Lipid compounds, lipid nanoparticles, and pharmaceutical compositions
Patent Information
- Application Number
- EP2024774213
- Authority / Receiving Office
- EP · EP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-03-22
- Filing Date
- 2024-03-21
- Publication Date
- 2026-01-28
Smart Images
Figure CN2024083026_26092024_PF_FP
Abstract
Description
LIPID COMPOUNDS, LIPID NANOPARTICLES, AND PHARMACEUTICAL COMPOSITIONS1. CROSS REFERENCE TO RELATED APPLICATIONSThe application claims the benefit of the priority of International Application No. PCT / CN2023 / 083176, filed on March 22, 2023; the disclosure of which is incorporated hererin by reference in its entirety.2. REFERENCE TO A SEQUENCE LISTINGThis application incorporates herein by reference a Sequence Listing submitted with this application as an XML file entitled “TFH00977PCT-Sequence Listing. xml” created on March 21, 2024 and having a size of 75, 013 bytes.3. FIELDProvided herein are lipid compounds, and lipid nanoparticles and pharmaceutical compositions thereof.4. BACKGROUNDLipid nanoparticles (LNPs) are a promising delivery vehicle for a variety of therapeutic agents, including small molecule drugs, proteins, and nucleic acids. Akinc et al., Nat. Nanotechnol. 2019, 14, 1084-87; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. The two FDA-approved COVID-19 mRNA vaccines, mRNA-1273 and BNT162b, employ lipid nanoparticles for antigen mRNA delivery. 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 deliver a highly charged nucleic acid as a therapeutic agent efficiently. Weng et al., Biotechnol. Adv. 2020, 40, 107534; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. To achieve therapeutic effects, for example, a highly charged nucleic acid has to reach its intracellular target. Torres-Canegas et al., Pharmaceutics 2021, 13, 428; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. Therefore, there is a need for a lipid compound for the efficient delivery of a therapeutic agent.5. SUMMARY OF THE DISCLOSUREProvided herein is 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:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;E1 and E2 are each independently -C (O) -or -C (O) O-;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 and M2 are each independently a linker;U1 and U2 are each independently -O-or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.Also 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:R1, R2, R5, and R6 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl; or R5 and R6 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is -O-or -N (R1a) -;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;X and Z are each independently a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.Additionally 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, or hydrate thereof; wherein:R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 is a linker;U1 is -O-or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.Furthermore, provided herein is a compound 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; wherein:R1, R2, and R7 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is a bond, -O-, or -N (R1a) -;L1 is independently C1-6 alkylene or C1-6 heteroalkylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.Provided herein is a compound 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; wherein:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.Provided herein is a lipid nanoparticle comprising a compound of any one of Formulae (I) to (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.Provided herein is a lipid nanoparticle comprising (i) a nucleic acid and (ii) a compound of any one of Formulae (I) to (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.Provided herein is a pharmaceutical composition comprising a lipid nanoparticle that comprises (i) a nucleic acid and (ii) a compound of any one of Formulae (I) to (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.6. ILLUSTRATIVE EMBODIMENTSA compound has the structure of Formula (I) , (II) , (III) , (IV) , or (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; wherein:each R1, R2, R5, R6, and R7 is independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;each R3 and R4 is independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;each A is independently -O-or -N (R1a) -;each E1 and E2 is independently -C (O) -or -C (O) O-;each L1 and L2 is independently C1-6 alkylene or C1-6 heteroalkylene;each L3 and L4 is independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;each M1 and M2 is independently a linker;each U1 and U2 is independently -O-or -N (R1b) -;each X and Z is independently a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.The compound of paragraph
[0013] has the structure 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:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;E1 and E2 are each independently -C (O) -or -C (O) O-;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 and M2 are each independently a linker;U1 and U2 are each independently -O-or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In the compound of paragraph
[0013] or
[0014] , M1 is a cleavable linker.In the compound of paragraph
[0013] or
[0014] , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-.In the compound of any one of paragraphs
[0013] to
[0014] , M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-.In the compound of any one of paragraphs
[0013] to
[0015] , M1 is -S-S-.In the compound of any one of paragraphs
[0013] to
[0016] , M2 is a cleavable linker.In the compound of any one of paragraphs
[0013] to
[0016] , M2 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-.In the compound of any one of paragraphs
[0013] to
[0018] , M2 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-.In the compound of any one of paragraphs
[0013] to
[0019] , M2 is -S-S-.In the compound of any one of paragraphs
[0013] to
[0020] , E1 is -C (O) -.In the compound of any one of paragraphs
[0013] to
[0020] , E1 is -C (O) O-.In the compound of any one of paragraphs
[0013] to
[0022] , E2 is -C (O) -.In the compound of any one of paragraphs
[0013] to
[0022] , E2 is -C (O) O-.In the compound of any one of paragraphs
[0013] to
[0024] , U1 is -O-.In the compound of any one of paragraphs
[0013] to
[0024] , U1 is -N (R1b) -.In the compound of any one of paragraphs
[0013] to
[0024] and
[0026] , U1 is -N (H) -.In the compound of any one of paragraphs
[0013] to
[0027] , U2 is -O-.In the compound of any one of paragraphs
[0013] to
[0027] , U2 is -N (R1b) -.In the compound of any one of paragraphs
[0013] to
[0027] and
[0029] , U2 is -N (H) -.The compound of paragraph
[0013] or
[0012] has the structure of Formula (Ib) :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.The compound of paragraph
[0013] or
[0012] has the structure of Formula (Ic) :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.The compound of paragraph
[0013] has the structure 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:R1, R2, R5, and R6 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl; or R5 and R6 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is -O-or -N (R1a) -;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;X and Z are each independently a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In the compound of paragraph
[0013] or
[0033] , A is -O-.In the compound of paragraph
[0013] or
[0033] , A is -N (R1b) -.In the compound of paragraph
[0013] ,
[0033] , or
[0035] , A is -N (H) -.The compound of paragraph
[0013] has the structure 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, or hydrate thereof; wherein:R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 is a linker;U1 is -O-or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In the compound of paragraph
[0037] , M1 is a cleavable linker.In the compound of paragraph
[0037] , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-.In the compound of any one of paragraphs
[0037] to
[0039] , M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-.In the compound of any one of paragraphs
[0037] to
[0040] , M1 is -S-S-.In the compound of any one of paragraphs
[0037] to
[0041] , U1 is -O-.In the compound of any one of paragraphs
[0037] to
[0041] , U1 is -N (R1b) -.In the compound of any one of paragraphs
[0037] to
[0041] and
[0043] , U1 is -N (H) -.The compound of paragraph
[0013] or
[0037] has the structure of Formula (IIIb) :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.The compound of paragraph
[0013] or
[0037] has the structure of Formula (IIIc) :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.The compound of paragraph
[0013] 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; wherein:R1, R2, and R7 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is a bond, -O-, or -N (R1a) -;L1 is independently C1-6 alkylene or C1-6 heteroalkylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In the compound of paragraph
[0047] , A is -O-.In the compound of paragraph
[0047] , A is -N (R1b) -.In the compound of paragraph
[0047] or
[0049] , A is -N (H) -.The compound of paragraph
[0013] 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; wherein:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In the compound of any one of paragraphs
[0013] to
[0051] , L1 is C1-6 alkylene, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0052] , L1 is - (CR2aR2b) a-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5, or 6.In the compound of any one of paragraphs
[0013] to
[0053] , L1 is - (CH2) a-and a is an integer of 1, 2, 3, 4, 5, or 6.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0054] , L2 is C1-6 alkylene, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0055] , L2 is - (CR2aR2b) b-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and b is an integer of 1, 2, 3, 4, 5, or 6.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0056] , L2 is - (CH2) b-and b is an integer of 1, 2, 3, 4, 5, or 6.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0057] , L3 is C1-10 alkylene, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0058] , L3 is - (CR2aR2b) c-or -CR2aR2b (CR2aR2b) c-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0059] , wherein L3 is - (CH2) c-or -C (CH3) 2 (CH2) c-; and each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0060] , L4 is C1-10 alkylene, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0061] , L4 is - (CR2aR2b) d-or -CR2aR2b (CR2aR2b) d-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.In the compound of any one of paragraphs
[0013] to
[0046] and
[0051] to
[0062] , wherein L4 is - (CH2) d-or -C (CH3) 2 (CH2) d-; and each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0014] has the structure of Formula (If) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0014] has the structure of Formula (Ig) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0033] has the structure of Formula (IIc) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0033] has the structure of Formula (IId) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0037] has the structure of Formula (IIId) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0037] has the structure of Formula (IIIe) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.The compound of paragraph
[0013] or
[0047] has the structure of Formula (IVc) :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 a is an integer of 1, 2, 3, 4, 5, or 6.The compound of paragraph
[0013] or
[0047] has the structure of Formula (IVd) :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 a is an integer of 1, 2, 3, 4, 5, or 6.The compound of paragraph
[0013] or
[0051] has the structure of Formula (Va) :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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.In the compound of any one of paragraphs
[0013] to
[0072] , R1 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.In the compound of any one of paragraphs
[0013] to
[0073] , R1 is C1-6 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0074] , R1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0050] ,
[0052] to,
[0066] to
[0071] , and
[0073] to
[0075] , R2 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0050] ,
[0052] to
[0063] ,
[0066] to
[0071] , and
[0073] to
[0076] , R2 is C1-6 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0050] ,
[0052] to
[0063] ,
[0066] to
[0071] , and
[0073] to
[0077] , R2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In the compound of any one of paragraphs
[0013] to
[0078] , R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0079] , R3 is C1-25 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0080] , R3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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.In the compound of any one of paragraphs
[0013] to
[0079] , R3 is C1-25 alkenyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0079] and
[0082] , R3 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.In the compound of any one of paragraphs
[0013] to
[0079] , R3 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0079] and
[0084] , R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.In the compound of any one of paragraphs
[0013] to
[0079] , wherein R3 is C6-14 aryl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0079] and
[0086] , R3 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.In the compound of any one of paragraphs
[0013] to
[0087] , R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0088] , R4 is C1-25 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0089] , R4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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.In the compound of any one of paragraphs
[0013] to
[0088] , R4 is C1-25 alkenyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0088] and
[0091] , R4 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.In the compound of any one of paragraphs
[0013] to
[0088] , R4 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0088] and
[0093] , R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.In the compound of any one of paragraphs
[0013] to
[0088] , R4 is C6-14 aryl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] to
[0088] and
[0095] , R4 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0036] ,
[0052] to
[0063] ,
[0066] ,
[0067] , and
[0073] to
[0096] , R5 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0036] ,
[0052] to
[0063] ,
[0066] ,
[0067] , and
[0073] to
[0097] , R5 is C1-6 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0036] ,
[0052] to
[0063] ,
[0066] ,
[0067] , and
[0073] to
[0098] , R5 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0036] ,
[0052] to
[0063] ,
[0066] ,
[0067] , and
[0073] to
[0099] , R6 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0036] ,
[0052] to
[0063] ,
[0066] ,
[0067] , and
[0073] to
[0100] , R6 is C1-6 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] ,
[0033] to
[0036] ,
[0052] to
[0063] ,
[0066] ,
[0067] , and
[0073] to
[0101] , R6 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In the compound of any one of paragraphs
[0013] ,
[0047] to
[0050] ,
[0052] to
[0063] ,
[0070] ,
[0071] , and
[0073] to
[0102] , R7 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.In the compound of any one of paragraphs
[0013] ,
[0047] to
[0050] ,
[0052] to
[0063] ,
[0070] ,
[0071] , and
[0073] to
[0103] , R7 is C1-6 alkyl, optionally substituted with one or more substituents Q.In the compound of any one of paragraphs
[0013] ,
[0047] to
[0050] ,
[0052] to
[0063] ,
[0070] ,
[0071] , and
[0073] to
[0104] , R7 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In the compound of any one of paragraphs
[0053] to
[0105] , a is an integer of 1, 2, 3, or 4.In the compound of any one of paragraphs
[0053] to
[0106] , a is an integer of 2.In the compound of any one of paragraphs
[0052] to
[0054] ,
[0056] to
[0069] , and
[0072] to
[0107] , b is an integer of 1, 2, 3, or 4.In the compound of any one of paragraphs
[0052] to
[0054] ,
[0056] to
[0069] , and
[0072] to
[0108] , b is an integer of 1 or 2.The compound of paragraph
[0013] has the structure of: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 e, f, and v is independently an integer of 0, 1, 2, 3, 4, or 5; each g and h is independently an integer of 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 i and j is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; each k, m, q, and r is independently an integer of 0, 1, 2, 3, 4, or 5; and each n is independently an integer of 1, 2, 3, 4, 5, or 6.In the compound of any one of paragraphs
[0052] to
[0057] ,
[0059] to
[0069] , and
[0072] to
[0110] , c is an integer of 1, 2, 3, or 4.In the compound of any one of paragraphs
[0052] to
[0057] ,
[0059] to
[0069] , and
[0072] to
[0111] , c is an integer of 2.In the compound of any one of paragraphs
[0052] to
[0060] ,
[0062] to
[0069] , and
[0072] to
[0112] , d is an integer of 1, 2, 3, or 4.In the compound of any one of paragraphs
[0052] to
[0060] ,
[0062] to
[0069] , and
[0072] to
[0113] , d is an integer of 2.In the compound of any one of paragraphs
[0110] to
[0114] , X is a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-.In the compound of any one of paragraphs
[0110] to
[0115] , 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-.In the compound of any one of paragraphs
[0110] to
[0116] , Z is a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-.In the compound of any one of paragraphs
[0110] to
[0117] , 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-.A compound of:bis (2- (pentyldisulfanyl) ethyl) ( (methylazanediyl) bis (ethane-2, 1-diyl) ) dicarbamate 1;N,N'- ( (methylazanediyl) bis (ethane-2, 1-diyl) ) bis (2, 2-dimethyl-4- (pentyldi-sulfanyl) butanamide) 2;4- (3, 3-bis (2- (dimethylamino) ethyl) ureido) heptane-1, 7-diyl dihexanoate 3;10- (3- (hexanoyloxy) propyl) -2-methyl-9-oxo-5, 6-dithia-2, 8, 10-triazatridecan-13-yl hexanoate 4;2- ( (butoxy (pentyloxy) phosphoryl) amino) -N, N, N-trimethylethan-1-aminium 5;2- ( (butoxy (pentyloxy) phosphoryl) oxy) -N, N, N-trimethylethan-1-aminium 6; or dipentyl ( ( ( (methylazanediyl) bis (ethane-2, 1-diyl) ) bis (dimethylammoniumdiyl) ) -bis (ethane-2, 1-diyl) ) bis (phosphonate) 7;or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.The compound of paragraph
[0013] has the structure of: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.The compound of paragraph
[0013] , wherein R3 is:wherein each p is independently an integer of 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; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.The compound of paragraph
[0013] , wherein R4 is:wherein each p is independently an integer of 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; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.The compound of paragraph
[0013] , wherein R3 and R4 are the same structure.The compound of paragraph
[0013] , wherein R3 is a branched tail.The compound of paragraph
[0013] , wherein R4 is a branched tail.The compound of paragraph
[0013] , wherein R3 is selected from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112 or T-0113.The compound of paragraph
[0013] , wherein R4 is selected from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112 or T-0113.The compound of paragraph
[0013] , wherein the number of carbon atoms in R3 ranges from 5 to 30.The compound of paragraph
[0013] , wherein the number of carbon atoms in R4 ranges from 5 to 30.The compound of paragraph
[0013] , wherein the number of carbon atoms in R3 is selected from: 12, 14, 15, 16, 17, 18, 20, 21, 24, 25 or 28.The compound of paragraph
[0013] , wherein the number of carbon atoms in R4 is selected from: 12, 14, 15, 16, 17, 18, 20, 21, 24, 25 or 28.The compound of paragraph
[0013] , wherein the compound is selected from Group 1.The compound of paragraph
[0013] , wherein the compound is selected from Group 2.The compound of paragraph
[0013] , wherein the compound is selected from Group 3.A lipid nanoparticle comprises a compound of any one of paragraphs
[0013] to
[0136] , 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.A pharmaceutical composition comprises a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) mRNA; (ii) a compound of any one of paragraphs
[0013] to
[0136] , 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; wherein administration of the mRNA to the subject results in a higher expression relative to administration of a circular RNA to the subject.A pharmaceutical composition comprises a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) circular RNA; (ii) a compound of any one of paragraphs
[0013] to
[0136] , 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; wherein administration of the circular RNA to the subject results in a higher expression relative to administration of a mRNA to the subject.The pharmaceutical composition of paragraphs
[0138] and
[0139] further comprises a conjugated lipid.In the pharmaceutical composition of paragraph
[0140] , the conjugated lipid comprises a polyethylene glycol-conjugated lipid.In the pharmaceutical composition of any one of paragraphs
[0138] to
[0141] , the pharmaceutical composition is preferentially distributed into a targeted organ of a subject in need thereof.In the pharmaceutical composition of paragraph
[0142] , the targeted organ is an eye, heart, lung, kidney, liver, or spleen of the subject.In the pharmaceutical composition of any one of paragraphs
[0138] to
[0143] , the pharmaceutical composition is preferentially distributed into a liver cell.In the pharmaceutical composition of paragraph
[0144] , the liver cell is a hepatocyte.In the pharmaceutical composition of any one of paragraphs
[0138] to
[0143] , the pharmaceutical composition is preferentially distributed into a spleen cell.In the pharmaceutical composition of paragraph
[0146] , wherein the spleen cell is a spleenocyte.In the pharmaceutical composition of any one of paragraphs
[0138] to
[0147] , the nucleic acid encodes a bioactive protein or enzyme.In the pharmaceutical composition of paragraph
[0148] , the bioactive protein or enzyme is produced in or systemically excreted from a liver cell.In the pharmaceutical composition of paragraphs
[0148] , the bioactive protein or enzyme is produced in or systemically excreted from a cell of a lung, heart, or ocular, or central nervous system.7. BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 shows in vitro evaluation of a luciferase-coding circular RNA for luciferase expression via LNPs containing different tail types of ionizable lipids. The human embryonic kidney 293T cells (HEK 293T cells) was used in this experiment. The figure was processed by calculating the average of the corresponding expression of LNP. The relative value of the expression of LNPs divided by the average of the expression of Reference 1 for the uniformity of the data. The F-luc luminescence values of each LNPs were normalized to that of ALC-0315-containing LNP and summarized by tail code and the C atom number of each lipid tails respectively.FIG. 2 shows in vitro evaluation of a luciferase-coding circular RNA for luciferase expression via LNPs containing different tail group of ionizable lipids. The human embryonic kidney 293T cells (HEK 293T cells) was used in this experiment. The figure was processed by calculating the average of the corresponding expression of LNP. The relative value of the expression of LNPs divided by the average of the expression of Reference 1 for the uniformity of the data. The Fluc luminescence values of each LNPs were normalized to that of ALC-0315-containing LNP and summarized by tail group.8. DETAILED DESCRIPTION8.1. DEFINITIONSTo facilitate understanding of the disclosure set forth herein, a number of terms are defined below.Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those 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.The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human) , cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.The terms “treat, ” “treating, ” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause (s) of the disorder, disease, or condition itself.The terms “prevent, ” “preventing, ” and “prevention” are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA) , cell, or tissue such that a physiological and / or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in 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 biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA) , cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.The term “pharmaceutically acceptable carrier, ” “pharmaceutically acceptable excipient, ” “physiologically acceptable carrier, ” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating 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 problems or complications, and 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.The term “about” or “approximately” means an acceptable error for a 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 certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means 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.The term “a” or “an, ” as used herein in the specification may mean one or more. The term “a” or “an” as used herein in the claim (s) , when used in conjunction with the term “comprising, ” may mean one or more.The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20) , 1 to 15 (C1-15) , 1 to 10 (C1-10) , or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20) , 3 to 15 (C3-15) , 3 to 10 (C3-10) , or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl. ” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl) , butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl) , pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl) , and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl) .The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally be substituted with one or more substituents Q as described herein. For example, C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30) , 1 to 20 (C1-20) , 1 to 15 (C1-15) , 1 to 10 (C1-10) , or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30) , 3 to 20 (C3-20) , 3 to 15 (C3-15) , 3 to 10 (C3-10) , or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl. ” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1, 1-diyl and ethane-1, 2-diyl) , propanediyl (including all isomeric forms, e.g., propane-1, 1-diyl, propane-1, 2-diyl, and propane-1, 3-diyl) , butanediyl (including all isomeric forms, e.g., butane-1, 1-diyl, butane-1, 2-diyl, butane-1, 3-diyl, and butane-1, 4-diyl) , pentanediyl (including all isomeric forms, e.g., pentane-1, 1-diyl, pentane-1, 2-diyl, pentane-1, 3-diyl, and pentane-1, 5-diyl) , and hexanediyl (including all isomeric forms, e.g., 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) -.The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20) , 1 to 15 (C1-15) , 1 to 10 (C1-10) , or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20) , 3 to 15 (C3-15) , 3 to 10 (C3-10) , or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “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) CH3 and -NHC (O) CH2CH3.The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20) , 1 to 15 (C1-15) , 1 to 10 (C1-10) , or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20) , 3 to 15 (C3-15) , 3 to 10 (C3-10) , or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “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) 10O-, -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-.The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond (s) . The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20) , 2 to 15 (C2-15) , 2 to 10 (C2-10) , or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20) , 3 to 15 (C3-15) , 3 to 10 (C3-10) , or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl) , and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl) .The terms “alkenylene” and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond (s) . The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term “alkenediyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30) , 2 to 20 (C2-20) , 2 to 15 (C2-15) , 2 to 10 (C2-10) , or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30) , 3 to 20 (C3-20) , 3 to 15 (C3-15) , 3 to 10 (C3-10) , or 3 to 6 (C3-6) 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) .The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond (s) . An alkynyl group does not contain a carbon-carbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20) , 2 to 15 (C2-15) , 2 to 10 (C2-10) , or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20) , 4 to 15 (C4-15) , 4 to 10 (C4-10) , or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) , propynyl (including all isomeric forms, e.g., 1-propynyl (-C≡CCH3) and propargyl (-CH2C≡CH) ) , butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl) , pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl) , and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl) .The terms “alkynylene” and “alkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond (s) . An alkynylene group does not contain a carbon-carbon double bond. The alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30) , 2 to 20 (C2-20) , 2 to 15 (C2-15) , 2 to 10 (C2-10) , or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30) , 4 to 20 (C4-20) , 4 to 15 (C4-15) , 4 to 10 (C4-10) , or 4 to 6 (C4-6) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1-propyne-1, 3-diyl and 1-propyne-3, 3-diyl) , butynediyl (including all isomeric forms, e.g., 1-butyne-1, 3-diyl, 1-butyne-1, 4-diyl, and 2-butyne-1, 1-diyl) , pentynediyl (including all isomeric forms, e.g., 1-pentyne-1, 3-diyl, 1-pentyne-1, 4-diyl, and 2-pentyne-1, 1-diyl) , and hexynediyl (including all isomeric forms, e.g., 1-hexyne-1, 3-diyl, 1-hexyne-1, 4-diyl, and 2-hexyne-1, 1-diyl) .The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20) , from 3 to 15 (C3-15) , from 3 to 10 (C3-10) , or from 3 to 7 (C3-7) 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 still 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 [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, decalinyl, and adamantyl.The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and / or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20) , from 6 to 15 (C6-15) , or from 6 to 10 (C6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30) , from 7 to 20 (C7-20) , or from 7 to 16 (C7-16) carbon atoms. Examples 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 certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic 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 certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In one embodiment, the heteroaryl 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 is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo [2, 3-b] pyridinyl, furo [2, 3-c] pyridinyl, furo [3, 2-b] pyridinyl, furo [3, 2-c] pyridinyl, furo [3, 4-b] pyridinyl, and furo [3, 4-c] pyridinyl) , imidazopyridinyl (including all isomeric forms, e.g., imidazo [1, 2-a] pyridinyl, imidazo [4, 5-b] pyridinyl, and imidazo [4, 5-c] pyridinyl) , imidazothiazolyl (including all isomeric forms, e.g., imidazo [2, 1-b] thiazolyl and imidazo [4, 5-d] thiazolyl) , indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo [c] thienyl) , isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, and 1, 8-naphthyridinyl) , 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, pyrrolopyridyl (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, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1, 2, 5] thiadiazolo [3, 4-d] pyrimidinyl and [1, 2, 3] thiadiazolo [4, 5-d] pyrimidinyl) , and thienopyridyl (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 yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1, 5-phenanthrolinyl, 1, 6-phenanthrolinyl, 1, 7-phenanthrolinyl, 1, 9-phenanthrolinyl, and 2, 10-phenanthrolinyl) , phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains 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 a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (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, dihydroisobenzofuranyl, dihydrobenzo [c] thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1, 4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1, 3, 5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.The term “halogen, ” “halide, ” or “halo” refers to fluoro, chloro, bromo, and / or iodo.The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D) , cyano (-CN) , halo, imino (=NH) , nitro (-NO2) , and oxo (=O) ; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted. ”In one embodiment, each Qa is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In certain embodiments, “optically active” and ” enantiomerically active” refer to a collection of molecules, which has 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 certain 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 question. In certain 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 question. In certain 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 in question.In describing an optically active compound, 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, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, 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 of the compound, R and S.The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H) , deuterium (2H) , tritium (3H) , carbon-11 (11C) , carbon-12 (12C) , carbon-13 (13C) , carbon-14 (14C) , nitrogen-13 (13N) , nitrogen-14 (14N) , nitrogen-15 (15N) , oxygen-14 (14O) , oxygen-15 (15O) , oxygen-16 (16O) , oxygen-17 (17O) , oxygen-18 (18O) , fluorine-17 (17F) , fluorine-18 (18F) , phosphorus-31 (31P) , phosphorus-32 (32P) , phosphorus-33 (33P) , sulfur-32 (32S) , sulfur-33 (33S) , sulfur-34 (34S) , sulfur-35 (35S) , sulfur-36 (36S) , chlorine-35 (35Cl) , chlorine-36 (36Cl) , chlorine-37 (37Cl) , bromine-79 (79Br) , bromine-81 (81Br) , iodine-123 (123I) , iodine-125 (125I) , iodine-127 (127I) , iodine-129 (129I) , and iodine-131 (131I) . In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H) , deuterium (2H) , carbon-12 (12C) , carbon-13 (13C) , nitrogen-14 (14N) , nitrogen-15 (15N) , oxygen-16 (16O) , oxygen-17 (17O) , oxygen-18 (18O) , fluorine-17 (17F) , phosphorus-31 (31P) , sulfur-32 (32S) , sulfur-33 (33S) , sulfur-34 (34S) , sulfur-36 (36S) , chlorine-35 (35Cl) , chlorine-37 (37Cl) , bromine-79 (79Br) , bromine-81 (81Br) , and iodine-127 (127I) . In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H) , carbon-11 (11C) , carbon-14 (14C) , nitrogen-13 (13N) , oxygen-14 (14O) , oxygen-15 (15O) , fluorine-18 (18F) , phosphorus-32 (32P) , phosphorus-33 (33P) , sulfur-35 (35S) , chlorine-36 (36Cl) , iodine-123 (123I) , iodine-125 (125I) , iodine-129 (129I) , and iodine-131 (131I) . It will be understood that, in a compound as provided herein, any hydrogen can be 2H, as example, or any carbon can be 13C, as example, or any nitrogen can be 15N, as example, or any oxygen can be 18O, as example, where feasible according to the judgment of one of ordinary skill in the art.The terms “nucleic acid, ” “polynucleotide, ” and “oligonucleotide” are used interchangeably herein and refer to a polymer or oligomer of nucleotides of any length. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides (such as methylated, hydroxymethylated, or glycosylated) , non-natural nucleotides, non-nucleotide building blocks that exhibit similar structure and / or function as natural nucleotides (i.e., “nucleotide analogs” ) , and / or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. The nucleic acids or polynucleotides can be heterogenous or homogenous in composition, can be isolated from naturally occurring sources, or can be artificially or synthetically produced. In addition, the nucleic acids may be DNA or RNA, or a mixture thereof, and can exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states. Nucleic acid structures also include, for instance, a DNA / RNA helix, peptide nucleic acid (PNA) , morpholino nucleic acid (see, e.g., Braasch and Corey, Biochemistry 2002, 4, 4503-10; and US 5, 034, 506) , locked nucleic acid (LNA; see, e.g., Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5633-8) , cyclohexenyl nucleic acid (see, e.g., Wang, Am. Chem. Soc. 2000, 122, 8595-602) , and / or a ribozyme.As used herein, “essentially free, ” in terms of a specified component, is used herein to mean that none of the specified component has been purposefully formulated into a composition and / or is present only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.1%, preferably below 0.05%, and more preferably below 0.01%. Most preferred is a composition in which no amount of the specified component can be detected with a standard analytical method.The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, 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 would not detectably alter the physical, chemical, biological, and / or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein 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 prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula -C (O) O-represents both -C (O) O-and -OC (O) -.The phrase “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” has the same meaning as the phrase “ (i) 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 of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate of 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 of the compound referenced therein. ”The term “mRNA” refers to messenger RNA.The terms “circRNA” , “cRNA” refers to circular RNA.8.2. LIPID COMPOUNDSIn one embodiment, provided herein is 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:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;E1 and E2 are each independently -C (O) -or -C (O) O-;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 and M2 are each independently a linker;U1 and U2 are each independently -O-or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In certain embodiments, in Formula (I) , M1 is a cleavable linker. In certain embodiments, in Formula (I) , M1 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (I) , M1 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (I) , M1 is a linker cleavable by glutathione. In certain embodiments, in Formula (I) , M1 is a linker cleavable by an enzyme. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a protease. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (I) , M1 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a β-glycosidase. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a β-galactosidase. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a β-glucuronidase. In certain embodiments, in Formula (I) , M1 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.In certain embodiments, in Formula (I) , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M1 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M1 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-. In certain embodiments, in Formula (I) , M1 is -S-S-.In certain embodiments, in Formula (I) , M1 isIn certain embodiments, in Formula (I) , M2 is a cleavable linker. In certain embodiments, in Formula (I) , M2 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (I) , M2 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (I) , M2 is a linker cleavable by glutathione. In certain embodiments, in Formula (I) , M2 is a linker cleavable by an enzyme. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a protease. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (I) , M2 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a β-glycosidase. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a β-galactosidase. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a β-glucuronidase. In certain embodiments, in Formula (I) , M2 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.In certain embodiments, in Formula (I) , M2 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M2 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M2 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M2 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (I) , M2 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-. In certain embodiments, in Formula (I) , M2 is -S-S-.In certain embodiments, in Formula (I) , M2 isIn one embodiment, provided herein is a compound of Formula (Ia) :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 R1, R3, R4, E1, E2, L1, L2, L3, L4, U1, and U2 are each as defined herein.In certain embodiments, in Formula (I) or (Ia) , E1 is -C (O) -. In certain embodiments, in Formula (I) or (Ia) , E1 is -C (O) O-. In certain embodiments, in Formula (I) or (Ia) , E2 is -C (O) -. In certain embodiments, in Formula (I) or (Ia) , E2 is -C (O) O-.In certain embodiments, in Formula (I) or (Ia) , U1 is -O-. In certain embodiments, in Formula (I) or (Ia) , U1 is -N (R1b) -, wherein R1b is as defined herein. In certain embodiments, in Formula (I) or (Ia) , U1 is -N (H) -. In certain embodiments, in Formula (I) or (Ia) , U2 is -O-. In certain embodiments, in Formula (I) or (Ia) , U2 is -N (R1b) -, wherein R1b is as defined herein. In certain embodiments, in Formula (I) or (Ia) , U2 is -N (H) -.In another embodiment, provided herein is a compound of Formula (Ib) :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 R1, R3, R4, L1, L2, L3, and L4 are each as defined herein.In yet another embodiment, provided herein is a compound of Formula (Ic) :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 R1, R3, R4, L1, L2, L3, and L4 are each as defined herein.In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L1 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L1 is - (CR2aR2b) a-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl, optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L1 is - (CH2) a-and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L1 is - (CH2) a-and a is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L1 is - (CH2) 2-.In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L2 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L2 is - (CR2aR2b) b-, wherein b is an integer of 1, 2, 3, 4, 5, or 6;and each R2a and R2b is as defined herein. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L2 is - (CH2) b-and b is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L2 is - (CH2) b-and b is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L2 is - (CH2) 2-.In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is - (CR2aR2b) c-, wherein c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R2a and R2b is as defined herein. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is - (CH2) c-and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is - (CR2aR2b) (CR2aR2b) c-, wherein c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R2a and R2b is as defined herein. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is - (C (CH3) 2) (CH2) c-and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is - (CH2) 2-. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L3 is - (CH2) 3-.In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is - (CR2aR2b) d-, wherein d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R2a and R2b is as defined herein. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is - (CH2) d-and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is - (CR2aR2b) (CR2aR2b) d-, wherein d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R2a and R2b is as defined herein. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is - (C (CH3) 2) (CH2) d-and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is - (CH2) 2-. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L4 is - (CH2) 3-.In yet another embodiment, provided herein is a compound of Formula (Id) :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 R1, R3, R4, M1, M2, a, b, c, and d are each as defined herein.In yet another embodiment, provided herein is a compound of Formula (Ie) :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 R1, R3, R4, M1, M2, a, b, c, and d are each as defined herein.In certain embodiments, in Formula (Id) or (Ie) , M1 is a cleavable linker. In certain embodiments, in Formula (Id) or (Ie) , M1 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (Id) or (Ie) , M1 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by glutathione. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by an enzyme. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a protease. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a β-glycosidase. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a β-galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a β-glucuronidase. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M1 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M1 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-. In certain embodiments, in Formula (Id) or (Ie) , M1 is -S-S-.In certain embodiments, in Formula (Id) or (Ie) , M1 isIn certain embodiments, in Formula (Id) or (Ie) , M2 is a cleavable linker. In certain embodiments, in Formula (Id) or (Ie) , M2 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (Id) or (Ie) , M2 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by glutathione. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by an enzyme. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a protease. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a β-glycosidase. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a β-galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a β-glucuronidase. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M2 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M2 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M2 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (Id) or (Ie) , M2 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-. In certain embodiments, in Formula (Id) or (Ie) , M2 is -S-S-.In certain embodiments, in Formula (Id) or (Ie) , M2 isIn yet another embodiment, provided herein is a compound of Formula (If) :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 R1, R3, R4, a, b, c, and d are each as defined herein.In still another embodiment, provided herein is a compound of Formula (Ig) :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 R1, R3, R4, a, b, c, and d are each as defined herein.In one 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:R1, R2, R5, and R6 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl; or R5 and R6 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is -O-or -N (R1a) -;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;X and Z are each independently a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In certain embodiments, in Formula (II) , A is -O-. In certain embodiments, in Formula (II) , A is -N (R1b) -, wherein R1b is as defined herein. In certain embodiments, in Formula (II) , A is -N (H) -.In one embodiment, provided herein is a compound of Formula (IIa) :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 R1, R2, R3, R4, R5, R6, L1, L2, L3, L4, X, and Z are each as defined herein.In another embodiment, provided herein is a compound of Formula (IIb) :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 R1, R2, R3, R4, R5, R6, L1, L2, L3, L4, X, and Z are each as defined herein:In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L1 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L1 is - (CR2aR2b) a-, wherein each R2a, R2b, and a is as defined herein. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L1 is - (CH2) a-and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L1 is - (CH2) a-and a is an integer of 2, 3, or 4. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L1 is - (CH2) 2-.In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L2 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L2 is - (CR2aR2b) b-, wherein each R2a, R2b, and b is as defined herein. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L2 is - (CH2) b-and b is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L2 is - (CH2) b-and b is an integer of 2, 3, or 4. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L2 is - (CH2) 2-.In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L3 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L3 is - (CR2aR2b) c-, wherein each R2a, R2b, and c is as defined herein. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L3 is - (CH2) c-and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L3 is - (CH2) 2-. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L3 is - (CH2) 3-.In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L4 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L4 is - (CR2aR2b) d-, wherein each R2a, R2b, and d is as defined herein. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L4 is - (CH2) d-and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L4 is - (CH2) 2-. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L4 is - (CH2) 3-.In yet another embodiment, provided herein is a compound of Formula (IIc) :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 R1, R2, R3, R4, R5, R6, X, Z, a, b, c, and d are each as defined herein.In still another embodiment, provided herein is a compound of Formula (IId) :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 R1, R2, R3, R4, R5, R6, X, Z, a, b, c, and d are each as defined herein.In one 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, or hydrate thereof; wherein:R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 is a linker;U1 is -O-or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In certain embodiments, in Formula (III) , M1 is a cleavable linker. In certain embodiments, in Formula (III) , M1 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (III) , M1 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (III) , M1 is a linker cleavable by glutathione. In certain embodiments, in Formula (III) , M1 is a linker cleavable by an enzyme. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a protease. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (III) , M1 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a β-glycosidase. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a β-galactosidase. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a β-glucuronidase. In certain embodiments, in Formula (III) , M1 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.In certain embodiments, in Formula (III) , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (III) , M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (III) , M1 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (III) , M1 is -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -NR1aC (O) N (R1b) -, -N=N-, or -S-S-, wherein each R1a and R1b is as defined herein. In certain embodiments, in Formula (III) , M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-. In certain embodiments, in Formula (III) , M1 is -S-S-.In certain embodiments, in Formula (III) , M1 isIn one embodiment, provided herein is a compound of Formula (IIIa) :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 R1, R2, R3, R4, L1, L2, L3, L4, U1, X, and Z are each as defined herein.In certain embodiments, in Formula (III) or (IIIa) , U1 is -O-. In certain embodiments, in Formula (III) or (IIIa) , U1 is -N (R1b) -, wherein R1b is as defined herein. In certain embodiments, in Formula (III) or (IIIa) , U1 is -N (H) -.In another embodiment, provided herein is a compound of Formula (IIIb) :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 R1, R2, R3, R4, L1, L2, L3, L4, X, and Z are each as defined herein.In yet another embodiment, provided herein is a compound of Formula (IIIc) :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 R1, R2, R3, R4, L1, L2, L3, L4, X, and Z are each as defined herein.In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L1 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L1 is - (CR2aR2b) a-, wherein each R2a, R2b, and a is as defined herein. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L1 is - (CH2) a-and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L1 is - (CH2) a-and a is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L1 is - (CH2) 2-.In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L2 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L2 is - (CR2aR2b) b-, wherein each R2a, R2b, and b is as defined herein. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L2 is - (CH2) b-and b is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L2 is - (CH2) b-and b is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L2 is - (CH2) 2-.In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L3 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L3 is - (CR2aR2b) c-, wherein each R2a, R2b, and c is as defined herein. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L3 is - (CH2) c-and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L3 is - (CH2) 2-. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L3 is - (CH2) 3-.In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L4 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L4 is - (CR2aR2b) d-, wherein each R2a, R2b, and d is as defined herein. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L4 is - (CH2) d-and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L4 is - (CH2) 2-. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L4 is - (CH2) 3-.In yet another embodiment, provided herein is a compound of Formula (IIId) :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 R1, R2, R3, R4, X, Z, a, b, c, and d are each as defined herein.In still another embodiment, provided herein is a compound of Formula (IIIe) :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 R1, R2, R3, R4, X, Z, a, b, c, and d are each as defined herein.In one embodiment, provided herein is a compound 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; wherein:R1, R2, and R7 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is a bond, -O-, or -N (R1a) -;L1 is independently C1-6 alkylene or C1-6 heteroalkylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In certain embodiments, in Formula (IV) , A is -O-. In certain embodiments, in Formula (IV) , A is -N (R1b) -, wherein R1b is as defined herein. In certain embodiments, in Formula (IV) , A is -N (H) -.In one embodiment, provided herein is a compound of Formula (IVa) :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 R1, R2, R3, R4, R7, and L1 are each as defined herein.In another embodiment, provided herein is a compound of Formula (IVb) :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 R1, R2, R3, R4, R7, and L1 are each as defined herein.In certain embodiments, in Formula (IV) , (IVa) , or (IVb) , L1 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (IV) , (IVa) , or (IVb) , L1 is - (CR2aR2b) a-, wherein each R2a, R2b, and a is as defined herein. In certain embodiments, in Formula (IV) , (IVa) , or (IVb) , L1 is - (CH2) a-and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in Formula (IV) , (IVa) , or (IVb) , L1 is - (CH2) a-and a is an integer of 2, 3, or 4. In certain embodiments, in Formula (IV) , (IVa) , or (IVb) , L1 is - (CH2) 2-.In still another embodiment, provided herein is a compound of Formula (IVc) :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 R1, R2, R3, R4, R7, and a are each as defined herein.In yet another embodiment, provided herein is a compound of Formula (IVd) :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 R1, R2, R3, R4, R7, and a are each as defined herein.In one embodiment, provided herein is a compound 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; wherein:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.In certain embodiments, in Formula (V) , L1 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V) , L1 is - (CR2aR2b) a-, wherein each R2a, R2b, and a is as defined herein. In certain embodiments, in Formula (V) , L1 is - (CH2) a-and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in Formula (V) , L1 is - (CH2) a-and a is an integer of 2, 3, or 4. In certain embodiments, in Formula (V) , L1 is - (CH2) 2-.In certain embodiments, in Formula (V) , L2 is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V) , L2 is - (CR2aR2b) b-, wherein each R2a, R2b, and b is as defined herein. In certain embodiments, in Formula (V) , L2 is - (CH2) b-and b is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in Formula (V) , L2 is - (CH2) b-and b is an integer of 2, 3, or 4. In certain embodiments, in Formula (V) , L2 is - (CH2) 2-.In certain embodiments, in Formula (V) , L3 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V) , L3 is - (CR2aR2b) c-, wherein each R2a, R2b, and c is as defined herein. In certain embodiments, in Formula (V) , L3 is - (CH2) c-and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in Formula (V) , L3 is - (CH2) 2-. In certain embodiments, in Formula (V) , L3 is - (CH2) 3-.In certain embodiments, in Formula (V) , L4 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V) , L4 is - (CR2aR2b) d-, wherein each R2a, R2b, and d is as defined herein. In certain embodiments, in Formula (V) , L4 is - (CH2) d-and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in Formula (V) , L4 is - (CH2) 2-. In certain embodiments, in Formula (V) , L4 is - (CH2) 3-.In one embodiment, Provided herein is a compound of Formula (Va) :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 R1, R3, R4, a, b, c, and d are each as defined herein.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a, wherein each R1a, R1b, and R1c is as defined herein.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthioureido, 3, 3-dimethylthioureido, guanidino, methoxy-imino, mercapto, or methylsulfonamido. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which 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-methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methyl, cyclopropylmethyl, cyclobutyl-methyl, 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- (methyl-sulfonamido) ethyl, isopropyl, 2-hydroxypropyl, (R) -2-hydroxypropyl, (S) -2-hydroxypropyl, 3-hydroxypropyl, 1, 3-dihydroxy-2-propyl, 2-methylpropoyl, 2-hydroxybutyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is 1- (dimethylamino) -2-nitrovinyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is 4-dimethylamino-phenyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is C7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is 4-methoxybenzyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (O) R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with -ORa, and Ra is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxy-acetyl, benzyloxyacetyl, propionyl, or isopropionyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (O) OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (O) OC1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methoxycarbonyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (O) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methylaminocarbonyl or dimethylamino-carbonyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (NR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is carbamimidoyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (NCN) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is N’-cyano-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (NOR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is N’-methoxy-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (NS (O2) R1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -C (S) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methylaminothiocarbonyl or dimethylaminothiocarbonyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is -S (O) 2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methylsulfonyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 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-yl-methyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthio-ureido) 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-methylpropoyl, 2-hydroxybutyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. 2-hydroxycyclo-heptyl, 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, methylamino-carbonyl, dimethylaminocarbonyl, carbamimidoyl, methylaminothiocarbonyl, dimethylamino-thiocarbonyl, (E) -N’-cyano-N, N-dimethylcarbamimidoyl, (Z) -N’-cyano-N, N-dimethyl-carbamimidoyl, (E) -N’-methoxy-N, N-dimethylcarbamimidoyl, (Z) -N’-methoxy-N, N-dimethyl-carbamimidoyl, (E) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, (Z) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, hydroxyl, methoxy, or methylsulfonyl. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylamino-methyl, or 2-dimethylaminoethyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a, wherein each R1a, R1b, and R1c is as defined herein.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which 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-methylthioureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl-methyl, 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-methylthio-ureido) 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-methylpropoyl, 2-hydroxy-butyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is 1- (dimethylamino) -2-nitrovinyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is 4-dimethylaminophenyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is C7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is 4-methoxybenzyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (O) R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with -ORa, and Ra is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxy-acetyl, benzyloxyacetyl, propionyl, or isopropionyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (O) OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (O) OC1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methoxycarbonyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (O) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (NR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is carbamimidoyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (NCN) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is N’-cyano-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (NOR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is N’-methoxy-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (NS (O2) R1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -C (S) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methylamino-thiocarbonyl or dimethylaminothiocarbonyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is -S (O) 2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methylsulfonyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethyl-amino) -2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexyl-methyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-yl-methyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylamino-ethyl, 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-hydroxy-propyl, (R) -2-hydroxypropyl, (S) -2-hydroxypropyl, 3-hydroxypropyl, 1, 3-dihydroxy-2-propyl, 2-methylpropoyl, 2-hydroxybutyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. 2-hydroxycycloheptyl, 2-dimethyl-amino-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, dimethyl-aminocarbonyl, carbamimidoyl, methylaminothiocarbonyl, dimethylaminothiocarbonyl, (E) -N’-cyano-N, N-dimethylcarbamimidoyl, (Z) -N’-cyano-N, N-dimethylcarbamimidoyl, (E) -N’-methoxy-N, N-dimethylcarbamimidoyl, (Z) -N’-methoxy-N, N-dimethylcarbamimidoyl, (E) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, (Z) -N’-methylsulfonyl-N, N-dimethyl-carbamimidoyl, hydroxyl, methoxy, or methylsulfonyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, pyridin-1-iumyl, or pyrimidin-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 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.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5, 5-, 5, 6-, or 6, 6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5, 5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5, 6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 6, 6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form purin-9-yl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 6-aminopurin-9-yl or 2-amino-6-oxo-1, 9-dihydro-purin-9-yl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 7-membered heterocyclyl, optionally substituted with one or more substituents Q.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, imidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, piperazin-1-yl, or isoindolin-2-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 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, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- (4-methoxybenzyl) piperazin-1-yl, 4- (2-hydroxethyl) piperazin-1-yl, or 1, 3-dioxoisoindolin-2-yl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, pyridin-1-iumyl, or pyrimidin-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R1 and R2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2, 4-dioxo-3, 4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IIc) , (IIIa) to (IIId) , and (IVa) to (IVc) , the moietyis dimethylamino, (2-cyanoethyl) (methyl) amino, (cyclopropylmethyl) (methyl) amino, (cyclobutylmethyl) (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-methyl-sulfonamidoethyl) (methyl) amino, (2- (3-methylureido) ethyl) (methyl) amino, (2- (3, 3-dimethyl-ureido) ethyl) (methyl) amino, (2- (3-methylthioureido) ethyl) (methyl) amino, (2- (3, 3-dimethylthio-ureido) ethyl) (methyl) amino, diethylamino, (1, 3-dihydroxyprop-2-yl) amino, (isopropyl) (methyl) -amino, (R) - (2-hydroxypropyl) (methyl) amino, (S) - (2-hydroxypropyl) (methyl) amino, (3-hydroxy-propyl) (methyl) amino, (1, 3-dihydroxyprop-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-hydroxyhexyl) (methyl) amino, 1- (methylamino) -2-nitrovinylamino, (cyclopropyl) (methyl) amino, (cyclobutyl) (methyl) amino, (cyclopentyl) - (methyl) amino, (cyclohexyl) (methyl) amino, (cycloheptyl) (methyl) amino, (2-hydroxycyclo-heptyl) (methyl) amino, 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl, (4-dimethylaminophenyl) -amino, (4-methoxybenzyl) (methyl) amino, imidazol-2-ylamino, thiazol-2-ylamino, (pyridin-2-yl) (methyl) amino, (pyridin-3-yl) (methyl) amino, methoxyformamido, methylaminoformamido, dimethylaminoformamido, methylaminothioformamido, dimethylaminothioformamido, acetamido, N- (methyl) acetamido, N- (2-hydroxy) acetamido, N- (2-methoxy) acetamido, N- (2-benzyloxy) acetamido, propamido, isobutamido, guanidino, 2-cyano-3, 3-dimethylguanidino, 2-methoxy-3, 3-dimethylguanidino, 2-methylsulfonyl-3, 3-dimethylguanidino, N- (methyl) hydroxy-amino, N- (methoxy) acetamido, N- (methoxy) methoxyformamido, methylsulfonamido, or N- (methoxy) (methylsulfonamido) .In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , the moietyis 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 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, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- (4-methoxybenzyl) piperazin-1-yl, 4- (2-hydroxethyl) piperazin-1-yl, or 1, 3-dioxoisoindolin-2-yl.In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , the moietyhas the structure of: wherein e and f are each independently an integer of 0, 1, 2, 3, 4, or 5; each k and m is independently an integer of 0, 1, 2, 3, 4, or 5; n is an integer of 0, 1, 2, 3, 4, 5, or 6; and each R1a is as defined herein; in one embodiment, each R1a is independently C1-6 alkyl, optionally substituted with one or more substituents Q; and in another embodiment, each R1a is methyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, or C6-14 aryl, each optionally substituted with one or more substituents Q.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-30 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-25 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octanyl, nonyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, penta-decanyl, hexadecanyl, heptadecanyl, octadecanyl, nonadecanyl, eicosanyl, heneicosanyl, docosanyl, tricosanyl, tetracosanyl, or pentacosanyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methyl-hex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-30 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-25 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C1-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 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 certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is (Z) -2-hexen-1-yl, (Z) -2-nonen-1-yl, (Z) -2-undecen-1-yl, (Z) -2-tri-decen-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-penta-decen-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.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is cyclohexyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyl-octan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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- (dodec-1-yldisulfaneyl) 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-difluoro-non-3-en-1-yl, (Z) -5, 5-difluoronon-3-en-1-yl, (Z) -3-decen-2-yl, (Z) -3-undecen-1-yl, (Z) -8-penta-decen-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, (8Z, 11Z, 14Z) -heptadeca-8, 11, 14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexyl-cyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 iswherein each p is independently an integer of 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.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R3 iswherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, or C6-14 aryl, each optionally substituted with one or more substituents Q.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-30 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-25 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octanyl, nonyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, penta-decanyl, hexadecanyl, heptadecanyl, octadecanyl, nonadecanyl, eicosanyl, heneicosanyl, docosanyl, tricosanyl, tetracosanyl, or pentacosanyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methyl-hex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-30 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-25 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C1-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 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 certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is (Z) -2-hexen-1-yl, (Z) -2-nonen-1-yl, (Z) -2-undecen-1-yl, (Z) -2-tri-decen-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-penta-decen-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.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is cyclohexyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methyl-hex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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- (dodec-1-yldisulfaneyl) 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-difluoro-non-3-en-1-yl, (Z) -5, 5-difluoronon-3-en-1-yl, (Z) -3-decen-2-yl, (Z) -3-undecen-1-yl, (Z) -8-penta-decen-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, (8Z, 11Z, 14Z) -heptadeca-8, 11, 14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexyl-cyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.In certain embodiments, in any one of Formulae (I) to (V) , (Ia) to (Ig) , (IIa) to (IId) , (IIIa) to (IIIe) , (IVa) to (IVd) , and (Va) , R4 iswherein each p is independently an integer of 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.In certain embodiments, in any one of Formulae (I) to (VII) , R4 iswherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.In certain embodiments, in any one of Formulae (I) to (VIII) , R3 is:wherein each p is independently an integer of 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; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.In certain embodiments, in any one of Formulae (I) to (VIII) , R4 is:wherein each p is independently an integer of 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; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.Preferably, in certain embodiments, R3 is T-0020. Preferably, in certain embodiments, R3 is T-0021. Preferably, in certain embodiments, R3 is T-0022. Preferably, in certain embodiments, R3 is T-0023. Preferably, in certain embodiments, R3 is T-0025. Preferably, in certain embodiments, R3 is T-0092. Preferably, in certain embodiments, R3 is T-0108. Preferably, in certain embodiments, R3 is T-0109. Preferably, in certain embodiments, R3 is T-0110. Preferably, in certain embodiments, R3 is T-0111. Preferably, in certain embodiments, R3 is T-0112. Preferably, in certain embodiments, R3 is T-0113.Preferably, in certain embodiments, R4 is T-0020. Preferably, in certain embodiments, R4 is T-0021. Preferably, in certain embodiments, R4 is T-0022. Preferably, in certain embodiments, R4 is T-0023. Preferably, in certain embodiments, R4 is T-0025. Preferably, in certain embodiments, R4 is T-0092. Preferably, in certain embodiments, R4 is T-0108. Preferably, in certain embodiments, R4 is T-0109. Preferably, in certain embodiments, R4 is T-0110. Preferably, in certain embodiments, R4 is T-0111. Preferably, in certain embodiments, R4 is T-0112. Preferably, in certain embodiments, R4 is T-0113.In certain embodiments, the number of carbon atoms in R3 is an integer of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27 or 28. Preferably, in certain embodiments, the number of carbon atoms in R3 is 12. Preferably, in certain embodiments, the number of carbon atoms in R3 is 14. Preferably, in certain embodiments, the number of carbon atoms in R3 is 15. Preferably, in certain embodiments, the number of carbon atoms in R3 is 16. Preferably, in certain embodiments, the number of carbon atoms in R3 is 17. Preferably, in certain embodiments, the number of carbon atoms in R3 is 18. Preferably, in certain embodiments, the number of carbon atoms in R3 is 20. Preferably, in certain embodiments, the number of carbon atoms in R3 is 21. Preferably, in certain embodiments, the number of carbon atoms in R3 is 24. Preferably, in certain embodiments, the number of carbon atoms in R3 is 25. Preferably, in certain embodiments, the number of carbon atoms in R3 is 28.In certain embodiments, the number of carbon atoms in R4 is an integer of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27 or 28. Preferably, in certain embodiments, the number of carbon atoms in R4 is 12. Preferably, in certain embodiments, the number of carbon atoms in R4 is 14. Preferably, in certain embodiments, the number of carbon atoms in R4 is 15. Preferably, in certain embodiments, the number of carbon atoms in R4 is 16. Preferably, in certain embodiments, the number of carbon atoms in R4 is 17. Preferably, in certain embodiments, the number of carbon atoms in R4 is 18. Preferably, in certain embodiments, the number of carbon atoms in R4 is 20. Preferably, in certain embodiments, the number of carbon atoms in R4 is 21. Preferably, in certain embodiments, the number of carbon atoms in R4 is 24. Preferably, in certain embodiments, the number of carbon atoms in R4 is 25. Preferably, in certain embodiments, the number of carbon atoms in R4 is 28.Preferably, in certain embodiments, R3 is branched C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl.Preferably, in certain embodiments, R4 is branched C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a, wherein each R1a, R1b, and R1c is as defined herein.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which 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-methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclo-heptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylamino-methyl, 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-dimethyl-thioureido) ethyl, 2-guanidinoethyl, 2- (methylsulfonamido) ethyl, isopropyl, 2-hydroxypropyl, (R) -2-hydroxypropyl, (S) -2-hydroxypropyl, 3-hydroxypropyl, 1, 3-dihydroxy-2-propyl, 2-methyl-propoyl, 2-hydroxybutyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is 1- (dimethylamino) -2-nitrovinyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is 4-dimethylaminophenyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is C7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is 4-methoxybenzyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (O) R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with -ORa, and Ra is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (O) OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (O) OC1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methoxy-carbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (O) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (NR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is carbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (NCN) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is N’-cyano-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (NOR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is N’-methoxy-N, N-dimethyl-carbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (NS (O2) R1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -C (S) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methylaminothiocarbonyl or dimethylamino-thiocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is -S (O) 2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methylsulfonyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, 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-methylpropoyl, 2-hydroxy-butyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) 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, carbamimidoyl, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E) -N’-cyano-N, N-dimethylcarbamimidoyl, (Z) -N’-cyano-N, N-dimethylcarbamimidoyl, (E) -N’-methoxy-N, N-dimethylcarbamimidoyl, (Z) -N’-methoxy-N, N-dimethylcarbamimidoyl, (E) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, (Z) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, hydroxyl, methoxy, or methylsulfonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a, wherein each R1a, R1b, and R1c is as defined herein.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethyl-amino, acetamido, methylureido, dimethylureido, methyl-thioureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which 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.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclo-heptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylamino-methyl, 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-dimethyl-thioureido) ethyl, 2-guanidinoethyl, 2- (methylsulfonamido) ethyl, isopropyl, 2-hydroxypropyl, (R) -2-hydroxypropyl, (S) -2-hydroxypropyl, 3-hydroxypropyl, 1, 3-dihydroxy-2-propyl, 2-methyl-propoyl, 2-hydroxybutyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is 1- (dimethylamino) -2-nitrovinyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is 4-dimethylaminophenyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is C7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is 4-methoxybenzyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (O) R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with -ORa, and Ra is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (O) OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (O) OC1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methoxy-carbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (O) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (NR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is carbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (NCN) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is N’-cyano-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (NOR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is N’-methoxy-N, N-dimethyl-carbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (NS (O2) R1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -C (S) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methylaminothiocarbonyl or dimethylamino-thiocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is -S (O) 2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methylsulfonyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, 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-methylpropoyl, 2-hydroxy-butyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo-hexyl, 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, carbamimidoyl, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E) -N’-cyano-N, N-dimethylcarbamimidoyl, (Z) -N’-cyano-N, N-dimethylcarbamimidoyl, (E) -N’-methoxy-N, N-dimethylcarbamimidoyl, (Z) -N’-methoxy-N, N-dimethylcarbamimidoyl, (E) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, (Z) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, hydroxyl, methoxy, or methylsulfonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R6 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 5, 5-, 5, 6-, or 6, 6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 5, 5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 5, 6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 6, 6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form purin-9-yl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 6-aminopurin-9-yl or 2-amino-6-oxo-1, 9-dihydropurin-9-yl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 7-membered heterocyclyl, optionally substituted with one or more substituents Q.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, imidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, piperazin-1-yl, or isoindolin-2-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R5 and R6 together with the N atom to which they are attached form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxo-pyrrolidin-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, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- (4-methoxybenzyl) piperazin-1-yl, 4- (2-hydroxethyl) piperazin-1-yl, or 1, 3-dioxoisoindolin-2-yl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , the moiety is dimethylamino, (2-cyanoethyl) (methyl) amino, (cyclopropylmethyl) (methyl) amino, (cyclobutylmethyl) (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, (dimethylamino-methyl) (methyl) amino, (ethyl) (methyl) amino, (2-hydroxyethyl) (methyl) amino, (2-acetamido-ethyl) (methyl) amino, (2-guanidinoethyl) (methyl) amino, (2-methylsulfonamidoethyl) (methyl) -amino, (2- (3-methylureido) ethyl) (methyl) amino, (2- (3, 3-dimethyl-ureido) ethyl) (methyl) amino, (2- (3-methylthioureido) ethyl) (methyl) amino, (2- (3, 3-dimethylthioureido) ethyl) (methyl) amino, diethylamino, (1, 3-dihydroxyprop-2-yl) amino, (isopropyl) (methyl) amino, (R) - (2-hydroxy-propyl) (methyl) amino, (S) - (2-hydroxypropyl) (methyl) amino, (3-hydroxypropyl) (methyl) amino, (1, 3-dihydroxyprop-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-carboxy-pentyl) (methyl) amino, (6-hydroxyhexyl) (methyl) amino, 1- (methylamino) -2-nitrovinylamino, (cyclopropyl) (methyl) amino, (cyclobutyl) (methyl) amino, (cyclopentyl) (methyl) amino, (cyclo-hexyl) (methyl) amino, (cycloheptyl) (methyl) amino, (2-hydroxycycloheptyl) (methyl) amino, 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl, (4-dimethylaminophenyl) amino, (4-methoxybenzyl) - (methyl) amino, imidazol-2-ylamino, thiazol-2-ylamino, (pyridin-2-yl) (methyl) amino, (pyridin-3-yl) (methyl) amino, methoxyformamido, methylaminoformamido, dimethylaminoformamido, methylaminothioformamido, dimethylaminothioformamido, acetamido, N- (methyl) acetamido, N- (2-hydroxy) acetamido, N- (2-methoxy) acetamido, N- (2-benzyloxy) acetamido, propamido, isobutamido, guanidino, 2-cyano-3, 3-dimethylguanidino, 2-methoxy-3, 3-dimethylguanidino, 2-methylsulfonyl-3, 3-dimethylguanidino, N- (methyl) hydroxyamino, N- (methoxy) acetamido, N- (methoxy) methoxyformamido, methylsulfonamido, or N- (methoxy) (methylsulfonamido) .In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , the moiety is 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 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, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4- (4-methoxybenzyl) piperazin-1-yl, 4- (2-hydroxethyl) piperazin-1-yl, or 1, 3-dioxoisoindolin-2-yl.In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , the moiety has the structure of: wherein e and f are each independently an integer of 0, 1, 2, 3, 4, or 5; each k and m is independently an integer of 0, 1, 2, 3, 4, or 5; n is an integer of 0, 1, 2, 3, 4, 5, or 6; and each R1a is as defined herein; in one embodiment, each R1a is independently C1-6 alkyl, optionally substituted with one or more substituents Q; and in another embodiment, each R1a is methyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a, wherein each R1a, R1b, and R1c is as defined herein.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3, 3-dimethylureido, 3-methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclo-heptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylamino-methyl, 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-dimethyl-thioureido) ethyl, 2-guanidinoethyl, 2- (methylsulfonamido) ethyl, isopropyl, 2-hydroxypropyl, (R) -2-hydroxypropyl, (S) -2-hydroxypropyl, 3-hydroxypropyl, 1, 3-dihydroxy-2-propyl, 2-methyl-propoyl, 2-hydroxybutyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) butyl, 7-hydroxypentyl, or 6-hydroxyhexyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is 1- (dimethylamino) -2-nitrovinyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, =NORa, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethyl-amino-3, 4-dioxo-1-cyclobutenyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is 4-dimethylaminophenyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is C7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is 4-methoxybenzyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -ORa, -NRbRc, -NRaC (O) NRbRc, -NRaC (NRd) NRbRc, -NRaC (S) NRbRc, -SRa, or -NRaS (O) 2Rd, wherein each Ra, Rb, Rc, and Rd is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (O) R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (O) -C1-6 alkyl, wherein the alkyl is optionally substituted with -ORa, and Ra is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (O) OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (O) OC1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methoxycarbonyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (O) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (NR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is carbamimidoyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (NCN) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is N’-cyano-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (NOR1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is N’-methoxy-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (NS (O2) R1a) NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -C (S) NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methyl-aminothiocarbonyl or dimethylaminothiocarbonyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is -S (O) 2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methylsulfonyl.In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, 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-methylpropoyl, 2-hydroxy-butyl, (R) -2-hydroxybutyl, (S) -2-hydroxybutyl, 4-hydroxybutyl, 4- (2-hydroxyethoxy) butyl, (E) -4- (methoxyimino) 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, carbamimidoyl, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E) -N’-cyano-N, N-dimethylcarbamimidoyl, (Z) -N’-cyano-N, N-dimethylcarbamimidoyl, (E) -N’-methoxy-N, N-dimethylcarbamimidoyl, (Z) -N’-methoxy-N, N-dimethylcarbamimidoyl, (E) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, (Z) -N’-methylsulfonyl-N, N-dimethylcarbamimidoyl, hydroxyl, methoxy, or methylsulfonyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R7 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 1, 2, 3, or 4. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 1. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 2. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 3. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 4.In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 1, 2, 3, or 4. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 1. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 2. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 3. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 4.In one embodiment, provided herein is a compound of Formula A1:or 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 of 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 e is as defined herein.In another embodiment, provided herein is a compound of Formula A2:or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein e is as defined herein.In yet another embodiment, provided herein is a compound of Formula A3:or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein e is as defined herein.In yet another embodiment, provided herein is a compound of Formula A4:or 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 of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and e is as defined herein.In yet another embodiment, provided herein is a compound of Formula A5:or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein e, g, and h are each as defined herein.In still another embodiment, provided herein is a compound of Formula A6:or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or h...
Claims
1.A compound of Formula (I) , (II) , (III) , (IV) , or (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; wherein:each R1, R2, R5, R6, and R7 is independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;each R3 and R4 is independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;each A is independently -O- or -N (R1a) -;each E1 and E2 is independently -C (O) - or -C (O) O-;each L1 and L2 is independently C1-6 alkylene or C1-6 heteroalkylene;each L3 and L4 is independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;each M1 and M2 is independently a linker;each U1 and U2 is independently -O- or -N (R1b) -;each X and Z is independently a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.2.The compound of claim 1, having the structure 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:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;E1 and E2 are each independently -C (O) - or -C (O) O-;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 and M2 are each independently a linker;U1 and U2 are each independently -O- or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.3.The compound of claim 1 or 2, wherein M1 is a cleavable linker.4.The compound of claim 1 or 2, wherein M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-.5.The compound of any one of claims 1 to 4, wherein M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-.6.The compound of any one of claims 1 to 5, wherein M1 is -S-S-.7.The compound of any one of claims 1 to 6, wherein M2 is a cleavable linker.8.The compound of any one of claims 1 to 6, wherein M2 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-.9.The compound of any one of claims 1 to 8, wherein M2 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-.10.The compound of any one of claims 1 to 9, wherein M2 is -S-S-.11.The compound of any one of claims 1 to 10, wherein E1 is -C (O) -.12.The compound of any one of claims 1 to 10, wherein E1 is -C (O) O-.13.The compound of any one of claims 1 to 12, wherein E2 is -C (O) -.14.The compound of any one of claims 1 to 12, wherein E2 is -C (O) O-.15.The compound of any one of claims 1 to 14, wherein U1 is -O-.16.The compound of any one of claims 1 to 14, wherein U1 is -N (R1b) -.17.The compound of any one of claims 1 to 14 and 16, wherein U1 is -N (H) -.18.The compound of any one of claims 1 to 17, wherein U2 is -O-.19.The compound of any one of claims 1 to 17, wherein U2 is -N (R1b) -.20.The compound of any one of claims 1 to 17 and 19, wherein U2 is -N (H) -.21.The compound of claim 1 or 2, having the structure of Formula (Ib) : 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.22.The compound of claim 1 or 2, having the structure of Formula (Ic) : 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.23.The compound of claim 1, having the structure 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:R1, R2, R5, and R6 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl; or R5 and R6 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is -O- or -N (R1a) -;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;X and Z are each independently a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.24.The compound of claim 1 or 23, wherein A is -O-.25.The compound of claim 1 or 23, wherein A is -N (R1b) -.26.The compound of claim 1, 23, or 25, wherein A is -N (H) -.27.The compound of claim 1, having the structure 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, or hydrate thereof; wherein:R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene;M1 is a linker;U1 is -O- or -N (R1b) -; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.28.The compound of claim 27, wherein M1 is a cleavable linker.29.The compound of claim 27, wherein M1 is a linker comprising -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -N=N-, -S-, or -S-S-.30.The compound of any one of claims 27 to 29, wherein M1 is -C (O) O-, -C (O) N (H) -, -C (O) S-, -OC (O) O-, -OC (O) N (H) -, -OC (O) S-, -NHC (O) N (H) -, -N=N-, or -S-S-.31.The compound of any one of claims 27 to 30, wherein M1 is -S-S-.32.The compound of any one of claims 27 to 31, wherein U1 is -O-.33.The compound of any one of claims 27 to 31, wherein U1 is -N (R1b) -.34.The compound of any one of claims 27 to 31 and 33, wherein U1 is -N (H) -.35.The compound of claim 1 or 27, having the structure of Formula (IIIb) : 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.36.The compound of claim 1 or 27, having the structure of Formula (IIIc) : 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.37.The compound of claim 1, having 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; wherein:R1, R2, and R7 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;A is a bond, -O-, or -N (R1a) -;L1 is independently C1-6 alkylene or C1-6 heteroalkylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.38.The compound of claim 37, wherein A is -O-.39.The compound of claim 37, wherein A is -N (R1b) -.40.The compound of claim 37 or 39, wherein A is -N (H) -.41.The compound of claim 1, having 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; wherein:R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (O) SR1a, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) R1a, -C (S) OR1a, -C (S) NR1bR1c, -OR1a, -OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, -OC (O) SR1a, -OC (NR1a) NR1bR1c, -OC (S) R1a, -OC (S) OR1a, -OC (S) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, -NR1aC (O) NR1bR1c, -NR1aC (O) SR1d, -NR1aC (NR1d) NR1bR1c, -NR1aC (S) R1d, -NR1aC (S) OR1d, -NR1aC (S) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, -NR1aS (O) NR1bR1c, -NR1aS (O) 2NR1bR1c, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, or -S (O) 2NR1bR1c;R3 and R4 are each independently hydrogen, C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl;L1 and L2 are each independently C1-6 alkylene or C1-6 heteroalkylene;L3 and L4 are each independently C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, or C2-10 alkynylene; andeach R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (O) SRa, -C (NRa) NRbRc, -C (S) Ra, -C (S) ORa, -C (S) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (O) SRa, -OC (NRa) NRbRc, -OC (S) Ra, -OC (S) ORa, -OC (S) NRbRc, -OP (O) (ORb) ORc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) ORd, -NRaC (O) NRbRc, -NRaC (O) SRd, -NRaC (NRd) NRbRc, -NRaC (S) Rd, -NRaC (S) ORd, -NRaC (S) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, =NORa, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (O) SRe, -C (NRe) NRfRg, -C (S) Re, -C (S) ORe, -C (S) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (O) SRe, -OC (NRe) NRfRg, -OC (S) Re, -OC (S) ORe, -OC (S) NRfRg, -OP (O) (ORf) ORg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rh, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (O) SRf, -NReC (NRh) NRfRg, -NReC (S) Rh, -NReC (S) ORf, -NReC (S) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O) NRfRg, -NReS (O) 2NRfRg, =NORe, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.42.The compound of any one of claims 1 to 41, wherein L1 is C1-6 alkylene, optionally substituted with one or more substituents Q.43.The compound of any one of claims 1 to 42, wherein L1 is - (CR2aR2b) a-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5, or 6.44.The compound of any one of claims 1 to 43, wherein L1 is - (CH2) a- and a is an integer of 1, 2, 3, 4, 5, or 6.45.The compound of any one of claims 1 to 36 and 41 to 44, wherein L2 is C1-6 alkylene, optionally substituted with one or more substituents Q.46.The compound of any one of claims 1 to 36 and 41 to 45, wherein L2 is - (CR2aR2b) b-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and b is an integer of 1, 2, 3, 4, 5, or 6.47.The compound of any one of claims 1 to 36 and 41 to 46, wherein L2 is - (CH2) b-and b is an integer of 1, 2, 3, 4, 5, or 6.48.The compound of any one of claims 1 to 36 and 41 to 47, wherein L3 is C1-10 alkylene, optionally substituted with one or more substituents Q.49.The compound of any one of claims 1 to 36 and 41 to 48, wherein L3 is - (CR2aR2b) c- or - CR2aR2b (CR2aR2b) c-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.50.The compound of any one of claims 1 to 36 and 41 to 49, wherein L3 is - (CH2) c-or -C (CH3) 2 (CH2) c-; and each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.51.The compound of any one of claims 1 to 36 and 41 to 50, wherein L4 is C1-10 alkylene, optionally substituted with one or more substituents Q.52.The compound of any one of claims 1 to 36 and 41 to 51, wherein L4 is - (CR2aR2b) d- or - CR2aR2b (CR2aR2b) d-, wherein each R2a and R2b is independently (i) hydrogen; or (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl, optionally substituted with one or more substituents Q; and each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.53.The compound of any one of claims 1 to 36 and 41 to 52, wherein L4 is - (CH2) d-or -C (CH3) 2 (CH2) d-; and each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.54.The compound of claim 1 or 2, having the structure of Formula (If) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.55.The compound of claim 1 or 2, having the structure of Formula (Ig) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.56.The compound of claim 1 or 23, having the structure of Formula (IIc) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.57.The compound of claim 1 or 23, having the structure of Formula (IId) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.58.The compound of claim 1 or 27, having the structure of Formula (IIId) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.59.The compound of claim 1 or 27, having the structure of Formula (IIIe) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.60.The compound of claim 1 or 37, having the structure of Formula (IVc) : 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 a is an integer of 1, 2, 3, 4, 5, or 6.61.The compound of claim 1 or 37, having the structure of Formula (IVd) : 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 a is an integer of 1, 2, 3, 4, 5, or 6.62.The compound of claim 1 or 41, having the structure of Formula (Va) : 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 a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.63.The compound of any one of claims 1 to 62, wherein R1 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.64.The compound of any one of claims 1 to 63, wherein R1 is C1-6 alkyl, optionally substituted with one or more substituents Q.65.The compound of any one of claims 1 to 64, wherein R1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.66.The compound of any one of claims 1, 23 to 40, 42 to 53, 56 to 61, and 63 to 65, wherein R2 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.67.The compound of any one of claims 1, 23 to 40, 42 to 53, 56 to 61, and 63 to 66, wherein R2 is C1-6 alkyl, optionally substituted with one or more substituents Q.68.The compound of any one of claims 1, 23 to 40, 42 to 53, 56 to 61, and 63 to 67, wherein R2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.69.The compound of any one of claims 1 to 68, wherein R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each optionally substituted with one or more substituents Q.70.The compound of any one of claims 1 to 69, wherein R3 is C1-25 alkyl, optionally substituted with one or more substituents Q.71.The compound of any one of claims 1 to 70, wherein R3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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.72.The compound of any one of claims 1 to 69, wherein R3 is C1-25 alkenyl, optionally substituted with one or more substituents Q.73.The compound of any one of claims 1 to 69 and 72, wherein R3 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.74.The compound of any one of claims 1 to 69, wherein R3 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.75.The compound of any one of claims 1 to 69 and 74, wherein R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.76.The compound of any one of claims 1 to 69, wherein R3 is C6-14 aryl, optionally substituted with one or more substituents Q.77.The compound of any one of claims 1 to 69 and 76, wherein R3 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.78.The compound of any one of claims 1 to 77, wherein R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each optionally substituted with one or more substituents Q.79.The compound of any one of claims 1 to 78, wherein R4 is C1-25 alkyl, optionally substituted with one or more substituents Q.80.The compound of any one of claims 1 to 79, wherein R4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-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.81.The compound of any one of claims 1 to 78, wherein R4 is C1-25 alkenyl, optionally substituted with one or more substituents Q.82.The compound of any one of claims 1 to 78 and 81, wherein R4 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.83.The compound of any one of claims 1 to 78, wherein R4 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.84.The compound of any one of claims 1 to 78 and 83, wherein R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.85.The compound of any one of claims 1 to 78, wherein R4 is C6-14 aryl, optionally substituted with one or more substituents Q.86.The compound of any one of claims 1 to 78 and 85, wherein R4 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.87.The compound of any one of claims 1, 23 to 26, 42 to 53, 56, 57, and 63 to 86, wherein R5 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.88.The compound of any one of claims 1, 23 to 26, 42 to 53, 56, 57, and 63 to 87, wherein R5 is C1-6 alkyl, optionally substituted with one or more substituents Q.89.The compound of any one of claims 1, 23 to 26, 42 to 53, 56, 57, and 63 to 88, wherein R5 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.90.The compound of any one of claims 1, 23 to 26, 42 to 53, 56, 57, and 63 to 89, wherein R6 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.91.The compound of any one of claims 1, 23 to 26, 42 to 53, 56, 57, and 63 to 90, wherein R6 is C1-6 alkyl, optionally substituted with one or more substituents Q.92.The compound of any one of claims 1, 23 to 26, 42 to 53, 56, 57, and 63 to 91, wherein R6 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.93.The compound of any one of claims 1, 37 to 40, 42 to 53, 60, 61, and 63 to 92, wherein R7 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (ii) -C (O) R1a, -C (O) OR1a, -C (O) NR1bR1c, -C (NR1a) NR1bR1c, -C (NCN) NR1bR1c, -C (NOR1a) NR1bR1c, -C (NS (O2) R1a) NR1bR1c, -C (S) NR1bR1c, -OR1a, or -S (O) 2R1a.94.The compound of any one of claims 1, 37 to 40, 42 to 53, 60, 61, and 63 to 93, wherein R7 is C1-6 alkyl, optionally substituted with one or more substituents Q.95.The compound of any one of claims 1, 37 to 40, 42 to 53, 60, 61, and 63 to 94, wherein R7 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.96.The compound of any one of claims 43 to 95, wherein a is an integer of 1, 2, 3, or 4.97.The compound of any one of claims 43 to 96, wherein a is an integer of 2.98.The compound of any one of claims 42 to 44, 46 to 59, and 62 to 97, wherein b is an integer of 1, 2, 3, or 4.99.The compound of any one of claims 42 to 44, 46 to 59, and 62 to 98, wherein b is an integer of 1 or 2.100.The compound of claim 1, wherein the compound has the structure of: 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 e, f, and v is independently an integer of 0, 1, 2, 3, 4, or 5; each g and h is independently an integer of 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 i and j is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; each k, m, q, and r is independently an integer of 0, 1, 2, 3, 4, or 5; and each n is independently an integer of 1, 2, 3, 4, 5, or 6.101.The compound of any one of claims 42 to 47, 49 to 59, and 62 to 100, wherein c is an integer of 1, 2, 3, or 4.102.The compound of any one of claims 42 to 47, 49 to 59, and 62 to 101, wherein c is an integer of 2.103.The compound of any one of claims 42 to 50, 52 to 59, and 62 to 102, wherein d is an integer of 1, 2, 3, or 4.104.The compound of any one of claims 42 to 50, 52 to 59, and 62 to 103, wherein d is an integer of 2.105.The compound of any one of claims 100 to 104, wherein X is a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-.106.The compound of any one of claims 100 to 105, wherein 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-.107.The compound of any one of claims 100 to 106, wherein Z is a bond, -C (O) O-, -C (O) N (R1a) -, -C (O) S-, -O-, -OC (O) O-, -OC (O) N (R1a) -, -OC (O) S-, -N (R1a) -, -NR1aC (O) N (R1b) -, -S-, or -S-S-.108.The compound of any one of claims 100 to 107, wherein 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-.109.A compound of:bis (2- (pentyldisulfanyl) ethyl) ( (methylazanediyl) bis (ethane-2, 1-diyl) ) dicarbamate 1;N, N'- ( (methylazanediyl) bis (ethane-2, 1-diyl) ) bis (2, 2-dimethyl-4- (pentyldi-sulfanyl) butanamide) 2;4- (3, 3-bis (2- (dimethylamino) ethyl) ureido) heptane-1, 7-diyl dihexanoate 3;10- (3- (hexanoyloxy) propyl) -2-methyl-9-oxo-5, 6-dithia-2, 8, 10-triazatridecan-13-yl hexanoate 4;2- ( (butoxy (pentyloxy) phosphoryl) amino) -N, N, N-trimethylethan-1-aminium 5;2- ( (butoxy (pentyloxy) phosphoryl) oxy) -N, N, N-trimethylethan-1-aminium 6; ordipentyl ( ( ( (methylazanediyl) bis (ethane-2, 1-diyl) ) bis (dimethylammoniumdiyl) ) -bis (ethane-2, 1-diyl) ) bis (phosphonate) 7;or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.110.The compound of claim 1 has the structure of: 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.111.The compound of claim 1, wherein R3 is: wherein each p is independently an integer of 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; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.112.The compound of claim 1, wherein R4 is: wherein each p is independently an integer of 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; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.113.The compound of claim 1, wherein R3 and R4 are the same structure.114.The compound of claim 1, wherein R3 is a branched tail.115.The compound of claim 1, wherein R4 is a branched tail.116.The compound of claim 1, wherein R3 is selected from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112 or T-0113.117.The compound of claim 1, wherein R4 is selected from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112 or T-0113.118.The compound of claim 1, wherein the number of carbon atoms in R3 ranges from 5 to 30.119.The compound of claim 1, wherein the number of carbon atoms in R4 ranges from 5 to 30.120.The compound of claim 1, wherein the number of carbon atoms in R3 is selected from: 12, 14, 15, 16, 17, 18, 20, 21, 24, 25 or 28.121.The compound of claim 1, wherein the number of carbon atoms in R4 is selected from: 12, 14, 15, 16, 17, 18, 20, 21, 24, 25 or 28.122.The compound of claim 1, wherein the compound is selected from Group 1.123.The compound of claim 1, wherein the compound is selected from Group 2.124.The compound of claim 1, wherein the compound is selected from Group 3.125.A lipid nanoparticle comprising a compound of any one of claims 1 to 124, 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.126.A pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) mRNA; (ii) a compound of any one of claims 1 to 124, 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; wherein administration of the mRNA to the subject results in a higher expression relative to administration of a circular RNA to the subject.127.A pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) circular RNA; (ii) a compound of any one of claims 1 to 124, 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; wherein administration of the circular RNA to the subject results in a higher expression relative to administration of a mRNA to the subject.128.The pharmaceutical composition of claims 126 and 127, further comprising a conjugated lipid.129.The pharmaceutical composition of claim 128, wherein the conjugated lipid comprises a polyethylene glycol-conjugated lipid.130.The pharmaceutical composition of any one of claims 126 to 129, wherein the pharmaceutical composition is preferentially distributed into a targeted organ of a subject in need thereof.131.The pharmaceutical composition of claim 130, wherein the targeted organ is an eye, heart, lung, kidney, liver, or spleen of the subject.132.The pharmaceutical composition of any one of claims 126 to 131, wherein the pharmaceutical composition is preferentially distributed into a liver cell.133.The pharmaceutical composition of claim 132, wherein the liver cell is a hepatocyte.134.The pharmaceutical composition of any one of claims 126 to 131, wherein the pharmaceutical composition is preferentially distributed into a spleen cell.135.The pharmaceutical composition of claim 134, wherein the spleen cell is a spleenocyte.136.The pharmaceutical composition of any one of claims 126 to 135, wherein the nucleic acid encodes a bioactive protein or enzyme.137.The pharmaceutical composition of claim 136, wherein the bioactive protein or enzyme is produced in or systemically excreted from a liver cell.138.The pharmaceutical composition of claim 137, wherein the bioactive protein or enzyme is produced in or systemically excreted from a cell of a lung, heart, or ocular, or central nervous system.