon-carbon double bond. The alkenyl group is optionally substituted with one or more substituents Q as described herein. As understood by one of ordinary skill in the art, the term "alkenyl" includes groups having "cis" or "trans" configurations or mixtures thereof, or, alternatively, includes groups having "Z" or "E" configurations or mixtures thereof. For example, a C2-C6alkenyl group can be either an E or Z configuration, such as: 2-6 Alkenyl refers to a straight-chain unsaturated monovalent hydrocarbon radical having 2-6 carbon atoms, or a branched-chain unsaturated monovalent hydrocarbon radical having 3-6 carbon atoms. In some embodiments, the alkenyl group is a straight-chain monovalent hydrocarbon radical having 2-20 (C 2-20 ), 2-15 (C 2-15 ), 2-10 (C 2-10 ), or 2-6 (C 2-6 ) carbon atoms, or a branched-chain monovalent hydrocarbon radical having 3-20 (C 3-20 ), 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to: ethenyl, propenyl (including all isomeric forms such as propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms such as buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0126] The terms "alkenylene" and "alkendiyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon group containing one or more, in one embodiment, one, two, three, or four, in another embodiment, one carbon-carbon double bond. The alkenediyl group is optionally substituted with one or more substituents Q as described herein. The term "alkendiyl" includes groups having "cis" or "trans" configuration or mixtures thereof, or groups having "Z" or "E" configuration or mixtures thereof, as known to one of ordinary skill in the art. For example, C 2-6 alkendiyl refers to a straight-chain unsaturated divalent hydrocarbon group of 2-6 carbon atoms, or a branched unsaturated divalent hydrocarbon group of 3-6 carbon atoms. In some embodiments, the alkenediyl is a straight-chain divalent hydrocarbon group of 2-30 (C 2-30 ), 2-20 (C 2-20 ), 2-15 (C 2-15 ), 2-10 (C 2-10 ), or 2-6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon group of 3-30 (C 3-30 ), 3-20 (C 3-20 ), 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-6 (C 3-6 ) carbon atoms. Examples of alkenediyl groups include, but are not limited to: ethenediyl (including all isomeric forms, e.g., ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, e.g., 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, e.g., 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, e.g., 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl).

[0127] The term "heteroalkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical that contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one carbon-carbon double bond, and that contains one or more heteroatoms in the hydrocarbon chain, each independently selected from the group consisting of: O, S, and N. The heteroalkenyl is optionally substituted with one or more substituents Q as described herein. The term "heteroalkenyl" includes radicals having a "cis" or "trans" configuration or mixtures thereof, or radicals having a "Z" or "E" configuration or mixtures thereof, as known to one of ordinary skill in the art. For example, C 2-6 heteroalkenyl refers to a straight-chain unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms, or a branched-chain unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, the heteroalkenyl is a straight-chain monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched-chain monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.

[0128] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical that contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one carbon-carbon triple bond. The alkynyl does not contain a carbon-carbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 alkynyl refers to a straight-chain unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms, or a branched-chain unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In some embodiments, the alkynyl is a straight-chain monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched-chain monovalent hydrocarbon radical of 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ), or 4 to 6 (C 4-6A branched monovalent hydrocarbon group with 1 carbon atom. Examples of alkynyl groups include, but are not limited to: ethynyl (-C≡CH), propynyl (including all isomers, e.g., 1-propynyl (-C≡CCH3) and propynyl (-CH2C≡CH)), butynyl (including all isomers, e.g., 1-butyn-1-yl and 2-butyn-1-yl), penynyl (including all isomers, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomers, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0129] The terms "acetylenol" and "acetylenol" are used interchangeably herein when referring to a straight-chain or branched divalent hydrocarbon group containing one or more, in one embodiment one, two, three, or four, and in another embodiment one carbon-carbon triple bond. The acetylenol does not contain a carbon-carbon double bond. The acetylenol may optionally be substituted by one or more substituents Q as described herein. For example, C 2-6 A diacetylene group refers to a straight-chain unsaturated divalent hydrocarbon group with 2-6 carbon atoms, or a branched unsaturated divalent hydrocarbon group with 4-6 carbon atoms. In some embodiments, the diacetylene group is 2-30 (C 2-30 ), 2-20 (C 2-20 ), 2-15 (C 2-15 ), 2-10 (C 2-10 ), or 2-6 (C 2-6 A straight-chain divalent hydrocarbon group with 4-30 carbon atoms, or 4-30 (C 4-30 ), 4-20 (C 4-20 ), 4-15 (C 4-15 ), 4-10 (C 4-10 ), or 4-6 (C 4-6 A branched divalent hydrocarbon group with 1 carbon atom. Examples of ynyl groups include, but are not limited to: acetylenic diyl, propynic diyl (including all isomers, e.g., 1-propyn-1,3-diyl and 1-propyn-3,3-diyl), butynic diyl (including all isomers, e.g., 1-butyn-1,3-diyl, 1-butyn-1,4-diyl and 2-butyn-1,1-diyl), pentylenic diyl (including all isomers, e.g., 1-pentyn-1,3-diyl, 1-pentyn-1,4-diyl and 2-pentyn-1,1-diyl), and hexynic diyl (including all isomers, e.g., 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl and 2-hexyn-1,1-diyl).

[0130] The term "cycloalkyl" is a cyclic monovalent hydrocarbon radical, optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is saturated or unsaturated but non-aromatic, and / or bridged or unbridged, and / or a fused bicyclic radical. In some embodiments, the cycloalkyl has 3-20 (C 3-20 ), 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-7 (C 3-7 ) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[l. l. l]pentyl, bicyclo[2. l. l]hexyl, bicyclo[2.2. l]heptyl, bicyclo[2.2.2]octyl, norbornyl, and adamantyl.

[0131] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon radical and / or a monovalent polycyclic aromatic hydrocarbon radical containing at least one aromatic carbon ring. In some embodiments, the aryl group has 6-20 (C 6-20 ), 6-15 (C 6-15 ), or 6-10 (C 6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbon ring in which one ring is aromatic, while the remaining rings can be saturated, partially unsaturated, or aromatic, such as indanyl, indenyl, indaninyl, or tetralinyl. In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In yet another embodiment, the aryl is polycyclic. In some embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0132] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In some embodiments, the aralkyl has 7-30 (C 7-30 ), 7-20 (C 7-20 ), or 7-16 (C 7-16Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0133] The term "heteroaryl" refers to a monovalent monocyclic aromatic radical or a monovalent polycyclic aromatic radical comprising at least one aromatic ring, wherein at least one aromatic ring comprises one or more heteroatoms in the ring, independently selected from O, S, and N. For heteroaryl groups containing heteroaromatic rings and non-aromatic heterocyclic rings, the heteroaryl group is not bound to the remainder of the molecule through its non-aromatic heterocyclic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic.Examples of bicyclic heteroaryl groups include, but are not limited to: benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl (including all isomeric forms, e.g., furopyrido[2,3-b]pyridinyl, furopyrido[2,3-c]pyridinyl, furopyrido[3,2-b]pyridinyl, furopyrido[3.2-c]pyridinyl, furopyrido[3,4-b]pyridinyl, and furopyrido[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,l-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolinizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthridinyl (including all isomeric forms, e.g., 1,5-naphthridinyl, 1,6-naphthridinyl, 1,7-naphthridinyl, and 1,8-naphthridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridinyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridinyl, pyrrolo[2-3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-d]pyrimidinyl and [l,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridinyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2-3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to: acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenoxazinyl, phenothiazinyl, phenoxathiinyl, and xanthenyl. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0134] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms each independently selected from: O, S, and N; and the remaining ring atoms are carbon atoms. For heterocyclyl groups containing both heteroaromatic and non-aromatic heterocyclic rings, the heterocyclyl group is not bound to the remainder of the molecule through a heteroaromatic ring. In some embodiments, the heterocyclyl group or heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, which can be fused or bridged, and wherein a nitrogen or sulfur atom can optionally be oxidized, a nitrogen atom can optionally be quaternized, and some rings can be partially or fully saturated or aromatic. The heterocyclyl group can be attached to the main structure at any heteroatom or carbon atom, which results in the production of a stable compound. Examples of heterocyclyl groups and heterocyclic groups include, but are not limited to: azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, dihydrobenzo[b]thiophenyl, dihydrobenzo[b]isothiazolyl, dihydrobenzo[b]isoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]-oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzo-furanyl, dihydrobenzo[c]thiophenyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, and isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, dihydrobenzothiopyranyl (thiochromanyl), tetrahydroquinolinyl, and 1,3,5-trithianyl. In some embodiments, the heterocyclyl group is optionally substituted with one or more substituents Q as described herein.

[0135] The term "halogen," "halogenated," or "halo" refers to fluoro, chloro, bromo, and / or iodo.

[0136] The term "optionally substituted" refers to a group or substituent, such as alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, which can be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each independently selected from, for example, (a) deuterium (-D), cyano (-CN), halogen, imino (=NH), nitro (-NO2), and oxo (=O); (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b )OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR bR c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , =NOR a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c , wherein each R a , R b , R c , and R d is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R ctogether with the N atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more, in one embodiment, one, two, three, or four substituents Q a As used herein, all groups that can be substituted are "optionally substituted."

[0137] In one embodiment, each Q a is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f )OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h-NR e C(O)OR f -NR e C(O)NR f R g -NR e C(O)SR f -NR e C(NR h )NR f R g -NR e C(S)R h -NR e C(S)OR f -NR e C(S)NR f R g -NR e S(O)R h -NR e S(O)2R h -NR e S(O)NR f R g -NR e S(O)2NR f R g =NO e -SR e -S(O)R e -S(O)2R e -S(O)NR f R g -S(O)2NR f R g ; wherein each R e , R f , R g and R h is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

[0138] In some embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules that have an enantiomeric excess of 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 about 99.8%. In some embodiments, an optically active 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 enantiomeric mixture. In some embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In some embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture.

[0139] In describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction in which the polarized light plane is rotated by an optically active compound. The (-) prefix indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation (+) and (-) is not related to the absolute configuration R and S of the compound.

[0140] The term "isotopically enriched" refers to a compound that contains a non-natural proportion of an isotope at one or more atoms that constitute such a compound. In some embodiments, an isotopically enriched compound contains a non-natural proportion of one or more isotopes, including but not limited to: hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-3131 P), phosphorus-32 32 P), phosphorus-33 33 P), sulfur-32 32 S), sulfur-33 33 S), sulfur-34 34 S), sulfur-35 35 S), sulfur-36 36 S), chlorine-35 35 Cl), chlorine-36 36 Cl), chlorine-37 37 Cl), bromine-79 79 Br), bromine-81 81 Br), iodine-123 123 I), iodine-125 125 I), iodine-127 127 I), iodine-129 129 I), and iodine-131 131 I). In some embodiments, the isotopically enriched compound is in a stable form, i.e., non-radioactive. In some embodiments, the isotopically enriched compound contains unnatural proportions of one or more isotopes, including but not limited to: hydrogen-1 1 H), deuterium 2 H), carbon-12 12 C), carbon-13 13 C), nitrogen-14 14 N), nitrogen-15 15 N), oxygen-16 16 O), oxygen-17 17 O), oxygen-18 18 O), fluorine-17 17 F), phosphorus-31 31 P), sulfur-32 32 S), sulfur-33 33 S), sulfur-34 34 S), sulfur-36 36 S), chlorine-35 35 Cl), chlorine-37 37 Cl), bromine-79 79 Br), bromine-81 81 Br), and iodine-127 127 I). In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotopically enriched compound contains unnatural proportions of one or more isotopes, including but not limited to: tritium 3 H), carbon-11 11 C), carbon-1414 C) Nitrogen-13 ( 13 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Fluorine-18 ( 18 F), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), sulfur-35 ( 35 S), Chlorine-36 ( 36 Cl), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and Iodine-131 131 I). It should be understood that, in the compounds of this application, to the judgment of a person skilled in the art, where feasible, any hydrogen may be, for example, 2 H, or any carbon, could be, for example, H, or any carbon. 13 C, or any nitrogen, can be, for example, 15 N, or any oxygen, could be 18 O.

[0141] The terms “nucleic acid,” “polynucleotide,” and “oligonucleotide” are used interchangeably herein and refer to polymers or oligomers of nucleotides of any length. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides (such as methylated, hydroxymethylated, or glycosylated), non-natural nucleotides, non-nucleotide building blocks exhibiting similar structure and / or function to natural nucleotides (i.e., “nucleotide analogs”), and / or any substrate that can be bound to the polymer by DNA or RNA polymerases. The composition of nucleic acids or polynucleotides can be heterogeneous or homogeneous, and they can be isolated from natural sources or produced artificially or synthetically. Furthermore, nucleic acids can be DNA or RNA, or mixtures thereof, and can exist permanently or intermittently in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states. Nucleic acid structures also include, for example, DNA / RNA helices, peptide nucleic acids (PNAs), morpholinonucleotides (see, for example, Braasch and Corey, Biochemistry 2002, 4, 4503-10; and US 5,034, 506), locked nucleic acids (LNAs; see, for example, Wahllestedt et al., Proc. Natl. Acad. Sci. USA 2000, 97, 5633-8), cyclohexenyl nucleic acids (see, for example, Wang, Am. Chem. Soc. 2000, 122, 8595-602) and / or ribonucleases.

[0142] As used herein, "substantially free of" with respect to a particular ingredient means that no amount of the particular ingredient has been intentionally formulated into the composition and / or is present only as a contaminant or in trace amounts. Thus, the total amount of a particular ingredient resulting from any inadvertent contamination of the composition is far less than 0.1%, preferably less than 0.05%, more preferably less than 0.01%. Most preferred are compositions wherein the amount of the particular ingredient is not detectable by standard analytical methods.

[0143] The terms "substantially pure" and "substantially homogeneous" refer to a material that is sufficiently homogeneous to appear to be a single enantiomer, a single diastereomer, a single geometric isomer, or a single tautomer, as determined by standard analytical methods, including, but not limited to: thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties of the material, such as enzymatic activity and biological activity. In some embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular, less common isotope, the molecule is an impurity with respect to the isotopically enriched compound if it contains another isotope at that particular position. Thus, for a deuterated compound in which a particular position is designated as deuterium, a compound containing protium at the same position is an impurity.

[0144] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound of the application, and one or more molecules of a solvent. Solvates can exist as either stoichiometric or non-stoichiometric compositions. Suitable solvents include, but are not limited to: water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to: hemi-hydrate, mono-hydrate, di-hydrate, tri-hydrate, tetra-hydrate, and penta-hydrate.

[0145] For divalent groups described herein, the orientation of presentation of the divalent group does not imply any orientation. For example, the formula -C(O)O- represents both -C(O)O- and -OC(O)-, unless a particular orientation is specified.

[0146] The phrase "enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof," has the same meaning as the phrase "(i) an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant of a compound referred to herein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of a compound referred to herein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate of an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant of a compound referred to herein." 8.2 Lipid compounds

[0147] In one embodiment, the present application provides a compound of Formula (I): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R 1 and R 2 each independently is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R1a -C(S)OR 1a -C(S)NR 1b R 1c -OR 1a -OC(O)R 1a -OC(O)OR 1a -OC(O)NR 1b R 1c -OC(O)SR 1a -OC(NR 1a )NR 1b R 1c -OC(S)R 1a -OC(S)OR 1a -OC(S)NR 1b R 1c -OS(O)R 1a -OS(O)2R 1a -OS(O)NR 1b R 1c -OS(O)2NR 1b R 1c -NR 1b R 1c -NR 1a C(O)R 1d -NR 1a C(O)OR 1d -NR 1a C(O)NR 1b R 1c -NR 1a C(O)SR 1d -NR 1a C(NR 1d )NR 1b R 1c -NR 1a C(S)R 1d -NR 1a C(S)OR 1d -NR 1a C(S)NR 1b R 1c -NR 1a S(O)R 1d -NR 1a S(O)2R 1d -NR 1a S(O)NR 1b R 1c -NR 1a S(O)2NR 1b R 1c -S(O)R 1a-S(O)2R 1a -S(O)NR 1b R 1c -S(O)2NR 1b R 1c ; or R 1 and R 2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl group; R 3 and R 4 are each independently C 1-40 alkyl, C 1-40 heteroalkyl, C 2-40 alkenyl, C 2-40 heteroalkenyl, C 2-40 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene; L 3 and L 4 are each independently C 1-20 alkylene, C 1-20 heteroalkylene, C 2-20 alkenylene, or C 2-20 alkynylene; A is -O- or -N(R 1a )-; E is -UC(O)N(R 1a )-, wherein U is -O- or -N(R 1b )-; X and Z are each independently a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; and each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b )OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c-NR b R c -NR a C(O)R d -NR a C(O)OR d -NR a C(O)NR b R c -NR a C(O)SR d -NR a C(NR d )NR b R c -NR a C(S)R d -NR a C(S)OR d -NR a C(S)NR b R c -NR a S(O)R d -NR a S(O)2R d -NR a S(O)NR b R c -NR a S(O)2NR b R c =NOR a -SR a -S(O)R a -S(O)2R a -S(O)NR b R c and -S(O)2NR b R c , where each R a ,R b ,R c and R d Independently: (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituented by one or more, in one embodiment, one, two, three, or four substituents. a Replace; or (iii)R b and R ctogether with the N atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more, in one embodiment, one, two, three, or four substituents Q a substituted; wherein each Q a is independently selected from: (a) deuterium, cyano, halogen, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f )OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NRe C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , =NOR e , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g ; wherein each R e , R f , R g , and R h is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

[0148] In another embodiment, the present application provides a compound of Formula (I): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R 1 and R 2 each independently is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R1c -NR 1b R 1c -NR 1a C(O)R 1d -NR 1a C(O)OR 1d -NR 1a C(O)NR 1b R 1c -NR 1a C(O)SR 1d -NR 1a C(NR 1d )NR 1b R 1c -NR 1a C(S)R 1d -NR 1a C(S)OR 1d -NR 1a C(S)NR 1b R 1c -NR 1a S(O)R 1d -NR 1a S(O)2R 1d -NR 1a S(O)NR 1b R 1c -NR 1a S(O)2NR 1b R 1c -S(O)R 1a -S(O)2R 1a -S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ; or R 1 and R 2 , together with the N atom to which they are attached, form a heteroaryl or heterocyclyl group; R 3 and R 4 are each independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene; L3 and L 4 each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene; A is -O- or -N(R 1a )-; E is -UC(O)N(R 1a )-, wherein U is -O- or -N(R 1b )-; X and Z are each independently a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; and each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from the group consisting of: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b Rc 、-C(O)SR a 、-C(NR a )NR b R c 、-C(S)R a 、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR b )OR c 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d, -NR a S(O)NR b R c , -NR a S(O)2NR b R c , =NOR a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c , wherein each R a , R b , R c , and R d is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c , together with the N atom to which they are attached, form a heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; wherein each Q a is independently selected from: (a) deuterium, cyano, halogen, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e, -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f )OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , =NOR e, -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g ; wherein each R e , R f , R g , and R h is independently: (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

[0149] In some embodiments, in formula (I), L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q. In some embodiments, in formula (I), L 1 is -(CR 2a R 2b ) a -, wherein each R 2a and R 2b is independently: (i) hydrogen; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5, or 6. In some embodiments, in formula (I), L 1 is -(CH2) a -, and a is an integer of 1, 2, 3, 4, 5, or 6. In some embodiments, in formula (I), L 1 is -(CH2) a -, and a is an integer of 2, 3, or 4. In some embodiments, in formula (I), L 1 is -(CH2)2-.

[0150] In some embodiments, in formula (I), L 2 is C 1-6alkylene, optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L 2 is -(CR 2a R 2b ) b -, wherein b is an integer 1, 2, 3, 4, 5, or 6; and each R 2a and R 2b are as defined herein. In some embodiments, in Formula (I), L 2 is -(CH2) b -, and b is an integer 1, 2, 3, 4, 5, or 6. In some embodiments, in Formula (I), L 2 is -(CH2) b -, and b is an integer 2, 3, or 4. In some embodiments, in Formula (I), L 2 is -(CH2)2-.

[0151] In some embodiments, in Formula (I), L 3 is C 1-10 alkylene, optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L 3 is -(CR 2a R 2b ) c -, wherein c is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b are as defined herein. In some embodiments, in Formula (I), L 3 is -(CH2) c -, and c is an integer 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, in Formula (I), L 3 is -(CH2)2-. In some embodiments, in Formula (I), L 3 is -(CH2)3-.

[0152] In some embodiments, in Formula (I), L 4 is C 1-10 alkylene, optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L 4 is -(CR 2a R 2b ) d -, wherein d is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b are as defined herein. In some embodiments, in Formula (I), L 4 is -(CH2)d and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, in Formula (I), L 4 is -(CH2)2-. In some embodiments, in Formula (I), L 4 is -(CH2)3-.

[0153] In yet another embodiment, provided herein is a compound of Formula (II): or an enantiomer, a mixture of enantiomers, a diastereomer, 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 R 1 , R 2 , R 3 , R 4 , A, E, X, Z, a, b, c, and d are each as defined herein.

[0154] In some embodiments, in Formula (I) or Formula (II), E is -OC(O)N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, in Formula (I) or Formula (II), E is -OC(O)N(H)-. In some embodiments, in Formula (I) or Formula (II), E is -N(R 1a )C(O)N(R 1b )-, wherein R 1a and R 1b are each as defined herein. In some embodiments, in Formula (I) or Formula (II), E is -N(H)C(O)N(H)-.

[0155] In yet another embodiment, provided herein is a compound of Formula (III): or an enantiomer, a mixture of enantiomers, a diastereomer, 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, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , A, U, X, Z, a, b, c, and d are each as defined herein.

[0156] In some embodiments, in any one of Formulas (I)-(III), A is -O-. In some embodiments, in any one of Formulas (I)-(III), A is -N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, in any one of Formulas (I)-(III), A is -N(H)-.

[0157] In some embodiments, in any one of Formulas (I)-(III), U is -O-. In some embodiments, in any one of Formulas (I)-(III), U is -N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, in any one of Formulas (I)-(III), U is -N(H)-.

[0158] In yet another embodiment, provided herein is a compound of Formula (IV): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , X, Z, a, b, c, and d are each as defined herein.

[0159] In yet another embodiment, provided herein is a compound of Formula (V): or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , X, Z, a, b, c, and d are each as defined herein.

[0160] In yet another embodiment, provided herein is a compound of Formula (VI): or an enantiomer, a mixture of enantiomers, a diastereomer, 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 R 1 , R 2 , R 3 , R 4 , X, Z, a, b, c, and d are each as defined herein.

[0161] In yet another embodiment, provided herein is a compound of Formula (VII): or an enantiomer, a mixture of enantiomers, a diastereomer, 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 R 1 , R 2 , R 3 , R 4 , X, Z, a, b, c, and d are each as defined herein.

[0162] In some embodiments, in any one of Formulas (I)-(VII), R 1 is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a, -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)2NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR1b R 1c or -S(O)2NR 1b R 1c ; wherein each R 1a , R 1b , R 1c , and R 1d is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is: (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)NR 1b R 1c , -OR 1a , or -S(O)2R 1a , wherein each R 1a , R 1b , and R 1c is as defined herein.

[0163] In some embodiments, in any one of Formulas (I)-(VII), R 1 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 1 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NRb R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , =NOR a , -SR a or -NR a S(O)2R d wherein each R a , R b , R c and R d is as defined herein.

[0164] In some embodiments, in any one of Formulas (I) to (VII), R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q is independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethyl- amino, acetamido, methylureido, dimethylureido, methylthioureido, 3,3- dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0165] In some embodiments, in any one of Formulas (I) to (VII), R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q is independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methyl- thioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0166] In some embodiments, in any one of Formulas (I) to (VII), R 1methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxy-butyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0167] In some embodiments, in any one of Formulas (I)-(VII), R 1 is C 2-6 alkenyl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halo, or nitro; (ii) C 1 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , =NOR a , -SR a , or -NR a S(O)2R d , wherein each R a , Rb R c and R d As defined herein. In some implementations, in any of equations (I) through (VII), R 1 It is 1-(dimethylamino)-2-nitrovinyl.

[0168] In some implementations, in any one of equations (I) to (VII), R 1 C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 1 C 3-10 Cycloalkyl group, optionally substituted with one, two or three substituents Q, each Q being independently: (i) cyano, halogen or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclic groups, each optionally substituent Q. a Substitution; or (iii)-C(O)OR a -C(O)NR b R c -C(O)SR a -OR a -NR b R c -NR a C(O)NR b R c -NR a C(NR d )NR b R c -NR a C(S)NR b R c =NOR a -SR a or -NR a S(O)2R d , where each R a R b R c and R d As defined in this article.

[0169] In some implementations, in any one of equations (I) to (VII), R 1 For single-ring C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 1 For single-ring C 3-10cycloalkyl, C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , =NOR a , -SR a , or -NR a S(O)2R d , wherein each R a , R b , R c , and R d is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-l-cyclobutenyl.

[0170] In some embodiments, in any one of formulas (I)-(VII), R 1 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa substituted; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , -SR a , or -NR a S(O)2R d , wherein each R a , R b , R c , and R d is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 1 is 4-dimethyl-aminophenyl.

[0171] In some embodiments, in any one of formulas (I)-(VII), R 1 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a substituted; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b Rc , -NR a C(S)NR b R c , -SR a or -NR a S(O)2R d wherein each R a , R b , R c and R d are as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is 4-methoxy-benzyl.

[0172] In some embodiments, in any one of Formulas (I)-(VII), R 1 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 1 is heteroaryl, optionally substituted with one, two or three substituents Q, each Q being independently: (i) cyano, halo or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , -SR a or -NR a S(O)2R d wherein each R a , R b , R c and R d are as defined herein.

[0173] In some embodiments, in any one of Formulas (I)-(VII), R 1is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halo, or nitro; (ii) C 1 alkyl, C 3-10 alkenyl, C 6-14 alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , -SR a , or -NR a S(O)2R d , wherein each R a , R b , R c , and R d is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 1 is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.

[0174] In some embodiments, in any one of formulas (I)-(VII), R 1 is -C(O)R 1a , wherein R 1a is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 1 is -C(O)-C 1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(O)OR 1a , wherein R 1a is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(O)OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 1 is methoxycarbonyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is methylaminocarbonyl, or dimethylaminocarbonyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b and R 1c are each as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is formamidinyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(NCN)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1is N'-cyano-N,N-dimethylformamidyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(NOR 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is N'-methoxy-N,N-dimethylformamidyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(NS(O2)R 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is N'-methylsulfonyl-N,N-dimethyl-formamidyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -C(S)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is methylaminothiocarbonyl, or dimethylaminothiocarbonyl. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -OR 1a wherein R 1a is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is hydroxyl or methoxy. In some embodiments, in any one of Formulas (I)-(VII), R 1 is -S(O)2R 1a wherein R 1a is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 1 is methylsulfonyl.

[0175] In some embodiments, in any one of Formulas (I)-(VII), R 1methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxy-ethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethyl-ureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxy-propyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxy-imino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4-dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, formamidinyl, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylformamidinyl, (Z)-N'-cyano-N,N-dimethylformamidinyl, (E)-N'-methoxy-N,N-dimethylformamidinyl, (Z)-N'-methoxy-N,N-dimethylformamidinyl, (E)-N'-methylsulfonyl-N,N-dimethylformamidinyl, (Z)-N'-methylsulfonyl-N,N-dimethylformamidinyl, hydroxy, methoxy, or methylsulfonyl. In some embodiments, in any one of formulae (I) to (VII), R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0176] In some embodiments, in any one of formulae (I) to (VII), R 2 is: (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R1c -NR 1a C(S)R 1d -NR 1a C(S)OR 1d -NR 1a C(S)NR 1b R 1c -NR 1a S(O)R 1d -NR 1a S(O)2R 1d -NR 1a S(O)NR 1b R 1c -NR 1a S(O)2NR 1b R 1c -S(O)R 1a -S(O)2R 1a -S(O)NR 1b R 1c or-S(O)2NR 1b R 1c ; wherein each R 1a , R 1b , R 1c , and R 1d is as defined herein. In some embodiments, in any one of formulae (I) to (VII), R 2 is: (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(NR 1a )NR 1b R 1c , -C(NCN)NR 1b R 1c , -C(NOR 1a )NR 1b R 1c , -C(NS(O2)R 1a )NR 1b R 1c , -C(S)NR 1b R 1c , -OR 1a , or -S(O)2R 1a , wherein each R1a R 1b and R 1c As defined in this article.

[0177] In some implementations, in any one of equations (I) to (VII), R 2 C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 2 C 1-6 Alkyl group, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclic groups, each optionally substituent Q. a Substitution; or (iii)-C(O)OR a -C(O)NR b R c -C(O)SR a -OR a -NR b R c -NR a C(O)NR b R c -NR a C(NR d )NR b R c -NR a C(S)NR b R c =NOR a -SR a or -NR a S(O)2R d , where each R a R b R c and R d As defined in this article.

[0178] In some implementations, in any one of equations (I) to (VII), R 2 It is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted by one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxy, hydroxyethoxy, dimethyl-amino, acetamyl, methylurea, dimethylurea, methylthiourea, 3,3-dimethylthiourea, guanidinyl, methoxyimino, mercapto, or methylsulfonamide.

[0179] In some embodiments, in any one of Formulas (I) to (VII), R 2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q is independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methyl-thioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0180] In some embodiments, in any one of Formulas (I) to (VII), R 2 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxy-butyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0181] In some embodiments, in any one of Formulas (I) to (VII), R 2 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 2 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each Q is independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -ORa -NR b R c -NR a C(O)NR b R c -NR a C(NR d )NR b R c -NR a C(S)NR b R c = N OR a -SR a or -NR a S(O)2R d wherein each R a , R b , R c and R d is as defined herein. In some embodiments, in any one of formulae (I) to (VII), R 2 is 1-(dimethylamino)-2-nitroethenyl.

[0182] In some embodiments, in any one of formulae (I) to (VII), R 2 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 2 is C 3-10 cycloalkyl, optionally substituted with one, two or three substituents Q, each Q being independently: (i) cyano, halo or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c = N OR a-SR a or -NR a S(O)2R d , where each R a R b R c and R d As defined in this article.

[0183] In some implementations, in any one of equations (I) to (VII), R 2 For single-ring C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 2 For single-ring C 3-10 Cycloalkyl group, optionally substituted with one, two or three substituents Q, each Q being independently: (i) cyano, halogen or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclic groups, each optionally substituent Q. a Substitution; or (iii)-C(O)OR a -C(O)NR b R c -C(O)SR a -OR a -NR b R c -NR a C(O)NR b R c -NR a C(NR d )NR b R c -NR a C(S)NR b R c =NOR a -SR a or -NR a S(O)2R d , where each R a R b R c and R d As defined herein. In some implementations, in any of equations (I) through (VII), R 2 The derivative is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, in any of formulas (I) to (VII), R... 2cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-l-cyclobutenyl.

[0184] In some embodiments, in any one of Formulas (I)-(VII), R 2 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 2 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , -SR a , or -NR a S(O)2R d , wherein each R a , R b , R c , and R d is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R 2 is 4-dimethyl-aminophenyl.

[0185] In some embodiments, in any one of Formulas (I)-(VII), R 2 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 2 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q a substituted; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , -SR a or -NR a S(O)2R d , wherein each R a , R b , R c and R d is as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2 is 4-methoxy-benzyl.

[0186] In some embodiments, in any one of formulas (I) to (VII), R 2 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 2 is heteroaryl, optionally substituted with one, two or three substituents Q, each Q being independently: (i) cyano, halo or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q a substituted; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c , -NR a C(O)NR b R c , -NR a C(NRd )NR b R c -NR a C(S)NR b R c -SR a or -NR a S(O)2R d , where each R a R b R c and R d As defined in this article.

[0187] In some implementations, in any one of equations (I) to (VII), R 2 It is a monocyclic heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 2 It is a monocyclic heteroaryl group, optionally substituted by one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclic groups, each optionally substituent Q. a Substitution; or (iii)-C(O)OR a -C(O)NR b R c -C(O)SR a -OR a -NR b R c -NR a C(O)NR b R c -NR a C(NR d )NR b R c -NR a C(S)NR b R c -SR a or -NR a S(O)2R d , where each R a R b R c and R d As defined herein. In some implementations, in any of equations (I) through (VII), R 2 It is a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 2is imidazolyl, thiazolyl, or pyridyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 2 is imidazol-2-yl, thiazol-2-yl, pyrid-2-yl, or pyrid-3-yl.

[0188] In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(O)R 1a wherein R 1a is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(O)OR 1a wherein R 1a is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(O)OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 2 is methoxycarbonyl. In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(O)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, in any one of formulas (I)-(VII), R 2 is methylaminocarbonyl, or dimethylaminocarbonyl. In some embodiments, in any one of formulas (I)-(VII), R 2 is -C(NR 1a )NR 1b R 1c wherein R 1a , R1b and R 1c each as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2 is formamidinyl. In some embodiments, in any one of formulas (I) to (VII), R 2 is -C(NCN)NR 1b R 1c wherein R 1b and R 1c each as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2 is N’-cyano-N,N-dimethylformamidinyl. In some embodiments, in any one of formulas (I) to (VII), R 2 is -C(NOR 1a )NR 1b R 1c wherein R 1a , R 1b and R 1c each as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2 is N’-methoxy-N,N-dimethylformamidinyl. In some embodiments, in any one of formulas (I) to (VII), R 2 is -C(NS(O2)R 1a )NR 1b R 1c wherein R 1a , R 1b and R 1c each as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2 is N’-methylsulfonyl-N,N-dimethyl-formamidinyl. In some embodiments, in any one of formulas (I) to (VII), R 2 is -C(S)NR 1b R 1c wherein R 1b and R 1c each as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2 is methylaminothiocarbonyl, or dimethylaminothiocarbonyl. In some embodiments, in any one of formulas (I) to (VII), R 2 is -OR 1a wherein R 1a is as defined herein. In some embodiments, in any one of formulas (I) to (VII), R 2hydroxyl or methoxy. In some embodiments, in any one of Formulas (I) to (VII), R 2 is -S(O)2R 1a wherein R 1a is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 is methylsulfonyl.

[0189] In some embodiments, in any one of Formulas (I) to (VII), R 2 is methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxy-ethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethyl-ureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxy-propyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxy-imino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4-dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, formamidinyl, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylformamidinyl, (Z)-N'-cyano-N,N-dimethylformamidinyl, (E)-N'-methoxy-N,N-dimethylformamidinyl, (Z)-N'-methoxy-N,N-dimethylformamidinyl, (E)-N'-methylsulfonyl-N,N-dimethylformamidinyl, (Z)-N'-methylsulfonyl-N,N-dimethylformamidinyl, hydroxyl, methoxy, or methylsulfonyl. In some embodiments, in any one of Formulas (I) to (VII), R 2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0190] In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a 5-membered heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a 6-membered heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a 1,2,3-triazol-1-yl, pyridin-1-ium, or pyrimidin-1-yl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-ium, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

[0191] In some embodiments, in any one of formulae (I) to (VII), R 1 and R 2 together with the N atom to which they are attached form a bicyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R1 and R 2 together with the N atom to which they are attached form a 5,5-, 5,6-, or 6,6- fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a 5,5- fused heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a 5,6- fused heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a 6,6- fused heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a purin-9-yl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a 6-aminopurin-9-yl or 2-amino-6-oxo-l,9-dihydropurin-9-yl.

[0192] In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 1 and R 2Together with the N atoms to which they are attached, they form a 3-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 1 and R 2 Together with the N atoms to which they are attached, they form a 4-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 1 and R 2 Together with the N atoms to which they are attached, they form a 5-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 1 and R 2 Together with the N atoms to which they are attached, they form a 6-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 1 and R 2 Together with the N atoms to which they are attached, they form a 7-membered heterocyclic group, which may optionally be substituted by one or more substituents Q.

[0193] In some implementations, in any one of equations (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form azircyclic propane-1-yl, azircyclic butane-1-yl, pyrrolidine-1-yl, oxazolidinone-3-yl, imidazolidine-1-yl, piperidin-1-yl, azircyclic heptane-1-yl, morpholino-4-yl, piperazinyl-1-yl, or isoindolinyl-2-yl, each optionally substituted by one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 1 and R 2 Together with the N atoms to which they are attached, they form 2-methylaziridin-1-yl, aziridine-1-yl, pyrrolidine-1-yl, 2-oxopyrrolidine-1-yl, 2,5-dioxopyrrolidine-1-yl, 2-oxooxazolidine-3-yl, 2,5-dioxoimidazolidine-1-yl, piperidin-1-yl, aziridine-heptane-1-yl, morpholino-4-yl, 3,5-dioxomorpholino-4-yl, piperazinyl-1-yl, 4-methylpiperazinyl-1-yl, 4-(4-methoxybenzyl)piperazinyl-1-yl, 4-(2-hydroxyethyl)piperazinyl-1-yl, or 1,3-dioxoisoindololinyl-2-yl.

[0194] In some implementations, in any one of formulas (I) to (VII), the portion dimethylamino, (2-cyanoethyl)(methyl)amino, (cyclopropylmethyl)(methyl)amino, (cyclobutyl-methyl)(methyl)amino, (cyclopentylmethyl)(methyl)amino, (cyclohexylmethyl)(methyl)amino, (cycloheptylmethyl)(methyl)amino, (pyridin-2-ylmethyl)(methyl)amino, (pyridin-3-ylmethyl)-(methyl)amino, (pyridin-4-ylmethyl)(methyl)amino, (dimethylaminomethyl)(methyl)amino, (ethyl)(methyl)amino, (2-hydroxyethyl)(methyl)amino, (2-acetamidoethyl)(methyl)amino, (2-guanidinoethyl)(methyl)amino, (2-methylsulfonamidoethyl)(methyl)amino, (2-(3-methylureido)-ethyl)(methyl)amino, (2-(3,3-dimethylureido)ethyl)(methyl)amino, (2-(3-methylthioureido)-ethyl)(methyl)amino, (2-(3,3-dimethylthioureido)ethyl)(methyl)amino, diethylamino, (1,3-dihydroxypropan-2-yl)amino, (isopropyl)(methyl)amino, (R)-(2-hydroxy-propyl)(methyl)amino, (S)-(2-hydroxypropyl)(methyl)amino, (3-hydroxypropyl)(methyl)amino, (1,3-dihydroxypropan-2-yl)(methyl)amino, (ethyl)(isopropyl)amino, diisopropylamino, (4-hydroxybutyl)(methyl)amino, (R)-(2-hydroxybutyl)(methyl)amino, (S)-(2-hydroxybutyl)-(methyl)amino, (5-hydroxypentyl)-(methyl)amino, (4-(2-hydroxyethoxy)butyl)(methyl)amino, 4-(methoxyimino)butylamino, (4-(methoxyimino)butyl)(methyl)amino, (5-hydroxy-5-carboxypentyl)(methyl)amino, (6-hydroxy-hexyl)(methyl)amino, 1 -(methylamino)-2-nitrovinylamino, (cyclopropyl)(methyl)amino, (cyclobutyl)(methyl)amino, (cyclopentyl)(methyl)amino, (cyclohexyl)(methyl)amino, (cycloheptyl)-(methyl)amino, (2-hydroxycycloheptyl)(methyl)amino, 2-dimethylamino-3,4-dioxy-1 -cyclobutenyl, (4-dimethylaminophenyl)amino, (4-methoxybenzyl)(methyl)amino, imidazol-2-yl-amino, thiazol-2-ylamino, (pyridin-2-yl)(methyl)amino, (pyridin-3-yl)(methyl)amino, methoxyformamido, methylaminocarbonylamido, dimethylaminocarbonylamido, methylaminothiocarbonylamido, dimethylaminothiocarbonylamido, acetyl-amido, N-(methyl)acetyl-amido, N-(2-hydroxy)acetyl-amido, N-(2-methoxy)acetyl-amido, N-(2-benzyloxy)acetyl-amido, propionyl-amido, isobutyryl-amido, guanidino, 2-cyano-3,3-dimethylguanidino, 2-methoxy-3,3-dimethylguanidino, 2-methylsulfonyl-3,3-dimethyl-guanidino, N-(methyl)hydroxylamino, N-(methoxy)acetamido, N- (methoxy)methoxymethylamido, methylsulfonamido, or N-(methoxy)(methylsulfonamido).

[0195] In some embodiments, in any one of Formulas (I)-(VII), the moiety is 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1- ylium, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, 4-amino-2-oxopyrimidin-1-yl, 6-aminopurin-9- yl, 2-amino-6-oxo-1,9-dihydropurin-9-yl, 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1- yl, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin- 1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazinyl-1-yl, 4- methylpiperazinyl-1-yl, 4-(4-methoxybenzyl)piperazinyl-1-yl, 4-(2-hydroxyethyl)piperazinyl-1- yl, or 1,3-dioxoisoindolinyl-2-yl.

[0196] In some embodiments, in any one of Formulas (I)-(VII), the moiety has the structure: wherein e and f are each independently an integer 0, 1, 2, 3, 4, or 5; k and m are each independently an integer 0, 1, 2, 3, 4, or 5; n is an integer 0, 1, 2, 3, 4, 5, or 6; and each R 1a as defined herein; in one embodiment, each R 1a is independently C 1-6 alkyl, optionally substituted with one or more substituents Q; and in another embodiment, each R 1a is methyl.

[0197] In some embodiments, in any one of Formulas (I)-(VII), R 3 is C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl or C 6-14 aryl, each optionally substituted with one or more substituents Q.

[0198] In some embodiments, in any one of formulae (I) to (VII), R 3 is C 1-30 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is C 1-25 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is C 1-20 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methoxynonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, hepta- decan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0199] In some embodiments, in any one of formulae (I) to (VII), R 3 is C 1-30 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is C 1-25alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 3 is C 1-20 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 3 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosene, tetracosenyl, or pentacosenyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 3 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3- octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5- difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8- heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-hepta-deca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)- heptadeca-8,11,14-trien-1-yl.

[0200] In some embodiments, in any one of formulas (I)-(VII), R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 3 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 3 is cyclohexyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 3 is 4-pentylcyclohexyl, or 4-cyclohexylcyclohexyl.

[0201] In some embodiments, in any one of formulae (I) to (VII), R 3 is C 6-14 aryl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is phenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0202] In some embodiments, in any one of formulae (I) to (VII), R 3 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, heneicosan-1-yl, 2-(dodecan-1-yl disulfanyl)ethyl, (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexyl-cyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0203] In some embodiments, in any one of formulae (I) to (VII), R 3 is:

[0204] In some embodiments, in any one of Formulas (I)-(VII), R 3 is: wherein each p is independently an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0205] In some embodiments, in any one of Formulas (I)-(VII), R 3 is: wherein each s and t is independently an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0206] In some embodiments, in any one of Formulas (I)-(VII), R 3 is:

[0207] In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, or C 6-14 aryl, each optionally substituted with one or more substituents Q.

[0208] In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-30 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-25 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-20 alkyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, hepta-decan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0209] In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-30 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-25 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4 is C 1-20 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R 4is ethenyl, n-propenyl, i-propenyl, n-butenyl, i-butenyl, s-butenyl, t-butenyl, n-pentenyl, i-pentenyl, s-pentenyl, 3-methyl-2-butenyl, 3-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, n-hexenyl, i-hexenyl, s-hexenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 2, 3-dimethyl-2-butenyl, 2-ethyl-2-butenyl, n-heptenyl, i-heptenyl, s-heptenyl, 3-methyl-6-hexenyl, 4-methyl-6-hexenyl, 5-methyl-6-hexenyl, 5-methyl-3-hexenyl, 6-methyl-3-hexenyl, 2-methyl-5-hexenyl, 2-ethyl-5-hexenyl, 2, 3-dimethyl-5-hexenyl, 2, 4-dimethyl-5-hexenyl, 2, 5-dimethyl-5-hexenyl, 2-ethyl-2, 3-dimethyl-2-butenyl, 2-ethyl-3-methyl-2-butenyl, 2-ethyl-2-methyl-2-butenyl, 2-ethyl-2, 3-dimethyl-1-butenyl, 2-ethyl-3-methyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 2-ethyl-4-butenyl, 2-ethyl-5-butenyl, 2-ethyl-6-butenyl, 2-ethyl-7-butenyl, 2-ethyl-8-butenyl, 2-ethyl-9-butenyl, 2-ethyl-10-butenyl, 2-ethyl-11-butenyl, 2-ethyl-12-butenyl, 2-ethyl-13-butenyl, 2-ethyl-14-butenyl, 2-ethyl-15-butenyl, 2-ethyl-16-butenyl, 2-ethyl-17-butenyl, 2-ethyl-18-butenyl, 2-ethyl-19-butenyl, 2-ethyl-20-butenyl, 2-ethyl-21-butenyl, 2-ethyl-22-butenyl, 2-ethyl-23-butenyl, 2-ethyl-24-butenyl, or 2-ethyl-25-butenyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 4 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pent-decen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-undecen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

[0210] In some embodiments, in any one of formulas (I)-(VII), R 4 is C 3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 4 is monocyclic C 3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 4 is cyclohexyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 4 is 4-pentylcyclohexyl, or 4-cyclohexylcyclohexyl.

[0211] In some embodiments, in any one of formulas (I)-(VII), R 4 is C 6-14 aryl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R 4is phenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0212] In some embodiments, in any one of formulae (I) to (VII), R 4 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, heneicosan-1-yl, 2-(dodecan-1-yl disulfanyl)ethyl, (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexyl-cyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0213] In some embodiments, in any one of formulae (I) to (VII), R 4 is:

[0214] In some embodiments, in any one of Formulas (I)-(VII), R 4 is: wherein each p is independently an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0215] In some embodiments, in any one of Formulas (I)-(VII), R 4 is: wherein each s and t is independently an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0216] In some embodiments, in any one of Formulas (I)-(VII), R 4 is:

[0217] In one embodiment, provided herein is a compound of Formula A1: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 g and h are each independently an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; and X, Z, c, d, e, and f are each as defined herein.

[0218] In another embodiment, provided herein is a compound of Formula A2: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, e, and f are each as defined herein.

[0219] In yet another embodiment, provided herein is a compound of Formula A3: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, e, and f are each as defined herein.

[0220] In yet another embodiment, provided herein is a compound of Formula A4: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 i and j are each independently an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and X, Z, c, d, e, and f are each as defined herein.

[0221] In yet another embodiment, provided herein is a compound of Formula A5: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, e, f, g, and h are each as defined herein.

[0222] In yet another embodiment, provided herein is a compound of Formula A6: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, e, f, g, and h are each as defined herein.

[0223] In one embodiment, provided herein is a compound of Formula A7: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0224] In another embodiment, provided herein is a compound of Formula A8: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0225] In yet another embodiment, provided herein is a compound of Formula A9: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0226] In yet another embodiment, provided herein is a compound of Formula A10: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0227] In yet another embodiment, provided herein is a compound of Formula A11: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0228] In yet another embodiment, provided herein is a compound of Formula A12: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0229] In one embodiment, provided herein is a compound of Formula A13: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0230] In another embodiment, provided herein is a compound of Formula A14: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0231] In yet another embodiment, provided herein is a compound of Formula A15: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0232] In yet another embodiment, provided herein is a compound of Formula A16: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0233] In yet another embodiment, provided herein is a compound of Formula A17: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0234] In yet another embodiment, provided herein is a compound of Formula A18: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0235] In one embodiment, provided herein is a compound of Formula A19: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0236] In another embodiment, provided herein is a compound of Formula A20: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0237] In yet another embodiment, provided herein is a compound of Formula A21: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0238] In yet another embodiment, provided herein is a compound of Formula A22: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0239] In yet another embodiment, provided herein is a compound of Formula A23: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0240] In yet another embodiment, provided herein is a compound of Formula A24: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0241] In one embodiment, provided herein is a compound of Formula A25: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0242] In another embodiment, provided herein is a compound of Formula A26: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0243] In yet another embodiment, provided herein is a compound of Formula A27: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0244] In yet another embodiment, provided herein is a compound of Formula A28: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0245] In yet another embodiment, provided herein is a compound of Formula A29: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0246] In yet another embodiment, provided herein is a compound of Formula A30: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0247] In one embodiment, provided herein is a compound of Formula A31: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, k, and m is as defined herein.

[0248] In another embodiment, provided herein is a compound of Formula A32: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, k, and m is as defined herein.

[0249] In yet another embodiment, provided herein is a compound of Formula A33: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, k, and m is as defined herein.

[0250] In yet another embodiment, provided herein is a compound of Formula A34: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, j, k, and m is as defined herein.

[0251] In yet another embodiment, provided herein is a compound of Formula A35: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, k, and m is as defined herein.

[0252] In yet another embodiment, provided herein is a compound of Formula A36: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0253] In one embodiment, provided herein is a compound of Formula A37: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0254] In another embodiment, provided herein is a compound of Formula A38: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0255] In yet another embodiment, provided herein is a compound of Formula A39: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0256] In yet another embodiment, provided herein is a compound of Formula A40: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0257] In yet another embodiment, provided herein is a compound of Formula A41: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0258] In yet another embodiment, provided herein is a compound of Formula A42: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0259] In one embodiment, provided herein is a compound of Formula A43: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, and n is as defined herein.

[0260] In another embodiment, provided herein is a compound of Formula A44: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, and n is as defined herein.

[0261] In yet another embodiment, provided herein is a compound of Formula A45: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, and n is as defined herein.

[0262] In yet another embodiment, provided herein is a compound of Formula A46: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, j, and n are each as defined herein.

[0263] In yet another embodiment, provided herein is a compound of Formula A47: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0264] In yet another embodiment, provided herein is a compound of Formula A48: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0265] In one embodiment, provided herein is a compound of Formula A49: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0266] In another embodiment, provided herein is a compound of Formula A50: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0267] In yet another embodiment, provided herein is a compound of Formula A51: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0268] In yet another embodiment, provided herein is a compound of Formula A52: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0269] In yet another embodiment, provided herein is a compound of Formula A53: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0270] In yet another embodiment, provided herein is a compound of Formula A54: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0271] In one embodiment, provided herein is a compound of Formula B1: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0272] In another embodiment, provided herein is a compound of Formula B2: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, and f is as defined herein.

[0273] In yet another embodiment, provided herein is a compound of Formula B3: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, and f is as defined herein.

[0274] In yet another embodiment, provided herein is a compound of Formula B4: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, i, and j is as defined herein.

[0275] In yet another embodiment, provided herein is a compound of Formula B5: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0276] In yet another embodiment, provided herein is a compound of Formula B6: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0277] In one embodiment, provided herein is a compound of Formula B7: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0278] In another embodiment, provided herein is a compound of Formula B8: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0279] In yet another embodiment, provided herein is a compound of Formula B9: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0280] In yet another embodiment, provided herein is a compound of Formula B10: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0281] In yet another embodiment, provided herein is a compound of Formula B11: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0282] In yet another embodiment, provided herein is a compound of Formula B12: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0283] In one embodiment, provided herein is a compound of Formula B13: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0284] In another embodiment, provided herein is a compound of Formula B14: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0285] In yet another embodiment, provided herein is a compound of Formula B15: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0286] In yet another embodiment, provided herein is a compound of Formula B16: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0287] In yet another embodiment, provided herein is a compound of Formula B17: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0288] In yet another embodiment, provided herein is a compound of Formula B18: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0289] In one embodiment, provided herein is a compound of Formula B19: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0290] In another embodiment, provided herein is a compound of Formula B20: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0291] In yet another embodiment, provided herein is a compound of Formula B21: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0292] In yet another embodiment, provided herein is a compound of Formula B22: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0293] In yet another embodiment, provided herein is a compound of Formula B23: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0294] In yet another embodiment, provided herein is a compound of Formula B24: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0295] In one embodiment, provided herein is a compound of Formula B25: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0296] In another embodiment, provided herein is a compound of Formula B26: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0297] In yet another embodiment, provided herein is a compound of Formula B27: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0298] In yet another embodiment, provided herein is a compound of Formula B28: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0299] In yet another embodiment, provided herein is a compound of Formula B29: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0300] In yet another embodiment, provided herein is a compound of Formula B30: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0301] In one embodiment, provided herein is a compound of Formula B31: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, k, and m is as defined herein.

[0302] In another embodiment, provided herein is a compound of Formula B32: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, k, and m is as defined herein.

[0303] In yet another embodiment, provided herein is a compound of Formula B33: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, k, and m is as defined herein.

[0304] In yet another embodiment, provided herein is a compound of Formula B34: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, j, k, and m is as defined herein.

[0305] In yet another embodiment, provided herein is a compound of Formula B35: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, k, and m is as defined herein.

[0306] In yet another embodiment, provided herein is a compound of Formula B36: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0307] In one embodiment, provided herein is a compound of Formula B37: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0308] In another embodiment, provided herein is a compound of Formula B38: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0309] In yet another embodiment, provided herein is a compound of Formula B39: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0310] In yet another embodiment, provided herein is a compound of Formula B40: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0311] In yet another embodiment, provided herein is a compound of Formula B41: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0312] In yet another embodiment, provided herein is a compound of Formula B42: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0313] In one embodiment, provided herein is a compound of Formula B43: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0314] In another embodiment, provided herein is a compound of Formula B44: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, and n are each as defined herein.

[0315] In yet another embodiment, provided herein is a compound of Formula B45: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, and n are each as defined herein.

[0316] In yet another embodiment, provided herein is a compound of Formula B46: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, j, and n are each as defined herein.

[0317] In yet another embodiment, provided herein is a compound of Formula B47: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0318] In yet another embodiment, provided herein is a compound of Formula B48: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0319] In one embodiment, provided herein is a compound of Formula B49: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0320] In another embodiment, provided herein is a compound of Formula B50: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0321] In yet another embodiment, provided herein is a compound of Formula B51: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0322] In yet another embodiment, provided herein is a compound of Formula B52: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0323] In yet another embodiment, provided herein is a compound of Formula B53: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0324] In yet another embodiment, provided herein is a compound of Formula B54: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0325] In one embodiment, provided herein is a compound of Formula C1: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0326] In another embodiment, provided herein is a compound of Formula C2: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, and f is as defined herein.

[0327] In yet another embodiment, provided herein is a compound of Formula C3: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, and f is as defined herein.

[0328] In yet another embodiment, provided herein is a compound of Formula C4: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, i, and j is as defined herein.

[0329] In yet another embodiment, provided herein is a compound of Formula C5: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0330] In yet another embodiment, provided herein is a compound of Formula C6: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0331] In one embodiment, provided herein is a compound of Formula C7: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0332] In another embodiment, provided herein is a compound of Formula C8: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0333] In yet another embodiment, provided herein is a compound of Formula C9: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0334] In yet another embodiment, provided herein is a compound of Formula C10: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0335] In yet another embodiment, provided herein is a compound of Formula C11: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0336] In yet another embodiment, provided herein is a compound of Formula C12: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0337] In one embodiment, provided herein is a compound of Formula C13: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0338] In another embodiment, provided herein is a compound of Formula C14: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0339] In yet another embodiment, provided herein is a compound of Formula C15: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0340] In yet another embodiment, provided herein is a compound of Formula C16: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0341] In yet another embodiment, provided herein is a compound of Formula C17: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0342] In yet another embodiment, provided herein is a compound of Formula C18: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0343] In one embodiment, provided herein is a compound of Formula C19: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0344] In another embodiment, provided herein is a compound of Formula C20: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0345] In yet another embodiment, provided herein is a compound of Formula C21: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0346] In yet another embodiment, provided herein is a compound of Formula C22: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0347] In yet another embodiment, provided herein is a compound of Formula C23: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0348] In yet another embodiment, provided herein is a compound of Formula C24: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0349] In one embodiment, provided herein is a compound of Formula C25: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0350] In another embodiment, provided herein is a compound of Formula C26: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0351] In yet another embodiment, provided herein is a compound of Formula C27: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0352] In yet another embodiment, provided herein is a compound of Formula C28: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0353] In yet another embodiment, provided herein is a compound of Formula C29: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0354] In yet another embodiment, provided herein is a compound of Formula C30: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0355] In one embodiment, provided herein is a compound of Formula C31: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, k, and m is as defined herein.

[0356] In another embodiment, provided herein is a compound of Formula C32: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, k, and m is as defined herein.

[0357] In yet another embodiment, provided herein is a compound of Formula C33: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, k, and m is as defined herein.

[0358] In yet another embodiment, provided herein is a compound of Formula C34: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, j, k, and m is as defined herein.

[0359] In yet another embodiment, provided herein is a compound of Formula C35: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0360] In yet another embodiment, provided herein is a compound of Formula C36: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0361] In one embodiment, provided herein is a compound of Formula C37: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0362] In another embodiment, provided herein is a compound of Formula C38: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0363] In yet another embodiment, provided herein is a compound of Formula C39: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0364] In yet another embodiment, provided herein is a compound of Formula C40: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0365] In yet another embodiment, provided herein is a compound of Formula C41: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0366] In yet another embodiment, provided herein is a compound of Formula C42: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0367] In one embodiment, provided herein is a compound of Formula C43: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0368] In another embodiment, provided herein is a compound of Formula C44: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, and n are each as defined herein.

[0369] In yet another embodiment, provided herein is a compound of Formula C45: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, and n are each as defined herein.

[0370] In yet another embodiment, provided herein is a compound of Formula C46: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, j, and n are each as defined herein.

[0371] In yet another embodiment, provided herein is a compound of Formula C47: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0372] In yet another embodiment, provided herein is a compound of Formula C48: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0373] In one embodiment, provided herein is a compound of Formula C49: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0374] In another embodiment, provided herein is a compound of Formula C50: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0375] In yet another embodiment, provided herein is a compound of Formula C51: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0376] In yet another embodiment, provided herein is a compound of Formula C52: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0377] In yet another embodiment, provided herein is a compound of Formula C53: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0378] In yet another embodiment, provided herein is a compound of Formula C54: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0379] In one embodiment, provided herein is a compound of Formula D1: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0380] In another embodiment, provided herein is a compound of Formula D2: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, and f is as defined herein.

[0381] In yet another embodiment, provided herein is a compound of Formula D3: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, and f is as defined herein.

[0382] In yet another embodiment, provided herein is a compound of Formula D4: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, i, and j is as defined herein.

[0383] In yet another embodiment, provided herein is a compound of Formula D5: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0384] In yet another embodiment, provided herein is a compound of Formula D6: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0385] In one embodiment, provided herein is a compound of Formula D7: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, e, f, g, and h is as defined herein.

[0386] In another embodiment, provided herein is a compound of Formula D8: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0387] In yet another embodiment, provided herein is a compound of Formula D9: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0388] In yet another embodiment, provided herein is a compound of Formula D10: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0389] In yet another embodiment, provided herein is a compound of Formula D11: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0390] In yet another embodiment, provided herein is a compound of Formula D12: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0391] In one embodiment, provided herein is a compound of Formula D13: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0392] In another embodiment, provided herein is a compound of Formula D14: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0393] In yet another embodiment, provided herein is a compound of Formula D15: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0394] In yet another embodiment, provided herein is a compound of Formula D16: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0395] In yet another embodiment, provided herein is a compound of Formula D17: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0396] In yet another embodiment, provided herein is a compound of Formula D18: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0397] In one embodiment, provided herein is a compound of Formula D19: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0398] In another embodiment, provided herein is a compound of Formula D20: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0399] In yet another embodiment, provided herein is a compound of Formula D21: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0400] In yet another embodiment, provided herein is a compound of Formula D22: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0401] In yet another embodiment, provided herein is a compound of Formula D23: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0402] In yet another embodiment, provided herein is a compound of Formula D24: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0403] In one embodiment, provided herein is a compound of Formula D25: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0404] In another embodiment, provided herein is a compound of Formula D26: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0405] In yet another embodiment, provided herein is a compound of Formula D27: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0406] In yet another embodiment, provided herein is a compound of Formula D28: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0407] In yet another embodiment, provided herein is a compound of Formula D29: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0408] In yet another embodiment, provided herein is a compound of Formula D30: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0409] In one embodiment, provided herein is a compound of Formula D31: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0410] In another embodiment, provided herein is a compound of Formula D32: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, k, and m are each as defined herein.

[0411] In yet another embodiment, provided herein is a compound of Formula D33: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, k, and m are each as defined herein.

[0412] In yet another embodiment, provided herein is a compound of Formula D34: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, j, k, and m are each as defined herein.

[0413] In yet another embodiment, provided herein is a compound of Formula D35: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0414] In yet another embodiment, provided herein is a compound of Formula D36: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, k, and m are each as defined herein.

[0415] In one embodiment, provided herein is a compound of Formula D37: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0416] In another embodiment, provided herein is a compound of Formula D38: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0417] In yet another embodiment, provided herein is a compound of Formula D39: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, and d is as defined herein.

[0418] In yet another embodiment, provided herein is a compound of Formula D40: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, i, and j is as defined herein.

[0419] In yet another embodiment, provided herein is a compound of Formula D41: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0420] In yet another embodiment, provided herein is a compound of Formula D42: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, and h is as defined herein.

[0421] In one embodiment, provided herein is a compound of Formula D43: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 each of X, Z, c, d, g, h, and n is as defined herein.

[0422] In another embodiment, provided herein is a compound of Formula D44: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, and n are each as defined herein.

[0423] In another embodiment, provided herein is a compound of Formula D45: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, and n are each as defined herein.

[0424] In another embodiment, provided herein is a compound of Formula D46: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, j, and n are each as defined herein.

[0425] In another embodiment, provided herein is a compound of Formula D47: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0426] In another embodiment, provided herein is a compound of Formula D48: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, h, and n are each as defined herein.

[0427] In one embodiment, provided herein is a compound of Formula D49: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0428] In another embodiment, provided herein is a compound of Formula D50: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0429] In yet another embodiment, provided herein is a compound of Formula D51: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, and d are each as defined herein.

[0430] In yet another embodiment, provided herein is a compound of Formula D52: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, i, and j are each as defined herein.

[0431] In yet another embodiment, provided herein is a compound of Formula D53: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0432] In yet another embodiment, provided herein is a compound of Formula D54: or an enantiomer, a mixture of enantiomers, a diastereomer, 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 X, Z, c, d, g, and h are each as defined herein.

[0433] In any of Formulas (I)-(VII), A1-A54, B1-B54, C1-C54, and D1-D54, in one embodiment, X is a chemical bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; in another embodiment, X is a chemical bond; in yet another embodiment, X is -C(O)O-; in yet another embodiment, X is -C(O)N(R 1a )-; in yet another embodiment, X is -C(O)N(H)-; in yet another embodiment, X is -C(O)S-; in yet another embodiment, X is -O-; in yet another embodiment, X is -OC(O)O-; in yet another embodiment, X is -OC(O)N(R 1a )-; in yet another embodiment, X is -OC(O)N(H)-; in yet another embodiment, X is -OC(O)S-; in yet another embodiment, X is -N(R 1a )-; in yet another embodiment, X is -N(H)-; in yet another embodiment, X is -NR 1a C(O)N(R 1b)-; in yet another embodiment, X is -NHC(O)N(H)-; in yet another embodiment, X is -S-; in yet another embodiment, X is -S-S-; and in yet another embodiment, X is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-; wherein each R 1a and R 1b as defined herein.

[0434] In any of Formulas (I)-(VII), A1-A54, B1-B54, C1-C54, and D1-D54, in one embodiment, Z is a bond, -C(O)O-, -C(O)N(R 1a )-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R 1a )-, -OC(O)S-, -N(R 1a )-, -NR 1a C(O)N(R 1b )-, -NR 1a C(O)N(R 1b )-, -S-, or -S-S-; in another embodiment, Z is a bond; in yet another embodiment, Z is -C(O)O-; in yet another embodiment, Z is -C(O)N(R 1a )-; in yet another embodiment, Z is -C(O)N(H)-; in yet another embodiment, Z is -C(O)S-; in yet another embodiment, Z is -O-; in yet another embodiment, Z is -OC(O)O-; in yet another embodiment, Z is -OC(O)N(R 1a )-; in yet another embodiment, Z is -OC(O)N(H)-; in yet another embodiment, Z is -OC(O)S-; in yet another embodiment, Z is -N(R 1a )-; in yet another embodiment, Z is -N(H)-; in yet another embodiment, Z is -NR 1a C(O)N(R 1b )-; in yet another embodiment, Z is -NHC(O)N(H)-; in yet another embodiment, Z is -S-; in yet another embodiment, Z is -S-S-; and in yet another embodiment, Z is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-; wherein each R 1a and R 1b as defined herein.

[0435] In some embodiments, in any one of formulae (II) to (VII), a is an integer 1. In some embodiments, in any one of formulae (II) to (VII), a is an integer 2. In some embodiments, in any one of formulae (II) to (VII), a is an integer 3. In some embodiments, in any one of formulae (II) to (VII), a is an integer 4. In some embodiments, in any one of formulae (II) to (VII), a is an integer 5.

[0436] In some embodiments, in any one of formulae (II) to (VII), b is an integer 1. In some embodiments, in any one of formulae (II) to (VII), b is an integer 2. In some embodiments, in any one of formulae (II) to (VII), b is an integer 3. In some embodiments, in any one of formulae (II) to (VII), b is an integer 4. In some embodiments, in any one of formulae (II) to (VII), b is an integer 5.

[0437] In any one of formulae (II) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, c is an integer 1; in another embodiment, c is an integer 2; in yet another embodiment, c is an integer 3; in yet another embodiment, c is an integer 4; in yet another embodiment, c is an integer 5; in yet another embodiment, c is an integer 6; in yet another embodiment, c is an integer 7; in yet another embodiment, c is an integer 8; and in yet another embodiment, c is an integer 2, 3, 4, 5, or 6.

[0438] In any one of formulae (II) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, d is an integer 1; in another embodiment, d is an integer 2; in yet another embodiment, d is an integer 3; in yet another embodiment, d is an integer 4; in yet another embodiment, d is an integer 5; in yet another embodiment, d is an integer 6; in yet another embodiment, d is an integer 7; in yet another embodiment, d is an integer 8; and in yet another embodiment, d is an integer 2, 3, 4, 5, or 6.

[0439] In any one of formulae A1 to A6, B1 to B6, C1 to C6, and D1 to D6, in one embodiment, e is an integer 1; in another embodiment, e is an integer 2; in yet another embodiment, e is an integer 3; in yet another embodiment, e is an integer 4; and in yet another embodiment, e is an integer 5.

[0440] In any of Formulas A1 to A6, B1 to B6, C1 to C6, and D1 to D6, in an embodiment, f is an integer 1 ; in another embodiment, f is an integer 2; in yet another embodiment, f is an integer 3; in yet another embodiment, f is an integer 4; and in yet another embodiment, f is an integer 5.

[0441] In any of Formulas A1, A5 to A7, A11 to A13, A17 to A19, A23 to A25, A29 to A31, A35 to A37, A41 to A43, A47 to A49, A53, A54, B1, B5 to B7, B11 to B13, B17 to B19, B23 to B25, B29 to B31, B35 to B37, B41 to B43, B47 to B49, B53, B54, C1, C5 to C7, C11 to C13, C17 to C19, C23 to C25, C29 to C31, C35 to C37, C41 to C43, C47 to C49, C53, C54, D1, D5 to D7, D11 to D13, D17 to D19, D23 to D25, D29 to D31, D35 to D37, D41 to D43, D47 to D49, D53, and D54, in an embodiment, g is an integer 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in another embodiment, g is an integer 1 ; in yet another embodiment, g is an integer 2; in yet another embodiment, g is an integer 3; in yet another embodiment, g is an integer 4; in yet another embodiment, g is an integer 5; in yet another embodiment, g is an integer 6; in yet another embodiment, g is an integer 7; in yet another embodiment, g is an integer 8; in yet another embodiment, g is an integer 9; in yet another embodiment, g is an integer 10; in yet another embodiment, g is an integer 11 ; in yet another embodiment, g is an integer 12; in yet another embodiment, g is an integer 13; in yet another embodiment, g is an integer 14; in yet another embodiment, g is an integer 15; in yet another embodiment, g is an integer 16; in yet another embodiment, g is an integer 17; in yet another embodiment, g is an integer 18; in yet another embodiment, g is an integer 19; in yet another embodiment, g is an integer 20; in yet another embodiment, g is an integer 21 ; in yet another embodiment, g is an integer 22; in yet another embodiment, g is an integer 23; in yet another embodiment, g is an integer 24; and in yet another embodiment, g is an integer 25.

[0442] In any of Formula A1, A5 to A7, A11 to A13, A17 to A19, A23 to A25, A29 to A31, A35 to A37, A41 to A43, A47 to A49, A53, A54, B1, B5 to B7, B11 to B13, B17 to B19, B23 to B25, B29 to B31, B35 to B37, B41 to B43, B47 to B49, B53, B54, C1, C5 to C7, C11 to C13, C17 to C19, C23 to C25, C29 to C31, C35 to C37, C41 to C43, C47 to C49, C53, C54, D1, D5 to D7, D11 to D13, D17 to D19, D23 to D25, D29 to D31, D35 to D37, D41 to D43, D47 to D49, D53, and D54, in one embodiment, h is an integer 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in another embodiment, h is an integer 1; in yet another embodiment, h is an integer 2; in yet another embodiment, h is an integer 3; in yet another embodiment, h is an integer 4; in yet another embodiment, h is an integer 5; in yet another embodiment, h is an integer 6; in yet another embodiment, h is an integer 7; in yet another embodiment, h is an integer 8; in yet another embodiment, h is an integer 9; in yet another embodiment, h is an integer 10; in yet another embodiment, h is an integer 11; in yet another embodiment, h is an integer 12; in yet another embodiment, h is an integer 13; in yet another embodiment, h is an integer 14; in yet another embodiment, h is an integer 15; in yet another embodiment, h is an integer 16; in yet another embodiment, h is an integer 17; in yet another embodiment, h is an integer 18; in yet another embodiment, h is an integer 19; in yet another embodiment, h is an integer 20; in yet another embodiment, h is an integer 21; in yet another embodiment, h is an integer 22; in yet another embodiment, h is an integer 23; in yet another embodiment, h is an integer 24; and in yet another embodiment, h is an integer 25.

[0443] In any of Formula A4, A10, A16, A22, A28, A34, A40, A46, A52, B4, B10, B16, B22, B28, B34, B40, B46, B52, C4, C10, C16, C22, C28, C34, C40, C46, C52, D4, D10, D16, D22, D28, D34, D40, D46, and D52, in one embodiment, i is an integer 5, 7, 9, 11, or 13; in another embodiment, i is an integer 1; in yet another embodiment, i is an integer 2; in yet another embodiment, i is an integer 3; in yet another embodiment, i is an integer 4; in yet another embodiment, i is an integer 5; in yet another embodiment, i is an integer 6; in yet another embodiment, i is an integer 7; in yet another embodiment, i is an integer 8; in yet another embodiment, i is an integer 9; in yet another embodiment, i is an integer 10; in yet another embodiment, i is an integer 11; in yet another embodiment, i is an integer 12; in yet another embodiment, i is an integer 13; in yet another embodiment, i is an integer 14; and in yet another embodiment, i is an integer 15.

[0444] In any of Formula A4, A10, A16, A22, A28, A34, A40, A46, A52, B4, B10, B16, B22, B28, B34, B40, B46, B52, C4, C10, C16, C22, C28, C34, C40, C46, C52, D4, D10, D16, D22, D28, D34, D40, D46, and D52, in one embodiment, j is an integer 5, 7, 9, 11, or 13; in another embodiment, j is an integer 1; in yet another embodiment, j is an integer 2; in yet another embodiment, j is an integer 3; in yet another embodiment, j is an integer 4; in yet another embodiment, j is an integer 5; in yet another embodiment, j is an integer 6; in yet another embodiment, j is an integer 7; in yet another embodiment, j is an integer 8; in yet another embodiment, j is an integer 9; in yet another embodiment, j is an integer 10; in yet another embodiment, j is an integer 11; in yet another embodiment, j is an integer 12; in yet another embodiment, j is an integer 13; in yet another embodiment, j is an integer 14; and in yet another embodiment, j is an integer 15.

[0445] In any of Formulas A31-A36, B31-B36, C31-C36, and D31-D36, in one embodiment, k is an integer of 1 ; in another embodiment, k is an integer of 2; in yet another embodiment, k is an integer of 3; in yet another embodiment, k is an integer of 4; and in yet another embodiment, k is an integer of 5.

[0446] In any of Formulas A31-A36, B31-B36, C31-C36, and D31-D36, in one embodiment, m is an integer of 1 ; in another embodiment, m is an integer of 2; in yet another embodiment, m is an integer of 3; in yet another embodiment, m is an integer of 4; and in yet another embodiment, m is an integer of 5.

[0447] In any of Formulas A43-A48, B43-B48, C43-C48, and D43-D48, in one embodiment, n is an integer of 1 ; in another embodiment, n is an integer of 2; in yet another embodiment, n is an integer of 3; in yet another embodiment, n is an integer of 4; in yet another embodiment, n is an integer of 5; and in yet another embodiment, n is an integer of 6.

[0448] In the chemical formulas described herein including Formulas (I)-(VII), A1-A54, B1-B54, C1-C54, and D1-D54, the groups R 1 , R 2 , R 3 , R 4 , A, E, L 1 , L 2 , L 3 , L 4 , U, X, Z, a, b, c, and d are further defined in the embodiments described herein. All combinations of these embodiments of the present application with respect to the groups in these chemical formulas described herein including R 1 , R 2 , R 3 , R 4 , A, E, L 1 , L 2 , L 3 , L 4 , U, X, Z, a, b, c, d, e, f, g, h, i, j, k, m, n, p, s, and t are within the scope of the present disclosure.

[0449] In another embodiment, the present application provides a compound of Formula E-1-0001 to E-1-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0450] In another embodiment, the present application provides a compound of Formula E-2-0001 to E-2-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0451] In another embodiment, the present application provides a compound of Formula E-3-0001 to E-3-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0452] In another embodiment, the present application provides a compound of Formula E-4-0001 to E-4-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

[0453] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; or (iii) -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -OR a , -NR b R c, -NR a C(O)NR b R c , -NR a C(NR d )NR b R c , -NR a C(S)NR b R c , =NOR a , -SR a , or -NR a S(O)2R d wherein each R a , R b , R c and R d is as defined herein. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxy-ethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hmethyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxy-butyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0454] In some embodiments, R 1 is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is 1-(dimethylamino)-2-nitroethenyl. In some embodiments, R 1 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl. In some embodiments, R 1 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is 4-dimethylaminophenyl. In some embodiments, R 1 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R1 is 4-methoxybenzyl. In some embodiments, R 1 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is imidazolyl, thiazolyl, or pyridyl, each optionally substituted with one or more substituents Q. In some embodiments, R 1 is imidazol-2-yl, thiazol-2-yl, pyrid-2-yl, or pyrid-3-yl. In some embodiments, R 1 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

[0455] In some embodiments, R 1 is -C(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 1 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a and R a is as defined herein. In some embodiments, R 1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, R 1 is -C(O)OR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -C(O)OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 1 is methoxycarbonyl. In some embodiments, R 1 is -C(O)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1is methylaminocarbonyl, or dimethylaminocarbonyl. In some embodiments, R 1 is -C(O)SR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -C(NR 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 1 is formamidinyl. In some embodiments, R 1 is -C(NCN)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1 is N'-cyano-N,N-dimethylformamidinyl. In some embodiments, R 1 is -C(NOR 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 1 is N'-methoxy-N,N-dimethylformamidinyl. In some embodiments, R 1 is -C(NS(O2)R 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 1 is N'-methylsulfonyl-N,N-dimethylformamidinyl. In some embodiments, R 1 is -C(S)R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -C(S)OR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -C(S)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1is -OR 1 is -OR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is hydroxy or methoxy. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is -OC(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OC(O)OR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OC(O)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1 is -OC(O)SR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OC(NR 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 1 is -OC(S)R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OC(S)OR 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OC(S)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1 is -OS(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OS(O)2R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -OS(O)NR 1b R1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1 is -OS(O)2NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1 is -NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 1 is -NR 1a C(O)R 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 1 is -NR 1a C(O)OR 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 1 is -NR 1a C(O)NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 1 is -NR 1a C(O)SR 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 1 is -NR 1a C(NR 1d )NR 1b R 1c wherein R 1a , R 1b , R 1c , and R 1d are each as defined herein. In some embodiments, R 1 is -NR 1a C(S)R 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 1 is -NR 1a C(S)OR 1d wherein R1a and R 1d each as defined herein. In some embodiments, R 1 is -NR 1a C(S)NR 1b R 1c wherein R 1a , R 1b and R 1c each as defined herein. In some embodiments, R 1 is -NR 1a S(O)R 1d wherein R 1a and R 1d each as defined herein. In some embodiments, R 1 is -NR 1a S(O)2R 1d wherein R 1a and R 1d each as defined herein. In some embodiments, R 1 is -NR 1a S(O)NR 1b R 1c wherein R 1a , R 1b and R 1c each as defined herein. In some embodiments, R 1 is -NR 1a S(O)2NR 1b R 1c wherein R 1a , R 1b and R 1c each as defined herein. In some embodiments, R 1 is -S(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is -S(O)2R 1a wherein R 1a is as defined herein. In some embodiments, R 1 is methylsulfonyl. In some embodiments, R 1 is -S(O)NR 1b R 1c wherein R 1b and R 1c each as defined herein. In some embodiments, R 1 is -S(O)2NR 1b R 1c wherein R 1b and R 1c each as defined herein.

[0456] In some implementation schemes, R 2 It is hydrogen. In some implementations, R 2 C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 2 C 1-6 Alkyl group, optionally substituted with one, two, or three substituents Q, each Q being independently: (i) cyano, halogen, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclic groups, each optionally substituent Q. a Substitution; or (iii)-C(O)OR a -C(O)NR b R c -C(O)SR a -OR a -NR b R c -NR a C(O)NR b R c -NR a C(NR d )NR b R c -NR a C(S)NR b R c =NOR a -SR a , or -NR a S(O)2R d , where each R a R b R c and R d As defined herein. In some implementations, R 2 The group is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each Q being independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxy, hydroxy-ethoxy, dimethylamino, acetamyl, methylurea, dimethylurea, methylthiourea, 3,3-dimethylthiourea, guanidinyl, methoxy-imino, mercapto, or methylsulfonamide. In some embodiments, R... 2methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with one, two, or three substituents Q, each Q is independently: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethyl-ureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In some embodiments, R 2 methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxy-butyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0457] In some embodiments, R 2 C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 1-(dimethylamino)-2-nitroethenyl. In some embodiments, R 2 C 2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 2is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-l-cyclobutenyl. In some embodiments, R 2 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is 4-dimethylaminophenyl. In some embodiments, R 2 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is 4-methoxybenzyl. In some embodiments, R 2 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R 2 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In some embodiments, R 2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl. In some embodiments, R 2 is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

[0458] In some embodiments, R 2 is -C(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 2 is -C(O)-C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a and R a is as defined herein. In some embodiments, R 2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, R 2 is -C(O)OR 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -C(O)OC1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 2 is methoxycarbonyl. In some embodiments, R 2 is -C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is methylaminocarbonyl, or dimethylaminocarbonyl. In some embodiments, R 2 is -C(O)SR 1a , wherein R 1a is as defined herein. In some embodiments, R 2 is -C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 2 is formamidinyl. In some embodiments, R 2 is -C(NCN)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is N'-cyano-N,N-dimethylformamidinyl. In some embodiments, R 2 is -C(NOR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 2 is N'-methoxy-N,N-dimethylformamidinyl. In some embodiments, R 2 is -C(NS(O2)R 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 2 is N'-methylsulfonyl-N,N-dimethylformamidinyl. In some embodiments, R 2 is -C(S)R 1a , wherein R 1a is as defined herein. In some embodiments, R2 -C(S)OR 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -C(S)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is methylaminosulfinyl or dimethylaminosulfinyl. In some embodiments, R 2 is -OR 1a wherein R 1a is as defined herein. In some embodiments, R 2 is hydroxy or methoxy. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is -OC(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OC(O)OR 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OC(O)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is -OC(O)SR 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OC(NR 1a )NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 2 is -OC(S)R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OC(S)OR 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OC(S)NR 1b R 1c wherein R 1b and R 1ceach as defined herein. In some embodiments, R 2 is -OS(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OS(O)2R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -OS(O)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is -OS(O)2NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is -NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 is -NR 1a C(O)R 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 2 is -NR 1a C(O)OR 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 2 is -NR 1a C(O)NR 1b R 1c wherein R 1a , R 1b , and R 1c are each as defined herein. In some embodiments, R 2 is -NR 1a C(O)SR 1d wherein R 1a and R 1d are each as defined herein. In some embodiments, R 2 is -NR 1a C(NR 1d )NR 1b R 1c wherein R 1a , R 1b , R1c and R 1d each as defined herein. In some embodiments, R 2 is -NR 1a C(S)R 1d wherein R 1a and R 1d each as defined herein. In some embodiments, R 2 is -NR 1a C(S)OR 1d wherein R 1a and R 1d each as defined herein. In some embodiments, R 2 is -NR 1a C(S)NR 1b R 1c wherein R 1a , R 1b , and R 1c each as defined herein. In some embodiments, R 2 is -NR 1a S(O)R 1d wherein R 1a and R 1d each as defined herein. In some embodiments, R 2 is -NR 1a S(O)2R 1d wherein R 1a and R 1d each as defined herein. In some embodiments, R 2 is -NR 1a S(O)NR 1b R 1c wherein R 1a , R 1b , and R 1c each as defined herein. In some embodiments, R 2 is -NR 1a S(O)2NR 1b R 1c wherein R 1a , R 1b , and R 1c each as defined herein. In some embodiments, R 2 is -S(O)R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is -S(O)2R 1a wherein R 1a is as defined herein. In some embodiments, R 2 is methylsulfonyl. In some embodiments, R2 -S(O)NR 1b R 1c wherein R 1b and R 1c are each as defined herein. In some embodiments, R 2 -S(O)2NR 1b R 1c wherein R 1b and R 1c are each as defined herein.

[0459] In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a 5-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a 6-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a 1,2,3-triazol-1-yl, pyridin-1-ium, or pyrimidin-1-yl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-ium, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl group.

[0460] In some embodiments, R 1 and R 2 together with the N atom to which they are attached form a bicyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2Together with the N atoms to which they are attached, they form 5,5-, 5,6-, or 6,6-fused heteroaryl groups, each optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atoms to which they are attached, they form 5,5-fused heteroaryl groups, which are optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atoms to which they are attached, they form 5,6-fused heteroaryl groups, which are optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atoms to which they are attached, they form 6,6-fused heteroaryl groups, which are optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a purine-9- group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atoms to which they are attached, they form 6-aminopurine-9-yl or 2-amino-6-oxo-1,9-dihydropurine-9-yl.

[0461] In some implementation schemes, R 1 and R 2 Together with the N atoms they are attached to, they form heterocyclic groups, which are optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atoms they are attached to, they form a monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form 3-, 4-, 5-, 6-, or 7-membered heterocyclic groups, each optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 3-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 4-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 5-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2Together with the N atom to which they are attached, they form a 6-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 7-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form azircyclic propane-1-yl, azircyclic butane-1-yl, pyrrolidine-1-yl, oxazolidinone-3-yl, imidazolidine-1-yl, piperidin-1-yl, azircyclic heptane-1-yl, morpholino-4-yl, piperazinyl-1-yl, or isoindolinyl-2-yl, each optionally substituted by one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atoms to which they are attached, they form 2-methylaziridin-1-yl, aziridine-1-yl, pyrrolidine-1-yl, 2-oxopyrrolidine-1-yl, 2,5-dioxopyrrolidine-1-yl, 2-oxooxazolidine-3-yl, 2,5-dioxoimidazolidine-1-yl, piperidin-1-yl, aziridine-heptane-1-yl, morpholino-4-yl, 3,5-dioxomorpholino-4-yl, piperazinyl-1-yl, 4-methylpiperazinyl-1-yl, 4-(4-methoxybenzyl)piperazinyl-1-yl, 4-(2-hydroxyethyl)piperazinyl-1-yl, or 1,3-dioxoisoindololinyl-2-yl.

[0462] In some implementation schemes, R 3 C 1-30 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 3 C 1-25 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 3 C 1-20 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 3 It is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, tetradecyl, or pentadecyl, each optionally substituted by one or more substituents Q. In some embodiments, R 3prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8- trifluoromethoxy-carbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2- methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0463] In some embodiments, R 3 is C 1-30 heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is 2-(dodecan-1-yl disulfanyl)ethyl. In some embodiments, R 3 is C 1-30 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 1-25 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 1-20 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosanenyl, heneicosanen, docosanenyl, tricosanen, tetracosanenyl, or pentacosanenyl, each optionally substituted with one or more substituents Q. In some embodiments, R 3(Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3- octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoro-nona-3-en-1-yl, (Z)-5,5-difluoronona-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8- heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

[0464] In some embodiments, R 3 is C 2-30 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is cyclohexyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is 4-pentylcyclohexyl, or 4-cyclohexylcyclohexyl. In some embodiments, R 3 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is phenyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is 3-pentyl-phenyl, 4-pentylphenyl, or 3,4-dipentylphenyl. In some embodiments, R 3 is C 7-30 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 3 is heterocyclyl, optionally substituted with one or more substituents Q.

[0465] In some embodiments, R 4 is C 1-30alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 1-25 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 1-20 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each optionally substituted with one or more substituents Q. In some embodiments, R 4 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxy- carbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methylnonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0466] In some embodiments, R 4 is C 1-30 heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is 2-(dodecan-1-yl disulfanyl)ethyl. In some embodiments, R 4 is C 1-30 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 1-25 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 1-20 alkenyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, or pentacosenyl, each optionally substituted with one or more substituents Q. In some embodiments, R4 (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3- octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoro-nona-3-en-1-yl, (Z)-5,5-difluoronona-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8- heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

[0467] In some embodiments, R 4 is C 2-30 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is cyclohexyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is 4-pentylcyclohexyl, or 4-cyclohexylcyclohexyl. In some embodiments, R 4 is C 6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is phenyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is 3-pentyl-phenyl, 4-pentylphenyl, or 3,4-dipentylphenyl. In some embodiments, R 4 is C 7-30 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 4 is heterocyclyl, optionally substituted with one or more substituents Q.

[0468] In some embodiments, A is -0-. In some embodiments, A is -N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, A is -N(H)-.

[0469] In some embodiments, E is -UC(O)N(R 1a )-, wherein R 1a and U are each as defined herein. In some embodiments, E is -OC(O)N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, E is -OC(O)N(H)-. In some embodiments, E is -N(R 1b )C(O)N(R 1a )-, wherein R 1a and R 1b are each as defined herein. In some embodiments, E is -N(H)C(O)N(H)-.

[0470] In some embodiments, L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q. In some embodiments, L 1 is -(CR 2a R 2b ) a -, wherein each R 2a , R 2b and a are as defined herein. In some embodiments, L 1 is -(CH2) a -, wherein a is as defined herein. In some embodiments, L 1 is -(CH2)-. In some embodiments, L 1 is -(CH2)2-. In some embodiments, L 1 is -(CH2)3-. In some embodiments, L 1 is -(CH2)4-. In some embodiments, L 1 is -(CH2)5-. In some embodiments, L 1 is -(CH2)6-.

[0471] In some embodiments, L 2 is C 1-6 alkylene, optionally substituted with one or more substituents Q. In some embodiments, L 2 is -(CR 2a R 2b ) b -, wherein each R 2a, R 2b and b are as defined herein. In some embodiments, L 2 is -(CH2) b - wherein b is as defined herein. In some embodiments, L 2 is -(CH2)-. In some embodiments, L 2 is -(CH2)2-. In some embodiments, L 2 is -(CH2)3-. In some embodiments, L 2 is -(CH2)4-. In some embodiments, L 2 is -(CH2)5-. In some embodiments, L 2 is -(CH2)6-.

[0472] In some embodiments, L 3 is C 1-10 alkylene optionally substituted with one or more substituents Q. In some embodiments, L 3 is -(CR 2a R 2b ) c - wherein each R 2a , R 2b and c are as defined herein. In some embodiments, L 3 is -(CH2) c - and c is an integer 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, L 3 is -(CH2)2-. In some embodiments, L 3 is -(CH2)3-. In some embodiments, L 3 is -(CH2)4-. In some embodiments, L 3 is -(CH2)5-. In some embodiments, L 3 is -(CH2)6-. In some embodiments, L 3 is C 1-10 heteroalkylene optionally substituted with one or more substituents Q. In some embodiments, L 3 is C 2-10 alkenylene optionally substituted with one or more substituents Q. In some embodiments, L 3 is C 2-10 alkynylene optionally substituted with one or more substituents Q.

[0473] In some embodiments, L 4 is C 1-10 alkylene optionally substituted with one or more substituents Q. In some embodiments, L 4 is -(CR2a R 2b ) d - wherein each R 2a , R 2b and d are as defined herein. In some embodiments, L 4 is -(CH2) d - and d is an integer 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, L 4 is -(CH2)2-. In some embodiments, L 4 is -(CH2)3-. In some embodiments, L 4 is -(CH2)4-. In some embodiments, L 4 is -(CH2)5-. In some embodiments, L 4 is -(CH2)6-. In some embodiments, L 4 is C 1-10 heteroalkylene, optionally substituted with one or more substituents Q. In some embodiments, L 4 is C 2-10 alkenylene, optionally substituted with one or more substituents Q. In some embodiments, L 4 is C 2-10 alkynylene, optionally substituted with one or more substituents Q.

[0474] In some embodiments, U is -O-. In some embodiments, U is -N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, U is -N(H)-.

[0475] In some embodiments, X is a bond. In some embodiments, X is -C(O)O-. In some embodiments, X is -C(O)N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, X is -C(O)N(H)-. In some embodiments, X is -C(O)S-. In some embodiments, X is -O-. In some embodiments, X is -OC(O)O-. In some embodiments, X is -OC(O)N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, X is -OC(O)N(H)-. In some embodiments, X is -OC(O)S-. In some embodiments, X is -N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, X is -N(H)-. In some embodiments, X is -NR 1aC(O)N(R 1b )-, wherein R 1a and R 1b are each as defined herein. In some embodiments, X is -NHC(O)N(H)-. In some embodiments, X is -S-. In some embodiments, X is -S-S-.

[0476] In some embodiments, Z is a bond. In some embodiments, Z is -C(O)O-. In some embodiments, Z is -C(O)N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, Z is -C(O)N(H)-. In some embodiments, Z is -C(O)S-. In some embodiments, Z is -O-. In some embodiments, Z is -OC(O)O-. In some embodiments, Z is -OC(O)N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, Z is -OC(O)N(H)-. In some embodiments, Z is -OC(O)S-. In some embodiments, Z is -N(R 1a )-, wherein R 1a is as defined herein. In some embodiments, Z is -N(H)-. In some embodiments, Z is -NR 1a C(O)N(R 1b )-, wherein R 1a and R 1b are each as defined herein. In some embodiments, Z is -NHC(O)N(H)-. In some embodiments, Z is -S-. In some embodiments, Z is -S-S-.

[0477] In some embodiments, a is an integer of 1. In some embodiments, a is an integer of 2. In some embodiments, a is an integer of 3. In some embodiments, a is an integer of 4. In some embodiments, a is an integer of 5. In some embodiments, a is an integer of 6.

[0478] In some embodiments, b is an integer of 1. In some embodiments, b is an integer of 2. In some embodiments, b is an integer of 3. In some embodiments, b is an integer of 4. In some embodiments, b is an integer of 5. In some embodiments, b is an integer of 6.

[0479] In some embodiments, c is an integer 1. In some embodiments, c is an integer 2. In some embodiments, c is an integer 3. In some embodiments, c is an integer 4. In some embodiments, c is an integer 5. In some embodiments, c is an integer 6. In some embodiments, c is an integer 7. In some embodiments, c is an integer 8. In some embodiments, c is an integer 9. In some embodiments, c is an integer 10.

[0480] In some embodiments, d is an integer 1. In some embodiments, d is an integer 2. In some embodiments, d is an integer 3. In some embodiments, d is an integer 4. In some embodiments, d is an integer 5. In some embodiments, d is an integer 6. In some embodiments, d is an integer 7. In some embodiments, d is an integer 8. In some embodiments, d is an integer 9. In some embodiments, d is an integer 10.

[0481] In one embodiment, provided herein is the following compound: 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyl-bis(hexanoate) 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyl-bis(hexanoate) 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)-carbamoyl)oxy)heptane-1,7-diyl-bis(hexanoate) 3; 4-(3-(2-((2-(dimethylamino)ethyl)amino)ethyl)-ureido)heptane-1,7-diyl-bis(hexanoate) 4; or 7-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)tridecane-1,13-diyl-bis(2-hexyldecanoate) 5; or a mixture of two or more tautomers thereof, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0482] In some embodiments, the compounds provided herein are isolated or purified. In some embodiments, the compounds provided herein have a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.

[0483] The compounds provided herein are intended to include all possible stereoisomers unless a particular stereochemistry is specified. In cases where the compound contains an alkenyl group, the compound can exist as either of two geometrical isomers (or Z / E isomers). Where structural isomers can interconvert, the compound can exist as a single tautomer or a mixture of tautomers. This can take the form of prototropic tautomerism in compounds containing, for example, imino, keto, or oxime groups; or so-called valence tautomerism in compounds containing aromatic moieties. Thus, a single compound can exhibit more than one type of isomerism.

[0484] The compounds provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or a stereoisomeric mixture, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Thus, one of ordinary skill in the art will recognize that, for a compound that undergoes epimerization in vivo, administration of the (R) form of the compound is equivalent to administration of the (S) form of the compound. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor, by asymmetric synthesis from a non-racemic starting material, or resolution of a racemic mixture, for example, by chiral chromatography, recrystallization, cleavage of diastereomeric salts, or derivatization into diastereomeric adducts followed by separation.

[0485] When the compounds provided herein contain acidic or basic moieties, they can also be provided as pharmaceutically acceptable salts. See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0486] Suitable acids for preparing pharmaceutically acceptable salts of the compounds of the present application include, but are not limited to: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galacturonic acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino- salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0487] Suitable bases for preparing pharmaceutically acceptable salts of the compounds of the present application include, but are not...

Claims

1. A compound, which is: or an enantiomer, a mixture of enantiomers, a diastereomer, 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. A lipid nanoparticle comprising: a compound of claim 1, or an enantiomer, a mixture of enantiomers, a diastereomer, 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.

3. A pharmaceutical composition comprising: a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a nucleic acid; (ii) a compound of claim 1, or an enantiomer, a mixture of enantiomers, a diastereomer, 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; (iii) a phospholipid; and (iv) cholesterol.

4. The pharmaceutical composition of claim 3, further comprising a conjugated lipid.

5. The pharmaceutical composition of claim 4, wherein the conjugated lipid comprises a polyethylene glycol-conjugated lipid.

6. The pharmaceutical composition of any one of claims 3-5, wherein the nucleic acid is mRNA.

7. The pharmaceutical composition of any one of claims 3-5, wherein the nucleic acid is circular RNA.

8. The pharmaceutical composition of any one of claims 3-5, wherein the pharmaceutical composition preferentially distributes into a target organ of a subject in need thereof.

9. The pharmaceutical composition of claim 8, wherein the target organ is an eye, heart, lung, kidney, liver, or spleen of a subject.

10. The pharmaceutical composition of any one of claims 3-5, wherein the pharmaceutical composition preferentially partitions into a liver cell.

11. The pharmaceutical composition of claim 10, wherein the liver cell is a hepatocyte.

12. The pharmaceutical composition of any one of claims 3-5, wherein the pharmaceutical composition preferentially partitions into a spleen cell.

13. The pharmaceutical composition of claim 12, wherein the spleen cell is a splenocyte.

14. The pharmaceutical composition of any one of claims 3-5, wherein the nucleic acid encodes a biologically active protein or enzyme.

15. The pharmaceutical composition of claim 14, wherein the biologically active protein or enzyme is produced or systemically secreted from a liver cell.

16. The pharmaceutical composition of claim 14, wherein the biologically active protein or enzyme is produced or systemically secreted from a cell of a lung, heart, or eye, or central nervous system.

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