Lipid compounds, lipid nanoparticles, and pharmaceutical compositions

Abstract

Provided herein are lipid compounds, e.g., a compound of Formula (I). Also provided are lipid nanoparticles and pharmaceutical compositions, each comprising a lipid compound of Formula (I).

Description

Attorney Docket No.277A003WO01 LIPID COMPOUNDS, LIPID NANOPARTICLES, AND PHARMACEUTICAL COMPOSITIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Application Nos.63 / 584,052, filed September 20, 2023, and 63 / 646,286, filed May 13, 2024; the disclosure of each of which is incorporated herein by reference in its entirety. FIELD

[0002] Provided herein are lipid compounds. Also provided are lipid nanoparticles and pharmaceutical compositions, each comprising a lipid compound. BACKGROUND

[0003] Lipid 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, 1084-7; 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 an 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 therapeutic agent efficiently, especially a highly charged nucleic acid, such as an mRNA. 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 mRNA molecule has to reach specific target cells and produce sufficient proteins of interest. Hou et al., Nat. Rev. Mater.2021, 6, 1078-94. Therefore, there is a need for a lipid compound for delivering a therapeutic agent efficiently. SUMMARY OF THE DISCLOSURE

[0004] Provided herein is a compound of Formula (I):Attorney Docket No.277A003WO01 or an enantiomer, a mixture of of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: A, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4or CH(OH); A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; or (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1and L4are each independently a bond, C1-20 alkylene, C1-20 heteroalkylene, C2-20alkenylene, or C2-20alkynylene; L2and L3are each independently a bond, C1-20alkylene, C1-20heteroalkylene, C2-20 alkenylene, C2-20 alkynylene, C3-20 cycloalkylene, heteroarylene, or heterocyclylene; R1and R4are each independently azido, heteroaryl, heterocyclyl, or –NR4aR4b; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, orAttorney Docket No.277A003WO01 heterocyclyl; R2aand R3aare each independently absent, hydrogen, C1-20 alkyl, C1-20 heteroalkyl, C2-20alkenyl, C2-20alkynyl, C1-20alkoxy, C1-20heteroalkoxy, C2-20alkenoxy, or C2-20alkynoxy; R2band R3bare each independently C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20alkynyl, C3-10cycloalkyl, C1-20alkoxy, C1-20heteroalkoxy, C2-20alkenoxy, or C2-20alkynoxy; R4aand R4bare each independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently a bond, C(H), or N, with the proviso that, when X is a bond, R2ais absent; and when Z is a bond, R3ais absent; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy 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) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, 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) Rband Rctogether 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;Attorney Docket No.277A003WO01 wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0005] Also provided herein is a compound of Formula (I): or an enantiomer, a mixture ofof two or more diastereomers, 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, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4or CH(OH); A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; orAttorney Docket No.277A003WO01 (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1, L2, L3, and L4are each independently a bond, C1-20alkylene, C1-20heteroalkylene, C2-20 alkenylene, or C2-20 alkynylene; R1and R4are each independently azido, heteroaryl, heterocyclyl, or –NR4aR4b; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; R2aand R3aare each independently hydrogen, C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R2band R3bare each independently C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20alkynyl, C1-20alkoxy, C1-20heteroalkoxy, C2-20alkenoxy, or C2-20alkynoxy; R4aand R4bare each independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently C(H) or N; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy 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, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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,Attorney Docket No.277A003WO01 –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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis 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) Rband Rctogether 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 Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0006] Additionally provided herein is a compound of Formula (I): or an enantiomer, a mixture ofof two or more diastereomers, 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, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4; A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–,Attorney Docket No.277A003WO01 –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; or (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1, L2, L3, and L4are each independently a bond, C1-20 alkylene, C1-20 heteroalkylene, C2-20alkenylene, or C2-20alkynylene; R1and R4are each independently heterocyclyl or –NR4aR4b; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; R2aand R3aare each independently hydrogen, C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20alkynyl, C1-20alkoxy, C1-20heteroalkoxy, C2-20alkenoxy, or C2-20alkynoxy; R2band R3bare each independently C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R4aand R4bare each independently hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently C(H) or N; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy is optionally substituted with one or more, in one embodiment, one, two,Attorney Docket No.277A003WO01 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, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15aralkyl, 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) Rband Rctogether 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 Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0007] Furthermore, provided herein is a lipid nanoparticle comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variantAttorney Docket No.277A003WO01 thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0008] Provided herein is a lipid nanoparticle comprising (i) a nucleic acid and (ii) a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0009] Provided herein is a pharmaceutical composition comprising a lipid nanoparticle that comprises (i) a nucleic acid and (ii) a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. DETAILED DESCRIPTION

[0010] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0011] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biochemistry 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.

[0012] 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 C1-6and branched C3-6alkyl 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 allAttorney Docket No.277A003WO01 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).

[0013] 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 substituted with one or more substituents Q as described herein. For example, C1-6alkanediyl 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)–.

[0014] 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),Attorney Docket No.277A003WO01 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 C3-6heteroalkyl 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)CH3and –NHC(O)CH2CH3.

[0015] 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 C1-6and branched C3-6heteroalkylene 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–.

[0016] 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 oneAttorney Docket No.277A003WO01 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, C2-6alkenyl 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).

[0017] 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).Attorney Docket No.277A003WO01

[0018] 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).

[0019] 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, C2-6alkynediyl 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).Attorney Docket No.277A003WO01

[0020] 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.

[0021] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 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. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohex-1,4- diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane-1,1-diyl, cycloheptane- 1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline-1,1-diyl, decaline-1,2-diyl, and decaline-1,8-diyl), and adamantdiyl (including all isomeric forms, e.g., adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0022] 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), orAttorney Docket No.277A003WO01 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.

[0023] 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.

[0024] 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,Attorney Docket No.277A003WO01 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.

[0025] The terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. For a heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring. Each ring of a heteroarylene 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 heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryleneAttorney Docket No.277A003WO01 groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrroldiyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazoldiyl, triazinediyl, and triazoldiyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3-b]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-b]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-b]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridindiyl, imidazo[4,5-b]pyridindiyl, and imidazo[4,5-c]- pyridindiyl), imidazothiazoldiyl (including all isomeric forms, e.g., imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazoldiyl), indazoldiyl, indolizindiyl, indoldiyl, isobenzofurandiyl, isobenzothiendiyl (i.e., benzo[c]thiendiyl), isoindoldiyl, isoquinolindiyl, naphthyridindiyl (including all isomeric forms, e.g., 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7- naphthyridindiyl, and 1,8-naphthyridindiyl), oxazolopyridindiyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridindiyl, oxazolo[4,5-c]pyridindiyl, oxazolo[5,4-b]pyridindiyl, and oxazolo[5,4-c]pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridindiyl, pyrrolo[2,3-c]pyridindiyl, pyrrolo[3,2-b]- pyridindiyl, and pyrrolo[3,2-c]pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidindiyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]- pyrimidindiyl and [1,2,3]thiadiazolo[4,5-d]pyrimidindiyl), and thienopyridindiyl (including all isomeric forms, e.g., thieno[2,3-b]pyridindiyl, thieno[2,3-c]pyridindiyl, thieno[3,2-b]pyridindiyl, and thieno[3,2-c]pyridindiyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.

[0026] 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, eachAttorney Docket No.277A003WO01 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.

[0027] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring. In certain embodiments, the heterocyclylene 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 heterocyclylene is a monocyclic, bicyclic,Attorney Docket No.277A003WO01 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 heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodioxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazindiyl, 3,4-dihydrobenzo[c][1,2]oxazindiyl, and 3,4-dihydrobenzo[d][1,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrroldiyl, dioxolandiyl, 1,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydroindoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1,3,5-trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.

[0028] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and / or iodo.

[0029] The term “alkoxy” or “alkyloxy” refers to –O–alkyl, where the alkyl group is as defined herein.

[0030] The term “heteroalkoxy” or “heteroalkyloxy” refers to –O–heteroalkyl, where the heteroalkyl group is as defined herein.

[0031] The term “alkenoxy” or “alkenyloxy” refers to –O–alkenyl, where the alkenyl group is as defined herein.

[0032] The term “alkynoxy” or “alkynyloxy” refers to –O–alkynyl, where the alkynylAttorney Docket No.277A003WO01 group is as defined herein.

[0033] 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, cycloalkylene, aryl, aralkyl, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene, alkoxy, heteroalkoxy, alkenoxy, or alkynoxy, 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, –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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, 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) Rband Rctogether 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.”

[0034] In one embodiment, each Qais 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, C6-14aryl, C7-15aralkyl, 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, –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,Attorney Docket No.277A003WO01 –NReC(S)ORf, –NReC(S)NRfRg, –NReS(O)Rh, –NReS(O)2Rh, –NReS(O)NRfRg, –NReS(O)2NRfRg, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0035] 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.

[0036] 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.

[0037] 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-11Attorney Docket No.277A003WO01 (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 be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, or any oxygen can be18O, as example, where feasible according to the judgment of one of ordinary skill in the art.

[0038] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g.,1H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0039] The term “isotopic enrichment factor” refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.Attorney Docket No.277A003WO01

[0040] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.

[0041] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).

[0042] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon-12 (12C) and carbon-13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.

[0043] The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon-13 at a given position in a molecule in the place of carbon. For example, carbon-13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).

[0044] The terms “substantially pure” and “substantially homogeneous” mean, whenAttorney Docket No.277A003WO01 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.

[0045] 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.

[0046] 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)–.

[0047] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixtureAttorney Docket No.277A003WO01 of two or more 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.”

[0048] The phrase “a diastereomer, a mixture of two or more 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) 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 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.” Compounds

[0049] In one embodiment, provided herein is a compound of Formula (I): or an enantiomer, a mixture ofof two or more diastereomers, 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, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4or CH(OH); A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–,Attorney Docket No.277A003WO01 –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; or (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1and L4are each independently a bond, C1-20 alkylene, C1-20 heteroalkylene, C2-20alkenylene, or C2-20alkynylene; L2and L3are each independently a bond, C1-20alkylene, C1-20heteroalkylene, C2-20 alkenylene, C2-20 alkynylene, C3-20 cycloalkylene, heteroarylene, or heterocyclylene; R1and R4are each independently azido, heteroaryl, heterocyclyl, or –NR4aR4b; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; R2aand R3aare each independently absent, hydrogen, C1-20alkyl, C1-20heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R2band R3bare each independently C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C2-20 alkynyl, C3-10 cycloalkyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R4aand R4bare each independently hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently a bond, C(H), or N, with the proviso that, when XAttorney Docket No.277A003WO01 is a bond, R2ais absent; and when Z is a bond, R3ais absent; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy 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) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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) Rband Rctogether 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 Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6Attorney Docket No.277A003WO01 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0050] In another embodiment, provided herein is a compound of Formula (I): or an enantiomer, a mixture of of two or morediastereomers, a tautomer, a two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: A, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4or C(H)(OH); A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; or (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1, L2, L3, and L4are each independently a bond, C1-20 alkylene, C1-20 heteroalkylene, C2-20alkenylene, or C2-20alkynylene; and R4are each independently azido, heteroaryl, heterocyclyl, or –NR4aR4b; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6Attorney Docket No.277A003WO01 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; R2aand R3aare each independently hydrogen, C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R2band R3bare each independently C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20alkynyl, C1-20alkoxy, C1-20heteroalkoxy, C2-20alkenoxy, or C2-20alkynoxy; R4aand R4bare each independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently C(H) or N; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy 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, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15aralkyl, 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) Rband Rctogether 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 Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl,Attorney Docket No.277A003WO01 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0051] In yet another embodiment, provided herein is a compound of Formula (I): or an enantiomer, a mixture ofof two or more diastereomers, 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, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4; A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; or (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–,Attorney Docket No.277A003WO01 –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1, L2, L3, and L4are each independently a bond, C1-20 alkylene, C1-20 heteroalkylene, C2-20alkenylene, or C2-20alkynylene; R1and R4are each independently heterocyclyl or –NR4aR4b; each R1a, R1b, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; R2aand R3aare each independently hydrogen, C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R2band R3bare each independently C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R4aand R4bare each independently hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently C(H) or N; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy 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) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, 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, –SRa, –S(O)Ra, –S(O)2Ra,Attorney Docket No.277A003WO01 –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15aralkyl, 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) Rband Rctogether 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 Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0052] In certain embodiments, A is C(H)–A4–L4–R4, wherein A4, L4, and R4are each as defined herein. In certain embodiments, A is C(H)(OH).

[0053] In one embodiment, provided herein is a compound of Formula (II): or an enantiomer, a mixture ofof two or more diastereomers, 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, R4, R2a, R2b, R3a, R3b, A1, A2, A3, A4, L1, L2, L3, L4, X, and Z are each as defined herein.

[0054] In certain embodiments, in Formula (II), A2is a bond. In certain embodiments, inAttorney Docket No.277A003WO01 Formula (II), A2is –C(O)O–. In certain embodiments, in Formula (II), A2is –C(O)S–. In certain embodiments, in Formula (II), A2is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (II), A2is –C(O)N(H)–. In certain embodiments, in Formula (II), A2is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (II), A2is –C(S)N(H)–. In certain embodiments, in Formula (II), A2is –CH2O–. In certain embodiments, in Formula (II), A2is –CH2OC(O)–. In certain embodiments, in Formula (II), A2is –C(O)O–, –CH2O–, or –CH2OC(O)–.

[0055] In certain embodiments, in Formula (II), A3is a bond. In certain embodiments, in Formula (II), A3is –C(O)O–. In certain embodiments, in Formula (II), A3is –C(O)S–. In certain embodiments, in Formula (II), A3is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (II), A3is –C(O)N(H)–. In certain embodiments, in Formula (II), A3is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (II), A3is –C(S)N(H)–. In certain embodiments, in Formula (II), A3is –CH2O–. In certain embodiments, in Formula (II), A3is –CH2OC(O)–. In certain embodiments, in Formula (II), A3is –C(O)O–, –CH2O–, or –CH2OC(O)–.

[0056] In certain embodiments, in Formula (II), A2and A3are each independently –C(O)O–, –CH2O–, or –CH2OC(O)–.

[0057] In one embodiment, provided herein is a compound of Formula (III): O R2aR1L1A1OL2X R2b3(III)O3b4L Z R R L4A4R3aO or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, 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, R4, R2a, R2b, R3a, R3b, A1, A4, L1, L2, L3, L4, X, and Z are each as defined herein.

[0058] In another embodiment, provided herein is a compound of Formula (IV):Attorney Docket No.277A003WO01 R2aR1L1A1OL2X R2b(IV)or an enantiomer, a mixture of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, A1, A4, L1, L2, L3, L4, X, and Z are each as defined herein.

[0059] In yet another embodiment, provided herein is a compound of Formula (V): or an enantiomer, a mixture of two or morediastereomers, 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, R4, R2a, R2b, R3a, R3b, A1, A4, L1, L2, L3, L4, X, and Z are each as defined herein.

[0060] In certain embodiments, in any one of Formulae (II) to (V), A1is –C(O)O–. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(O)S–. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(O)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(S)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A1is –OC(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –OC(O)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A1is –OC(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –OC(S)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A1is –N(R1a)C(O)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –N(H)C(O)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A1is –N(R1a)C(S)N(R1d)–, wherein R1aandAttorney Docket No.277A003WO01 R1dare each as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –N(H)C(S)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(O)O–, –OC(O)N(R1b)–, or –OC(S)N(R1b)–, wherein each R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A1is –C(O)O–, –OC(O)N(H)–, or –OC(S)N(H)–.

[0061] In certain embodiments, in any one of Formulae (II) to (V), A4is –C(O)O–. In certain embodiments, in any one of Formulae (II) to (V), A4is –C(O)S–. In certain embodiments, in any one of Formulae (II) to (V), A4is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (I) to (V), A4is –C(O)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A4is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (I) to (V), A4is –C(S)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A4is –OC(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A4is –OC(O)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A4is –OC(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A4is –OC(S)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A4is –N(R1a)C(O)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A4is –N(H)C(O)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A4is –N(R1a)C(S)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A4is –N(H)C(S)N(H)–. In certain embodiments, in any one of Formulae (II) to (V), A4is –C(O)O–, –OC(O)N(R1b)–, or –OC(S)N(R1b)–, wherein each R1bis as defined herein. In certain embodiments, in any one of Formulae (II) to (V), A4is –C(O)O–, –OC(O)N(H)–, or –OC(S)N(H)–.

[0062] In one embodiment, provided herein is a compound of Formula (VI):Attorney Docket No.277A003WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U1and U4are each independently O or S; V1and V4are each independently a bond, O, or N(R1b); and R1, R4, R1b, R2a, R2b, R3a, R3b, L1, L2, L3, L4, X, and Z are each as defined herein.

[0063] In another embodiment, provided herein is a compound of Formula (VII): or a diastereomer, a a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0064] In yet another embodiment, provided herein is a compound of Formula (VIII): or a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0065] In yet another embodiment, provided herein is a compound of Formula (IX):Attorney Docket No.277A003WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, 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, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0066] In yet another embodiment, provided herein is a compound of Formula (X): or a diastereomer, a a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0067] In yet another embodiment, provided herein is a compound of Formula (XI): or a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0068] In yet another embodiment, provided herein is a compound of Formula (XII): or an enantiomer, aof two or moreAttorney Docket No.277A003WO01 diastereomers, 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, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0069] In yet another embodiment, provided herein is a compound of Formula (XIII): or a diastereomer, a a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0070] In still another embodiment, provided herein is a compound of Formula (XIV): or a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R4, R2a, R2b, R3a, R3b, L1, L2, L3, L4, U1, U4, V1, V4, X, and Z are each as defined herein.

[0071] In certain embodiments, in any one of Formulae (I) to (XIV), L4is C1-20 alkylene or C1-20heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), L4is C1-6 alkylene or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), L4is C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), L4is C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one ofAttorney Docket No.277A003WO01 Formulae (I) to (XIV), L4is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), L4is methanediyl, ethane-1,2-diyl, propane- 1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, or hexane-1,6-diyl, each optionally substituted with one or more substituents Q.

[0072] In certain embodiments, in any one of Formulae (I) to (XIV), R4is azido.

[0073] In certain embodiments, in any one of Formulae (I) to (XIV), R4is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 5- or 6- membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is maleimido or 11,12- didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl.

[0074] In certain embodiments, in any one of Formulae (I) to (XIV), R4is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is ionizable heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is N-containing heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is ionizable N-containing heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 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 (I) to (XIV), R4is 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 4-membered heterocyclyl, optionally substituted with one or more substituents Q.Attorney Docket No.277A003WO01 In certain embodiments, in any one of Formulae (I) to (XIV), R4is 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXV), R4is azetidin-1-yl, azetidin-3-yl, pyrrolidin- 1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, morpholin-4-yl, or piperazin- 1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXV), R4is azetidin-1-yl, 1-methylazetidin-3-yl, pyrrolidin-1-yl, 2- methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperidin-3-yl, 1-methyl- piperidin-4-yl, morpholin-4-yl, or 4-methylpiperazin-1-yl.

[0075] In certain embodiments, in any one of Formulae (I) to (XIV), R4is –NR4aR4b, wherein R4aand R4bare each as defined herein. In certain embodiments, in any one of Formulae (I) to (XIV), R4is –NR4aR4b, wherein R4aand R4bare each independently C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is –NR4aR4b, wherein R4aand R4bare each independently methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XIV), R4is dimethylamino or ethyl(methyl)amino.

[0076] In certain embodiments, in any one of Formulae (VI) to (XIV), U1is O. In certain embodiments, in any one of Formulae (VI) to (XIV), U1is S.

[0077] In certain embodiments, in any one of Formulae (VI) to (XIV), U4is O. In certain embodiments, in any one of Formulae (VI) to (XIV), U4is S.

[0078] In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each O. In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each S.

[0079] In certain embodiments, in any one of Formulae (VI) to (XIV), V1is a bond. InAttorney Docket No.277A003WO01 certain embodiments, in any one of Formulae (VI) to (XIV), V1is O. In certain embodiments, in any one of Formulae (VI) to (XIV), V1is N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), V1is N(H). In certain embodiments, in any one of Formulae (VI) to (XIV), V1is a bond or N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), V1is a bond or N(H).

[0080] In certain embodiments, in any one of Formulae (VI) to (XIV), V4is a bond. In certain embodiments, in any one of Formulae (VI) to (XIV), V4is O. In certain embodiments, in any one of Formulae (VI) to (XIV), V4is N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), V4is N(H). In certain embodiments, in any one of Formulae (VI) to (XIV), V4is a bond or N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), V4is a bond or N(H).

[0081] In certain embodiments, in any one of Formulae (VI) to (XIV), V1and V4are each a bond. In certain embodiments, in any one of Formulae (VI) to (XIV), V1and V4are each O. In certain embodiments, in any one of Formulae (VI) to (XIV), V1and V4are each independently N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), V1and V4are each N(H).

[0082] In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each O; and V1and V4are each a bond. In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each O; and V1and V4are each independently N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each O; and V1and V4are each N(H). In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each S; and V1and V4are each independently N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (VI) to (XIV), U1and U4are each S; and V1and V4are each N(H).

[0083] In certain embodiments, in Formula (I), A and A1together with the carbon atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), A and A1together with the carbon atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), A and A1together with the carbonAttorney Docket No.277A003WO01 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 Formula (I), A and A1together with the carbon atom to which they are attached form 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), A and A1together with the carbon atom to which they are attached form 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), A and A1together with the carbon atom to which they are attached form 5- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), A and A1together with the carbon atom to which they are attached form 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), A and A1together with the carbon atom to which they are attached form 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0084] In one embodiment, provided herein is a compound of Formula (XV): or an enantiomer, a mixtureof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R5is (i) hydrogen or deuterium; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R1, R2a, R2b, R3a, R3b, A2, A3, L1, L2, L3, X, and Z are each as defined herein.

[0085] In certain embodiments, in Formula (XV), A2is a bond. In certain embodiments, in Formula (XV), A2is –C(O)O–. In certain embodiments, in Formula (XV), A2is –C(O)S–. In certain embodiments, in Formula (XV), A2is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XV), A2is –C(O)N(H)–. In certain embodiments, in Formula (XV), A2is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XV), A2is –C(S)N(H)–. In certain embodiments, in Formula (XV), A2is –CH2O–. In certain embodiments, in Formula (XV), A2is –CH2OC(O)–. In certain embodiments, in FormulaAttorney Docket No.277A003WO01 (XV), A2is –C(O)O–, –CH2O–, or –CH2OC(O)–.

[0086] In certain embodiments, in Formula (XV), A3is a bond. In certain embodiments, in Formula (XV), A3is –C(O)O–. In certain embodiments, in Formula (XV), A3is –C(O)S–. In certain embodiments, in Formula (XV), A3is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XV), A3is –C(O)N(H)–. In certain embodiments, in Formula (XV), A3is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XV), A3is –C(S)N(H)–. In certain embodiments, in Formula (XV), A3is –CH2O–. In certain embodiments, in Formula (XV), A3is –CH2OC(O)–. In certain embodiments, in Formula (XV), A3is –C(O)O–, –CH2O–, or –CH2OC(O)–.

[0087] In certain embodiments, in Formula (XV), A2and A3are each independently –C(O)O–, –CH2O–, or –CH2OC(O)–.

[0088] In one embodiment, provided herein is a compound of Formula (XVI): or an enantiomer, aof two or more diastereomers, 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, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0089] In another embodiment, provided herein is a compound of Formula (XVII): O R2aor a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.Attorney Docket No.277A003WO01

[0090] In yet another embodiment, provided herein is a compound of Formula (XVIII): or a diastereomer, a a mixture of two or moretautomers, or an isotopic or a salt, solvate, or hydrate thereof; wherein R1, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0091] In yet another embodiment, provided herein is a compound of Formula (XIX): or an enantiomer, a mixtureof two or more diastereomers, 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, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0092] In yet another embodiment, provided herein is a compound of Formula (XX): R2aO or a diastereomer, a mixturea mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0093] In yet another embodiment, provided herein is a compound of Formula (XXI):Attorney Docket No.277A003WO01 or a diastereomer, a mixture of two or more diastereomers, 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, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0094] In yet another embodiment, provided herein is a compound of Formula (XXII): or an enantiomer, a of two or morediastereomers, 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, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0095] In yet another embodiment, provided herein is a compound of Formula (XXIII): O R2aor a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0096] In still another embodiment, provided herein is a compound of Formula (XXIV): O R2aor a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R5, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as definedAttorney Docket No.277A003WO01 herein.

[0097] In certain embodiments, in any one of Formulae (XV) to (XXIV), R5is (i) hydrogen or deuterium; or (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (XV) to (XXIV), R5is hydrogen. In certain embodiments, in any one of Formulae (XV) to (XXIV), R5is deuterium. In certain embodiments, in any one of Formulae (XV) to (XXIV), R5is C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (XV) to (XXIV), R5is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (XV) to (XXIV), R5is hydrogen or methyl.

[0098] In one embodiment, provided herein is a compound of Formula (XXV): R2aR1L1A1A2L2X R2bor an enantiomer, a mixtureof two or more diastereomers, 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, R2a, R2b, R3a, R3b, A1, A2, A3, L1, L2, L3, X, and Z are each as defined herein.

[0099] In certain embodiments, in Formula (XXV), A2is –C(O)O–. In certain embodiments, in Formula (XXV), A2is –C(O)S–. In certain embodiments, in Formula (XXV), A2is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV), A2is –C(O)N(H)–. In certain embodiments, in Formula (XXV), A2is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV), A2is –C(S)N(H)–.

[0100] In certain embodiments, in Formula (XXV), A3is –C(O)O–. In certain embodiments, in Formula (XXV), A3is –C(O)S–. In certain embodiments, in Formula (XXV), A3is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV), A3is –C(O)N(H)–. In certain embodiments, in Formula (XXV), A3is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV), A3is –C(S)N(H)–.

[0101] In one embodiment, provided herein is a compound of Formula (XXVI):Attorney Docket No.277A003WO01 or an enantiomer, a of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2a, R2b, R3a, R3b, A1, L1, L2, L3, X, and Z are each as defined herein.

[0102] In certain embodiments, in Formula (XXV) or (XXVI), A1is a bond. In certain embodiments, in Formula (XXV) or (XXVI), A1is –C(O)O–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –C(O)S–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –C(O)N(H)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –C(S)N(H)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –OC(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –OC(O)N(H)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –OC(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –OC(S)N(H)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(R1b)–, wherein R1bis as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(R1b)–, wherein R1bis C1-6alkyl, optionally substituted with one or substituents Q. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(CH3)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(R1a)C(O)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(H)C(O)N(H)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(R1a)C(S)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is –N(H)C(S)N(H)–. In certain embodiments, in Formula (XXV) or (XXVI), A1is a bond, –C(O)O–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, or –N(R1b)–, wherein each R1bis as defined herein. In certain embodiments, in Formula (XXV) or (XXVI), A1is a bond, –C(O)O–, –OC(O)N(H)–, –OC(S)N(H)–, or –N(CH3)–.Attorney Docket No.277A003WO01

[0103] In one embodiment, provided herein is a compound of Formula (XXVII): or an enantiomer, a of two or morediastereomers, a a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2a, R2b, R3a, R3b, L1, L2, L3, U1, V1, X, and Z are each as defined herein.

[0104] In another embodiment, provided herein is a compound of Formula (XXVIII): or a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2a, R2b, R3a, R3b, L1, L2, L3, U1, V1, X, and Z are each as defined herein.

[0105] In yet another embodiment, provided herein is a compound of Formula (XXIX): or a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2a, R2b, R3a, R3b, L1, L2, L3, U1, V1, X, and Z are each as defined herein.

[0106] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1is O. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1is S.Attorney Docket No.277A003WO01

[0107] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U4is O. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U4is S.

[0108] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1and U4are each O. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1and U4are each S.

[0109] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1is a bond. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1is O. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1is N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1is N(H). In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1is a bond or N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1is a bond or N(H).

[0110] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V4is a bond. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V4is O. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V4is N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V4is N(H). In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V4is a bond or N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V4is a bond or N(H).

[0111] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1and V4are each a bond. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1and V4are each O. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1and V4are each independently N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), V1and V4are each N(H).

[0112] In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1and U4are each O; and V1and V4are each a bond. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1and U4are each O; and V1and V4are each independently N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) toAttorney Docket No.277A003WO01 (XXIX), U1and U4are each O; and V1and V4are each N(H). In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1and U4are each S; and V1and V4are each independently N(R1b), wherein R1bis as defined herein. In certain embodiments, in any one of Formulae (XXVII) to (XXIX), U1and U4are each S; and V1and V4are each N(H).

[0113] In one embodiment, provided herein is a compound of Formula (XXX): R1bO R2aN or an enantiomer, a mixture of two or morediastereomers, 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, R1b, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0114] In another embodiment, provided herein is a compound of Formula (XXXI): or a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R1b, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as defined herein.

[0115] In yet another embodiment, provided herein is a compound of Formula (XXXII): R1bO R2aor a diastereomer, aa mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R1b, R2a, R2b, R3a, R3b, L1, L2, L3, X, and Z are each as definedAttorney Docket No.277A003WO01 herein.

[0116] In certain embodiments, in any one of Formulae (XXX) to (XXXII), R1bis (i) hydrogen; or (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (XXX) to (XXXII), R1bis hydrogen. In certain embodiments, in any one of Formulae (XXX) to (XXXII), R1bis C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (XXX) to (XXXII), R1bis methyl.

[0117] In certain embodiments, in any one of Formulae (I) to (XXXII), R1is azido.

[0118] In certain embodiments, in any one of Formulae (I) to (XXXII), R1is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 5- or 6- membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is maleimido or 11,12- didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl.

[0119] In certain embodiments, in any one of Formulae (I) to (XXXII), R1is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is ionizable heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is N- containing heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is ionizable N-containing heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 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 (I) to (XXXII), R1is 3-membered heterocyclyl,Attorney Docket No.277A003WO01 optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 5- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is azetidin-1- yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, morpholin-4-yl, or piperazin-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is azetidin-1-yl, 1-methyl- azetidin-3-yl, pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-4-yl, or 4-methylpiperazin-1-yl.

[0120] In certain embodiments, in any one of Formulae (I) to (XXXII), R1is –NR4aR4b, wherein R4aand R4bare each as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is –NR4aR4b, wherein R4aand R4bare each independently C1-6 alkyl or C1-6 heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is –NR4aR4b, wherein R4aand R4bare each independently methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R1is dimethylamino or ethyl(methyl)amino.

[0121] In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais (i) absent or hydrogen; or (ii) C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais (i) hydrogen; or (ii) C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais (i) hydrogen; or (ii) C1-20alkyl, C2-20alkenyl, or C1-20alkoxy, each optionallyAttorney Docket No.277A003WO01 substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais absent and X is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais hydrogen. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais –(CH2)mCH3, wherein m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais C2-20alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais C1-20 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais –O(CH2)nCH3, wherein n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais hydrogen, ethyl, butyl, hexyl, heptyl, octyl, nonyl, undecyl, pentadecyl, hexadecyl, heptadecyl, (Z)-non-2-enyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadec-8- enyl, (Z)-heptadec-9-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)- heptadec-8,11-dienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (9Z,12Z)-octadec-9,12-dienyl. In certain embodiments, in any one of Formulae (I) to (XXXII), R2ais hydrogen, eth-1-yl, but-1- yl, hex-1-yl, hept-1-yl, oct-1-yl, non-1-yl, undec-1-yl, pentadec-1-yl, hexadec-1-yl, heptadec-1- yl, (Z)-non-2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)- heptadec-9-en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec- 8,11-dien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (9Z,12Z)-octadec-9,12-dien-1-yl.

[0122] In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-20 alkyl, C1-20heteroalkyl, C2-20alkenyl, C3-10cycloalkyl, C1-20alkoxy, C1-20heteroalkoxy, or C2-20alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-20alkyl, C2-20 alkenyl, or C1-20 alkoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-10alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis –(CH2)mCH3, wherein m is asAttorney Docket No.277A003WO01 defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis heptyl or tridecyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis hept-2-yl or 1-tridecyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis 6-methylhept-2-yl or 4,8,12-trimethyltridec-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-20heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis cyclohexenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis cyclohex- 1-en-1-yl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis 2,6,6-trimethylcyclohex-1-en-1-yl. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis C1-20alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis –O(CH2)nCH3, wherein n is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis ethyl, butyl, hexyl, heptyl, octyl, nonyl, undecyl, pentadecyl, hexadecyl, heptadecyl, (Z)-non-2-enyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)- heptadec-8-enyl, (Z)-heptadec-9-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)-heptadec-8,11-dienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (9Z,12Z)-octadec- 9,12-dienyl. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis eth-1-yl, but- 1-yl, hex-1-yl, hept-1-yl, oct-1-yl, non-1-yl, undec-1-yl, pentadec-1-yl, hexadec-1-yl, heptadec- 1-yl, (Z)-non-2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)- heptadec-9-en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec- 8,11-dien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (9Z,12Z)-octadec-9,12-dien-1-yl. In certain embodiments, in any one of Formulae (I) to (XXXII), R2bis 6-methylhept-2-yl, 4,8,12- trimethyltridec-1-yl, or cyclohex-1-en-1-yl.

[0123] In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais (i) absentAttorney Docket No.277A003WO01 or hydrogen; or (ii) C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais (i) hydrogen; or (ii) C1-20alkyl, C1-20heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais (i) hydrogen; or (ii) C1-20alkyl, C2-20alkenyl, or C1-20alkoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais absent and Z is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais hydrogen. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais C1-20alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais –(CH2)mCH3, wherein m is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais C1-20 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais –O(CH2)nCH3, wherein n is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais hydrogen, ethyl, butyl, hexyl, heptyl, octyl, nonyl, undecyl, pentadecyl, hexadecyl, heptadecyl, (Z)-non-2-enyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadec-8-enyl, (Z)-heptadec-9-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)-heptadec-8,11-dienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (9Z,12Z)-octadec-9,12-dienyl. In certain embodiments, in any one of Formulae (I) to (XXXII), R3ais hydrogen, eth-1-yl, but-1-yl, hex-1- yl, hept-1-yl, oct-1-yl, non-1-yl, undec-1-yl, pentadec-1-yl, hexadec-1-yl, heptadec-1-yl, (Z)-non- 2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-heptadec-9- en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1- yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (9Z,12Z)-octadec-9,12-dien-1-yl.

[0124] In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-20alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C3-10 cycloalkyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C1-20alkoxy, C1-20heteroalkoxy, or C2-20alkenoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-20Attorney Docket No.277A003WO01 alkyl, C2-20 alkenyl, or C1-20 alkoxy, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-10 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis –(CH2)mCH3, wherein m is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis heptyl or tridecyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis hept-2-yl or tridec-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis 6-methylhept-2-yl or 4,8,12-trimethyltridec-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C2-20alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C1-20 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis –O(CH2)nCH3, wherein n is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis C3-10monocyclic cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis cyclohexenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis cyclohex-1-en-1-yl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis 2,6,6-trimethylcyclohex-1-en-1-yl. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis ethyl, butyl, hexyl, heptyl, octyl, nonyl, undecyl, pentadecyl, hexadecyl, heptadecyl, (Z)-non-2-enyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadec-8- enyl, (Z)-heptadec-9-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)- heptadec-8,11-dienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (9Z,12Z)-octadec-9,12-dienyl. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis eth-1-yl, but-1-yl, hex-1- yl, hept-1-yl, oct-1-yl, non-1-yl, undec-1-yl, pentadec-1-yl, hexadec-1-yl, heptadec-1-yl, (Z)-non- 2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-heptadec-9-Attorney Docket No.277A003WO01 en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1- yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (9Z,12Z)-octadec-9,12-dien-1-yl. In certain embodiments, in any one of Formulae (I) to (XXXII), R3bis 6-methylhept-2-yl, 4,8,12- trimethyltridec-1-yl, or cyclohex-1-en-1-yl.

[0125] In certain embodiments, in any one of Formulae (I) to (XXXII), L1is (i) a bond; or (ii) C1-20alkylene or C1-20heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is (i) a bond; or (ii) C1-6 alkylene or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is –(CH2)p–, wherein p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L1is methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4- diyl, pentane-1,5-diyl, or hexane-1,6-diyl, each optionally substituted with one or more substituents Q.

[0126] In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (i) a bond; or (ii) C1-20 alkylene, C1-20 heteroalkylene, C2-20 alkenylene, C3-20 cycloalkylene, or heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (i) a bond; or (ii) C1-20alkylene, C1-20heteroalkylene, or C2-20 alkenylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (i) a bond; or (ii) C1-20 alkylene or C1-20heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is –(CH2)p–, wherein p is as defined herein. In certain embodiments, in any one ofAttorney Docket No.277A003WO01 Formulae (I) to (XXXII), L2is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is –OC(O)(CH2)q–, wherein q is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is –C(O)O(CH2)q–, wherein q is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is ethanediyl, butanediyl, pentanediyl, heptanediyl, –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is ethane-1,2-diyl, butane-1,4-diyl, petane-1,5-diyl, heptane-1,7-diyl, –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q.

[0127] In certain embodiments, in any one of Formulae (I) to (XXXII), L2is C2-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is heptadeca-2,4,6,8,10,12,14,16-octaene-2,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (2Z,4E,6E,8E,10E,12E,14E,16E)-heptadeca-2,4,6,8,10,12,14,16- octaene-2,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (2Z,4E,6E,8E,10E,12E,14E,16E)- 6,11,15-trimethylheptadeca-2,4,6,8,10,12,14,16-octaene-2,17-diyl.

[0128] In certain embodiments, in any one of Formulae (I) to (XXXII), L2is C3-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is monocyclic C3-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is bicyclic C4-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is tricyclic C5-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is tetracyclic C6-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (3S,8R,9S,13S,14S,17S)-Attorney Docket No.277A003WO01 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is (3S,8R,9S,13S,14S,17S)-10,13-dimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl.

[0129] In certain embodiments, in any one of Formulae (I) to (XXXII), L2is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is chromane-2,6-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L2is 2,5,7,8-tetramethylchromane-2,6-diyl.

[0130] In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (i) a bond; or (ii) C1-20 alkylene, C1-20 heteroalkylene, C2-20 alkenylene, C3-20 cycloalkylene, or heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (i) a bond; or (ii) C1-20alkylene, C1-20heteroalkylene, or C2-20 alkenylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (i) a bond; or (ii) C1-20 alkylene or C1-20heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is –(CH2)p–, wherein p is as defined herein. In certain embodiments, in any one ofAttorney Docket No.277A003WO01 Formulae (I) to (XXXII), L3is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is –OC(O)(CH2)q–, wherein q is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is –C(O)O(CH2)q–, wherein q is as defined herein. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is ethanediyl, butanediyl, pentanediyl, heptanediyl, –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is ethane-1,2-diyl, butane-1,4-diyl, petane-1,5-diyl, heptane-1,7-diyl, –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q.

[0131] In certain embodiments, in any one of Formulae (I) to (XXXII), L3is C2-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is heptadeca-2,4,6,8,10,12,14,16-octaene-2,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (2Z,4E,6E,8E,10E,12E,14E,16E)-heptadeca-2,4,6,8,10,12,14,16- octaene-2,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (2Z,4E,6E,8E,10E,12E,14E,16E)- 6,11,15-trimethylheptadeca-2,4,6,8,10,12,14,16-octaene-2,17-diyl.

[0132] In certain embodiments, in any one of Formulae (I) to (XXXII), L3is C3-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is monocyclic C3-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is bicyclic C4-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is tricyclic C5-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is tetracyclic C6-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (3S,8R,9S,13S,14S,17S)-Attorney Docket No.277A003WO01 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is (3S,8R,9S,13S,14S,17S)-10,13-dimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl.

[0133] In certain embodiments, in any one of Formulae (I) to (XXXII), L3is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is chromane-2,6-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (XXXII), L3is 2,5,7,8-tetramethylchromane-2,6-diyl.

[0134] In certain embodiments, in any one of Formulae (I) to (XXXII), X is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), X is C(H). In certain embodiments, in any one of Formulae (I) to (XXXII), X is N.

[0135] In certain embodiments, in any one of Formulae (I) to (XXXII), Z is a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), Z is C(H). In certain embodiments, in any one of Formulae (I) to (XXXII), Z is N.

[0136] In certain embodiments, in any one of Formulae (I) to (XXXII), X and Z are each a bond. In certain embodiments, in any one of Formulae (I) to (XXXII), X and Z are each C(H). In certain embodiments, in any one of Formulae (I) to (XXXII), X and Z are each N.Attorney Docket No.277A003WO01

[0137] In certain embodiments, in any one of Formulae (I) to (XXXII), the moiety .., ,

[0140] In certain embodiments, in any one of Formulae (I) to (XXXII), the moietyAttorney Docket No.277A003WO01 ,A3, A4, L1, L2, L3, L4, X, Y, m, n, p, and q in formulae described herein, including Formulae (I) to (XXXII), are defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of this disclosure.

[0142] In certain embodiments, R1is azido.

[0143] In certain embodiments, R1is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R1is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R1is 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R1is maleimido or 11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5- yl.

[0144] In certain embodiments, R1is an ionizable group. In certain embodiments, R1is an N-containing ionizable group. In certain embodiments, R1is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or moreAttorney Docket No.277A003WO01 substituents Q. In certain embodiments, R1is 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 5- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1is azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, morpholin-4-yl, or piperazin-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R1is azetidin-1-yl, 1-methylazetidin-3-yl, pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methyl- pyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-4-yl, or 4-methylpiperazin-1-yl.

[0145] In certain embodiments, R1is bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1is bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1is spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0146] In certain embodiments, R1is –NR4aR4b, wherein R4aand R4bare each as defined herein. In certain embodiments, R1is –NR4aR4b, wherein R4aand R4bare each independently C1-6 alkyl or C1-6 heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1is di(C1-6 alkyl)amino, optionally substituted with one or more substituents Q. In certain embodiments, R1is –NR4aR4b, wherein R4aand R4bare each independently methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1is dimethylamino or ethyl(methyl)amino.

[0147] In certain embodiments, R4is azido.Attorney Docket No.277A003WO01

[0148] In certain embodiments, R4is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R4is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R4is 5- membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R4is maleimido or 11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5- yl.

[0149] In certain embodiments, R4is an ionizable group. In certain embodiments, R4is an N-containing ionizable group. In certain embodiments, R4is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4is 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 5- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4is azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, morpholin-4-yl, or piperazin-1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R4is azetidin-1-yl, 1-methylazetidin-3-yl, pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methyl- pyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-4-yl, or 4-methylpiperazin-1-yl.

[0150] In certain embodiments, R4is bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4isAttorney Docket No.277A003WO01 bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4is spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0151] In certain embodiments, R4is –NR4aR4b, wherein R4aand R4bare each as defined herein. In certain embodiments, R4is –NR4aR4b, wherein R4aand R4bare each independently C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4is di(C1-6 alkyl)amino, optionally substituted with one or more substituents Q. In certain embodiments, R4is –NR4aR4b, wherein R4aand R4bare each independently methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4is dimethylamino or ethyl(methyl)amino.

[0152] In certain embodiments, R5is hydrogen. In certain embodiments, R5is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is methyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is C2-6alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is C2-6alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is monocyclic C3-10cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is bicyclic C4-10cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is bridged, fused, or spiro C4-10cycloalkyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R5is phenyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is bicyclic C8-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R5is C7-15 aralkyl, optionally substituted with one or more substituents Q.

[0153] In certain embodiments, R5is heteroaryl, optionally substituted with one or moreAttorney Docket No.277A003WO01 substituents Q. In certain embodiments, R5is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is 5- or 6-membered heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is bicyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, R5is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R5is bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R5is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.

[0154] In certain embodiments, R2ais absent. In certain embodiments, R2ais hydrogen. In certain embodiments, R2ais C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2ais unsubstituted C1-20 alkyl. In certain embodiments, R2ais C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R2ais C1-20alkyl, substituted with one or more halo. In certain embodiments, R2ais C1-20alkyl, substituted with one or more fluoro. In certain embodiments, R2ais C1-20 alkyl, substituted with one, two, or three fluoro.

[0155] In certain embodiments, R2ais methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n- eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionallyAttorney Docket No.277A003WO01 substituted with one or more substituents Q.

[0156] In certain embodiments, R2ais C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2ais trifluoromethyl, trifluoroethyl, trifluoro- propyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluoro- nonyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoropentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluoro- nonadecyl, or trifluoroeicosyl. In certain embodiments, R2ais trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluoro-tetradecyl, trifluoropentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluoro- octadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R2ais trifluoro- methyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent- 1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon- 1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R2ais 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13- trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16- trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19- trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl.

[0157] In certain embodiments, R2ais C2-20alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R2ais tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, tetradecdienyl, pentadecdienyl, hexadecdienyl, heptadecdienyl, octadecdienyl, nonadecdienyl, heptadectrienyl, or nonadectrienyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais (Z)-tridec-8-enyl, (Z)-tetradec-8-enyl, (Z)-pentadec-8-enyl, (Z)-hexadec-8- enyl, (Z)-heptadec-8-enyl, (Z)-octadec-8-enyl, (Z)-nonadec-8-enyl, (Z)-nonadec-10-enyl, (Z)- nonadec-12-enyl, (8Z,11Z)-tetradec-8,11-dienyl, (8Z,11Z)-pentadec-8,11-dienyl, (8Z,11Z)- hexadec-8,11-dienyl, (8Z,11Z)-heptadec-8,11-dienyl, (8Z,11Z)-octadec-8,11-dienyl, (8Z,11Z)-Attorney Docket No.277A003WO01 nonadec-8,11-dienyl, (5Z,8Z,11Z)-heptadec-5,8,11-trienyl, (8Z,11Z,14Z)-heptadec-8,11,14- trienyl, or (7Z,10Z,13Z)-nonadec-7,10,13-trienyl. In certain embodiments, R2ais (Z)-tridec-8-en- 1-yl, (Z)-tetradec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-hexadec-8-en-1-yl, (Z)-heptadec-8-en-1- yl, (Z)-octadec-8-en-1-yl, (Z)-nonadec-8-en-1-yl, (Z)-nonadec-10-en-1-yl, (Z)-nonadec-12-en-1- yl, (8Z,11Z)-tetradec-8,11-dien-1-yl, (8Z,11Z)-pentadec-8,11-dien-1-yl, (8Z,11Z)-hexadec-8,11- dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1-yl, (8Z,11Z)-octadec-8,11-dien-1-yl, (8Z,11Z)- nonadec-8,11-dien-1-yl, (5Z,8Z,11Z)-heptadec-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14- trien-1-yl, or (7Z,10Z,13Z)-nonadec-7,10,13-trien-1-yl. In certain embodiments, R2ais C2-20 alkynyl, optionally substituted with one or more substituents Q.

[0158] In certain embodiments, R2ais C1-20alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R2ais methoxy, ethoxy, propoxy, butoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais n-propoxy, n-butoxy, n-pentoxy, n- hexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecoxy, or n-dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R2ais C1-20heteroalkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R2ais C2-20 alkenoxy, optionally substituted with one or more substituents Q. In certain embodiments, R2ais C2-20alkynoxy, optionally substituted with one or more substituents Q.

[0159] In certain embodiments, R2bis C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis unsubstituted C1-20alkyl. In certain embodiments, R2bis C1-20alkyl, substituted with one or more substituents Q. In certain embodiments, R2bis C1-20 alkyl, substituted with one or more halo. In certain embodiments, R2bis C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, R2bis C1-20 alkyl, substituted with one, two, or three fluoro.

[0160] In certain embodiments, R2bis methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. InAttorney Docket No.277A003WO01 certain embodiments, R2bis hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n- eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis hept-2-yl or tridec- 1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis 6-methylhept-2-yl or 4,8,12-trimethyltridec-1-yl.

[0161] In certain embodiments, R2bis C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis trifluoromethyl, trifluoroethyl, trifluoro- propyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluoro- nonyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoropentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluoro- nonadecyl, or trifluoroeicosyl. In certain embodiments, R2bis trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluoro-tetradecyl, trifluoropentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluoro- octadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R2bis trifluoro- methyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent- 1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon- 1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R2bis 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13- trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16- trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19- trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl.Attorney Docket No.277A003WO01

[0162] In certain embodiments, R2bis C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, tetradecdienyl, pentadecdienyl, hexadic- dienyl, heptadecdienyl, octadecdienyl, nonadecdienyl, heptadectrienyl, or nonadectrienyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis (Z)- tridec-8-enyl, (Z)-tetradec-8-enyl, (Z)-pentadec-8-enyl, (Z)-hexadec-8-enyl, (Z)-heptadec-8-enyl, (Z)-octadec-8-enyl, (Z)-nonadec-8-enyl, (Z)-nonadec-10-enyl, (Z)-nonadec-12-enyl, (8Z,11Z)- tetradec-8,11-dienyl, (8Z,11Z)-pentadec-8,11-dienyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)- heptadec-8,11-dienyl, (8Z,11Z)-octadec-8,11-dienyl, (8Z,11Z)-nonadec-8,11-dienyl, (5Z,8Z,11Z)-heptadec-5,8,11-trienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (7Z,10Z,13Z)- nonadec-7,10,13-trienyl. In certain embodiments, R2bis (Z)-tridec-8-en-1-yl, (Z)-tetradec-8-en- 1-yl, (Z)-pentadec-8-en-1-yl, (Z)-hexadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-octadec-8-en-1- yl, (Z)-nonadec-8-en-1-yl, (Z)-nonadec-10-en-1-yl, (Z)-nonadec-12-en-1-yl, (8Z,11Z)-tetradec- 8,11-dien-1-yl, (8Z,11Z)-pentadec-8,11-dien-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)- heptadec-8,11-dien-1-yl, (8Z,11Z)-octadec-8,11-dien-1-yl, (8Z,11Z)-nonadec-8,11-dien-1-yl, (5Z,8Z,11Z)-heptadec-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (7Z,10Z,13Z)-nonadec-7,10,13-trien-1-yl. In certain embodiments, R2bis C2-20alkynyl, optionally substituted with one or more substituents Q.

[0163] In certain embodiments, R2bis C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis cyclohexenyl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis cyclohex- 1-en-1-yl, optionally substituted with one or more substituents Q. In certain embodiments, R2bis 2,6,6-trimethylcyclohex-1-en-1-yl.

[0164] In certain embodiments, R2bis C1-20 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R2bis methoxy, ethoxy, propoxy, butoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis n-propoxy, n-butoxy, n-pentoxy, n-Attorney Docket No.277A003WO01 hexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecoxy, or n-dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R2bis C1-20 heteroalkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R2bis C2-20alkenoxy, optionally substituted with one or more substituents Q. In certain embodiments, R2bis C2-20 alkynoxy, optionally substituted with one or more substituents Q.

[0165] In certain embodiments, R3ais absent. In certain embodiments, R3ais hydrogen. In certain embodiments, R3ais C1-20alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3ais unsubstituted C1-20 alkyl. In certain embodiments, R3ais C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R3ais C1-20alkyl, substituted with one or more halo. In certain embodiments, R3ais C1-20alkyl, substituted with one or more fluoro. In certain embodiments, R3ais C1-20 alkyl, substituted with one, two, or three fluoro.

[0166] In certain embodiments, R3ais methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n- eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionally substituted with one or more substituents Q.

[0167] In certain embodiments, R3ais C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3ais trifluoromethyl, trifluoroethyl, trifluoro- propyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluoro- nonyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoro-pentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluoro-Attorney Docket No.277A003WO01 nonadecyl, or trifluoroeicosyl. In certain embodiments, R3ais trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoro-pentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluoro- octadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R3ais trifluoro- methyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-prop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent- 1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon- 1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R3ais 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13- trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16- trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19- trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl.

[0168] In certain embodiments, R3ais C2-20alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R3ais tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, tetradecdienyl, pentadecdienyl, hexadic- dienyl, heptadecdienyl, octadecdienyl, nonadecdienyl, heptadectrienyl, or nonadectrienyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais (Z)- tridec-8-enyl, (Z)-tetradec-8-enyl, (Z)-pentadec-8-enyl, (Z)-hexadec-8-enyl, (Z)-heptadec-8-enyl, (Z)-octadec-8-enyl, (Z)-nonadec-8-enyl, (Z)-nonadec-10-enyl, (Z)-nonadec-12-enyl, (8Z,11Z)- tetradec-8,11-dienyl, (8Z,11Z)-pentadec-8,11-dienyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)- heptadec-8,11-dienyl, (8Z,11Z)-octadec-8,11-dienyl, (8Z,11Z)-nonadec-8,11-dienyl, (5Z,8Z,11Z)-heptadec-5,8,11-trienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (7Z,10Z,13Z)- nonadec-7,10,13-trienyl. In certain embodiments, R3ais (Z)-tridec-8-en-1-yl, (Z)-tetradec-8-en- 1-yl, (Z)-pentadec-8-en-1-yl, (Z)-hexadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-octadec-8-en-1- yl, (Z)-nonadec-8-en-1-yl, (Z)-nonadec-10-en-1-yl, (Z)-nonadec-12-en-1-yl, (8Z,11Z)-tetradec- 8,11-dien-1-yl, (8Z,11Z)-pentadec-8,11-dien-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)- heptadec-8,11-dien-1-yl, (8Z,11Z)-octadec-8,11-dien-1-yl, (8Z,11Z)-nonadec-8,11-dien-1-yl, (5Z,8Z,11Z)-heptadec-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, orAttorney Docket No.277A003WO01 (7Z,10Z,13Z)-nonadec-7,10,13-trien-1-yl. In certain embodiments, R3ais C2-20 alkynyl, optionally substituted with one or more substituents Q.

[0169] In certain embodiments, R3ais C1-20alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R3ais methoxy, ethoxy, propoxy, butoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais n-propoxy, n-butoxy, n-pentoxy, n- hexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecoxy, or n-dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R3ais C1-20heteroalkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R3ais C2-20 alkenoxy, optionally substituted with one or more substituents Q.

[0170] In certain embodiments, R3bis C1-20alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3bis unsubstituted C1-20 alkyl. In certain embodiments, R3bis C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R3bis C1-20alkyl, substituted with one or more halo. In certain embodiments, R3bis C1-20alkyl, substituted with one or more fluoro. In certain embodiments, R3bis C1-20alkyl, substituted with one, two, or three fluoro.

[0171] In certain embodiments, R3bis methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n- eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionallyAttorney Docket No.277A003WO01 substituted with one or more substituents Q. In certain embodiments, R3bis hept-2-yl or tridec- 1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis 6-methylhept-2-yl or 4,8,12-trimethyltridec-1-yl.

[0172] In certain embodiments, R3bis C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R3bis trifluoromethyl, trifluoroethyl, trifluoro- propyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluoro- nonyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoropentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluoro- nonadecyl, or trifluoroeicosyl. In certain embodiments, R3bis trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoropentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluoro- octadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R3bis trifluoro- methyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent- 1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon- 1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R3bis 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13- trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16- trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19- trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R3bis C1-20heteroalkyl, optionally substituted with one or more substituents Q.

[0173] In certain embodiments, R3bis tridecenyl, tetradecenyl, pentadecenyl, hexa- decenyl, heptadecenyl, octadecenyl, nonadecenyl, tetradecdienyl, pentadecdienyl, hexadecdienyl, heptadecdienyl, octadecdienyl, nonadecdienyl, heptadectrienyl, or nonadectrienyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis (Z)- tridec-8-enyl, (Z)-tetradec-8-enyl, (Z)-pentadec-8-enyl, (Z)-hexadec-8-enyl, (Z)-heptadec-8-enyl, (Z)-octadec-8-enyl, (Z)-nonadec-8-enyl, (Z)-nonadec-10-enyl, (Z)-nonadec-12-enyl, (8Z,11Z)-Attorney Docket No.277A003WO01 tetradec-8,11-dienyl, (8Z,11Z)-pentadec-8,11-dienyl, (8Z,11Z)-hexadec-8,11-dienyl, (8Z,11Z)- heptadec-8,11-dienyl, (8Z,11Z)-octadec-8,11-dienyl, (8Z,11Z)-nonadec-8,11-dienyl, (5Z,8Z,11Z)-heptadec-5,8,11-trienyl, (8Z,11Z,14Z)-heptadec-8,11,14-trienyl, or (7Z,10Z,13Z)- nonadec-7,10,13-trienyl. In certain embodiments, R3bis (Z)-tridec-8-en-1-yl, (Z)-tetradec-8-en- 1-yl, (Z)-pentadec-8-en-1-yl, (Z)-hexadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-octadec-8-en-1- yl, (Z)-nonadec-8-en-1-yl, (Z)-nonadec-10-en-1-yl, (Z)-nonadec-12-en-1-yl, (8Z,11Z)-tetradec- 8,11-dien-1-yl, (8Z,11Z)-pentadec-8,11-dien-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)- heptadec-8,11-dien-1-yl, (8Z,11Z)-octadec-8,11-dien-1-yl, (8Z,11Z)-nonadec-8,11-dien-1-yl, (5Z,8Z,11Z)-heptadec-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (7Z,10Z,13Z)-nonadec-7,10,13-trien-1-yl. In certain embodiments, R3bis C2-20alkynyl, optionally substituted with one or more substituents Q.

[0174] In certain embodiments, R3bis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3bis monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3bis cyclohexenyl, optionally substituted with one or more substituents Q. In certain embodiments, R3bis cyclohex- 1-en-1-yl, optionally substituted with one or more substituents Q. In certain embodiments, R3bis 2,6,6-trimethylcyclohex-1-en-1-yl.

[0175] In certain embodiments, R3bis C1-20 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R3bis methoxy, ethoxy, propoxy, butoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, or dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis n-propoxy, n-butoxy, n-pentoxy, n- hexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecoxy, or n-dodecoxy, each optionally substituted with one or more substituents Q. In certain embodiments, R3bis C1-20 heteroalkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R3bis C2-20alkenoxy, optionally substituted with one or more substituents Q. In certain embodiments, R3bis C2-20 alkynoxy, optionally substituted with one or more substituents Q.

[0176] In certain embodiments, R4ais hydrogen. In certain embodiments, R4ais C1-6Attorney Docket No.277A003WO01 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4ais C1-6heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais bicyclic C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais bridged, fused, or spiro C4-10cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4ais C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4ais bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.

[0177] In certain embodiments, R4bis hydrogen. In certain embodiments, R4bis C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4bis C1-6heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis bicyclic C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis bridged, fused, or spiro C4-10cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4bis C6-14 aryl, optionally substituted with one or moreAttorney Docket No.277A003WO01 substituents Q. In certain embodiments, R4bis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4bis bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.

[0178] In certain embodiments, R4aand R4btogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether 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, R4aand R4btogether with the N atom to which they are attached form 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q.

[0179] In certain embodiments, R4aand R4btogether with the N atom to which they are attached form bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituentsAttorney Docket No.277A003WO01 Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R4aand R4btogether with the N atom to which they are attached form spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0180] In certain embodiments, A1is a bond. In certain embodiments, A1is –C(O)O–. In certain embodiments, A1is –C(O)S–. In certain embodiments, A1is –OC(O)O–. In certain embodiments, A1is –OC(O)S–. In certain embodiments, A1is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A1is –C(O)N(H)–. In certain embodiments, A1is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A1is –C(S)N(H)–. In certain embodiments, A1is –OC(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A1is –OC(O)N(H)–. In certain embodiments, A1is –OC(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A1is –OC(S)N(H)–. In certain embodiments, A1is –N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A1is –N(R1b)–, wherein R1bis hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, A1is –N(H)–. In certain embodiments, A1is –N(CH3)–. In certain embodiments, A1is –N(R1a)C(O)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, A1is –N(H)C(O)N(H)–. In certain embodiments, A1is –N(R1a)C(S)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, A1is –N(H)C(S)N(H)–.

[0181] In certain embodiments, A2is a bond. In certain embodiments, A2is –C(O)O–. In certain embodiments, A2is –C(O)S–. In certain embodiments, A2is –OC(O)O–. In certain embodiments, A2is –OC(O)S–. In certain embodiments, A2is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A2is –C(O)N(H)–. In certain embodiments, A2is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A2is –C(S)N(H)–. In certain embodiments, A2is –CH2O–. In certain embodiments, A2is –CH2OC(O)–.

[0182] In certain embodiments, A3is a bond. In certain embodiments, A3is –C(O)O–. In certain embodiments, A3is –C(O)S–. In certain embodiments, A3is –OC(O)O–. In certainAttorney Docket No.277A003WO01 embodiments, A3is –OC(O)S–. In certain embodiments, A3is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A3is –C(O)N(H)–. In certain embodiments, A3is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A3is –C(S)N(H)–. In certain embodiments, A3is –CH2O–. In certain embodiments, A3is –CH2OC(O)–.

[0183] In certain embodiments, A4is –C(O)O–. In certain embodiments, A4is –C(O)S–. In certain embodiments, A4is –OC(O)O–. In certain embodiments, A4is –OC(O)S–. In certain embodiments, A4is –C(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A4is –C(O)N(H)–. In certain embodiments, A4is –C(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A4is –C(S)N(H)–. In certain embodiments, A4is –OC(O)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A4is –OC(O)N(H)–. In certain embodiments, A4is –OC(S)N(R1b)–, wherein R1bis as defined herein. In certain embodiments, A4is –OC(S)N(H)–. In certain embodiments, A4is –N(R1a)C(O)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, A4is –N(H)C(O)N(H)–. In certain embodiments, A4is –N(R1a)C(S)N(R1d)–, wherein R1aand R1dare each as defined herein. In certain embodiments, A4is –N(H)C(S)N(H)–.

[0184] In certain embodiments, L1is a bond. In certain embodiments, L1is C1-20alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1is C1-6 alkylene, each optionally substituted with one or more substituents Q. In certain embodiments, L1is C1-20heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1is C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1is –(CH2)p–, wherein p is as defined herein. In certain embodiments, L1is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1is methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5- diyl, or hexane-1,6-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1is C2-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L1is C2-20 alkynylene, optionally substituted with one or more substituents Q.

[0185] In certain embodiments, L2is a bond. In certain embodiments, L2is C1-20Attorney Docket No.277A003WO01 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is unsubstituted C1-20 alkylene. In certain embodiments, L2is C1-20 alkylene, substituted with one or more substituents Q. In certain embodiments, L2is C1-20alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is unsubstituted C1-10 alkylene. In certain embodiments, L2is C1-10 alkylene, substituted with one or more substituents Q. In certain embodiments, L2is –(CH2)p–, wherein p is as defined herein.

[0186] In certain embodiments, L2is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2is butanediyl, pentanediyl, hexanediyl, heptanediyl, or octanediyl, each optionally substituted with one or more substituents Q.

[0187] In certain embodiments, L2is methane-1,2-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9- diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane- 1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18- diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane- 1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q.

[0188] In certain embodiments, L2is methane-1,2-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9- diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane- 1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18- diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certainAttorney Docket No.277A003WO01 embodiments, L2is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane- 1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L1is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6- diyl, heptane-1,7-diyl, or octane-1,8-diyl, each of which is unsubstituted.

[0189] In certain embodiments, L2is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is – OC(O)-C1-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is –OC(O)(CH2)q–, wherein q is as defined herein. In certain embodiments, L2is – C(O)O-C1-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is –C(O)O(CH2)q–, wherein q is as defined herein. In certain embodiments, L2is –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q. In certain embodiments, L2is –(CH2)2O(CH2)2–, –(CH2)2O(CH2)3–, –(CH2)3O(CH2)3–, or –(CH2)2O(CH2)2O(CH2)2–, each optionally substituted with one or more substituents Q. In certain embodiments, L2is –N(H)-C1-20 alkenylene or –N(H)-C1-20 heteroalkenylene, each optionally substituted with one or more substituents Q. In certain embodiments, L2is –N(H)-C1-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is –N(H)-C1-10alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is –N(H)(CH2)2–, –N(H)(CH2)3–, –N(H)(CH2)4–, –N(H)(CH2)5–, –N(H)(CH2)6–, –N(H)(CH2)7–, or –N(H)(CH2)8–, each optionally substituted with one or more substituents Q. In certain embodiments, L2is –N(H)-C1-20heteroalkenylene, optionally substituted with one or more substituents Q.

[0190] In certain embodiments, L2is C2-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is heptadeca-2,4,6,8,10,12,14,16-octaene-2,17- diyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is (2Z,4E,6E,8E,10E,12E,14E,16E)-heptadeca-2,4,6,8,10,12,14,16-octaene-2,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is (2Z,4E,6E,8E,10E,12E,14E,16E)-6,11,15-trimethylheptadeca-2,4,6,8,10,12,14,16-octaene-2,17- diyl. In certain embodiments, L2is C2-20 alkynylene, optionally substituted with one or more substituents Q.Attorney Docket No.277A003WO01

[0191] In certain embodiments, L2is C3-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is monocyclic C3-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is bicyclic C4-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is tricyclic C5-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is tetracyclic C6-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is (3S,8R,9S,13S,14S,17S)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is (3S,8R,9S,13S,14S,17S)-10,13-dimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl.

[0192] In certain embodiments, L2is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, L2is 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2is chromane-2,6-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L2is 2,5,7,8-tetramethylchromane-2,6-diyl.

[0193] In certain embodiments, L3is a bond. In certain embodiments, L3is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is unsubstituted C1-20 alkylene. In certain embodiments, L3is C1-20 alkylene, substituted with one or more substituents Q. In certain embodiments, L3is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is unsubstituted C1-10alkylene. In certain embodiments, L3is C1-10alkylene, substituted with one or more substituents Q. In certainAttorney Docket No.277A003WO01 embodiments, L3is –(CH2)p–, wherein p is as defined herein.

[0194] In certain embodiments, L3is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3is butanediyl, pentanediyl, hexanediyl, heptanediyl, or octanediyl, each optionally substituted with one or more substituents Q.

[0195] In certain embodiments, L3is methane-1,2-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9- diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane- 1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18- diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane- 1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q.

[0196] In certain embodiments, L3is methane-1,2-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9- diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane- 1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18- diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certain embodiments, L3is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane- 1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L1is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6- diyl, heptane-1,7-diyl, or octane-1,8-diyl, each of which is unsubstituted.

[0197] In certain embodiments, L3is C1-20heteroalkylene, optionally substituted with oneAttorney Docket No.277A003WO01 or more substituents Q. In certain embodiments, L3is – OC(O)-C1-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is –OC(O)(CH2)q–, wherein q is as defined herein. In certain embodiments, L3is – C(O)O-C1-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is –C(O)O(CH2)q–, wherein q is as defined herein. In certain embodiments, L3is –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q. In certain embodiments, L3is –(CH2)2O(CH2)2–, –(CH2)2O(CH2)3–, –(CH2)3O(CH2)3–, or –(CH2)2O(CH2)2O(CH2)2–, each optionally substituted with one or more substituents Q. In certain embodiments, L3is –N(H)-C1-20alkenylene or –N(H)-C1-20heteroalkenylene, each optionally substituted with one or more substituents Q. In certain embodiments, L3is –N(H)-C1-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is –N(H)-C1-10 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is –N(H)(CH2)2–, –N(H)(CH2)3–, –N(H)(CH2)4–, –N(H)(CH2)5–, –N(H)(CH2)6–, –N(H)(CH2)7–, or –N(H)(CH2)8–, each optionally substituted with one or more substituents Q. In certain embodiments, L3is –N(H)-C1-20 heteroalkenylene, optionally substituted with one or more substituents Q.

[0198] In certain embodiments, L3is C2-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is heptadeca-2,4,6,8,10,12,14,16-octaene-2,17- diyl, optionally substituted with one or more substituents Q. In certain embodiments, L3is (2Z,4E,6E,8E,10E,12E,14E,16E)-heptadeca-2,4,6,8,10,12,14,16-octaene-2,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L3is (2Z,4E,6E,8E,10E,12E,14E,16E)-6,11,15-trimethylheptadeca-2,4,6,8,10,12,14,16-octaene-2,17- diyl. In certain embodiments, L3is C2-20alkynylene, optionally substituted with one or more substituents Q.

[0199] In certain embodiments, L3is C3-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is monocyclic C3-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is bicyclic C4-20 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is tricyclic C5-20cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is tetracyclic C6-20cycloalkylene, optionallyAttorney Docket No.277A003WO01 substituted with one or more substituents Q. In certain embodiments, L3is 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L3is (3S,8R,9S,13S,14S,17S)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- cyclopenta[a]phenanthrene-3,17-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L3is (3S,8R,9S,13S,14S,17S)-10,13-dimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl.

[0200] In certain embodiments, L3is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, L3is 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is 6,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L3is chromane-2,6-diyl, optionally substituted with one or more substituents Q. In certain embodiments, L3is 2,5,7,8-tetramethylchromane-2,6-diyl.

[0201] In certain embodiments, L4is a bond. In certain embodiments, L4is C1-20alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L4is C1-6 alkylene, each optionally substituted with one or more substituents Q. In certain embodiments, L4is C1-20heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L4is C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L4is –(CH2)p–, wherein p is as defined herein. In certain embodiments, L4is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L4is methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5- diyl, or hexane-1,6-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L4is C2-20alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L4is C2-20alkynylene, optionally substituted with one or more substituentsAttorney Docket No.277A003WO01 Q.

[0202] In certain embodiments, X is a bond. In certain embodiments, X is C(H). In certain embodiments, X is N.

[0203] In certain embodiments, Z is a bond. In certain embodiments, Z is C(H). In certain embodiments, Z is N.

[0204] In certain embodiments, m is an integer of 0. In certain embodiments, m is an integer of 1. In certain embodiments, m is an integer of 2. In certain embodiments, m is an integer of 3. In certain embodiments, m is an integer of 4. In certain embodiments, m is an integer of 5. In certain embodiments, m is an integer of 6. In certain embodiments, m is an integer of 7. In certain embodiments, m is an integer of 8. In certain embodiments, m is an integer of 9. In certain embodiments, m is an integer of 10. In certain embodiments, m is an integer of 11. In certain embodiments, m is an integer of 12. In certain embodiments, m is an integer of 13. In certain embodiments, m is an integer of 14. In certain embodiments, m is an integer of 15. In certain embodiments, m is an integer of 16. In certain embodiments, m is an integer of 17. In certain embodiments, m is an integer of 18. In certain embodiments, m is an integer of 19.

[0205] In certain embodiments, n is an integer of 0. In certain embodiments, n is an integer of 1. In certain embodiments, n is an integer of 2. In certain embodiments, n is an integer of 3. In certain embodiments, n is an integer of 4. In certain embodiments, n is an integer of 5. In certain embodiments, n is an integer of 6. In certain embodiments, n is an integer of 7. In certain embodiments, n is an integer of 8. In certain embodiments, n is an integer of 9. In certain embodiments, n is an integer of 10. In certain embodiments, n is an integer of 11. In certain embodiments, n is an integer of 12. In certain embodiments, n is an integer of 13. In certain embodiments, n is an integer of 14. In certain embodiments, n is an integer of 15. In certain embodiments, n is an integer of 16. In certain embodiments, n is an integer of 17. In certain embodiments, n is an integer of 18. In certain embodiments, n is an integer of 19.

[0206] In certain embodiments, p is an integer of 1. In certain embodiments, p is anAttorney Docket No.277A003WO01 integer of 2. In certain embodiments, p is an integer of 3. In certain embodiments, p is an integer of 4. In certain embodiments, p is an integer of 5. In certain embodiments, p is an integer of 6. In certain embodiments, p is an integer of 7. In certain embodiments, p is an integer of 8. In certain embodiments, p is an integer of 9. In certain embodiments, p is an integer of 10.

[0207] In certain embodiments, q is an integer of 1. In certain embodiments, q is an integer of 2. In certain embodiments, q is an integer of 3. In certain embodiments, q is an integer of 4. In certain embodiments, q is an integer of 5. In certain embodiments, q is an integer of 6. In certain embodiments, q is an integer of 7. In certain embodiments, q is an integer of 8. In certain embodiments, q is an integer of 9. In certain embodiments, q is an integer of 10.

[0208] In one embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2,3-bis((4-(dimethylamino)butanoyl)oxy)succinate A001; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis((3-(azetidin-1-yl)propanoyl)- oxy)succinate A002; bis(8-(heptyloxy)-8-oxooctyl) 2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)- succinate A003; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis((3-(piperidin-1-yl)propanoyl)- oxy)succinate A004; dipentadecyl 2,3-bis((4-(azetidin-1-yl)butanoyl)oxy)succinate A005; bis(7-(dodecanoyloxy)heptyl) 2,3-bis((4-(pyrrolidin-1-yl)butanoyl)oxy)succinate A006; bis(5-ethylnonyl) 2,3-bis((4-(piperidin-1-yl)butanoyl)oxy)succinate A007; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis((5-(pyrrolidin-1-yl)pentanoyl)oxy)- succinate A008; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis((5-(piperidin-1-yl)pentanoyl)oxy)- succinate A009; or 1-((Z)-octadec-9-en-1-yl) 4-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis((5- morpholinopentanoyl)oxy)succinate A010;Attorney Docket No.277A003WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0209] In another embodiment, provided herein is a compound of didodecyl 2,3-bis((4- (dimethylamino)butanoyl)oxy)succinate A011, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0210] In yet another embodiment, provided herein is a compound of: 2,3-bis((4-(dimethylamino)butanoyl)oxy)butane-1,4-diyl (9Z,9'Z)-bis(hexadec-9- enoate) A051; 1-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)-4-(oleoyloxy)butane-2,3-diyl bis(3- (azetidin-1-yl)propanoate) A052; 1-(heptadecanoyloxy)-4-(oleoyloxy)butane-2,3-diyl bis(3-(pyrrolidin-1-yl)- propanoate) A053; 1-((4,4-bis(octyloxy)butanoyl)oxy)-4-(oleoyloxy)butane-2,3-diyl bis(3-(piperidin- 1-yl)propanoate) A054; 2,3-bis((4-(azetidin-1-yl)butanoyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate) A055; 2,3-bis((4-(pyrrolidin-1-yl)butanoyl)oxy)butane-1,4-diyl diheptadecanoate A056; 2,3-bis((4-(piperidin-1-yl)butanoyl)oxy)butane-1,4-diyl bis(4,4-bis(octyloxy)- butanoate) A057; 1-((4,4-bis(octyloxy)butanoyl)oxy)-4-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)- butane-2,3-diyl bis(5-(pyrrolidin-1-yl)pentanoate) A058; 1-(heptadecanoyloxy)-4-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)butane-2,3-diyl bis(5-(piperidin-1-yl)pentanoate) A059; or 1-((4,4-bis(octyloxy)butanoyl)oxy)-4-(heptadecanoyloxy)butane-2,3-diyl bis(5- morpholinopentanoate) A060; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; orAttorney Docket No.277A003WO01 a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0211] In yet another embodiment, provided herein is a compound of: (2R,3S)-2,3-bis((3-(3-(hydroxymethyl)azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A061; (2R,3S)-2,3-bis((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A062; (2R,3S)-2,3-bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) A063; or (2R,3S)-2,3-bis((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A064; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0212] In yet another embodiment, provided herein is a compound of: 1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl bis(4-(dimethylamino)- butanoate) A101; di((Z)-non-2-en-1-yl) 6,6'-((2,3-bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl)bis(oxy))dihexanoate A102; dioctyl 8,8'-((2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)butane-1,4-diyl)- bis(oxy))dioctanoate A103; di(heptadecan-9-yl) 8,8'-((2,3-bis((3-(piperidin-1-yl)propanoyl)oxy)butane-1,4- diyl)bis(oxy))dioctanoate A104; 1,4-bis(pentadecyloxy)butane-2,3-diyl bis(4-(azetidin-1-yl)butanoate) A105; ((2,3-bis((4-(pyrrolidin-1-yl)butanoyl)oxy)butane-1,4-diyl)bis(oxy))bis(heptane- 7,1-diyl) didodecanoate A106; 1,4-bis((5-ethylnonyl)oxy)butane-2,3-diyl bis(4-(piperidin-1-yl)butanoate) A107; ((2,3-bis((5-(pyrrolidin-1-yl)pentanoyl)oxy)butane-1,4-diyl)bis(oxy))bis(hexane- 6,1-diyl) bis(2-hexyldecanoate) A108; 1,4-bis(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane-2,3-diyl bis(5-(piperidin-1- yl)pentanoate) A109; orAttorney Docket No.277A003WO01 1-(((Z)-octadec-9-en-1-yl)oxy)-4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane- 2,3-diyl bis(5-morpholinopentanoate) A110; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0213] In yet another embodiment, provided herein is a compound of: (2R,3S)-2,3-bis((4-(dimethylamino)butanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A111; (2R,3S)-2,3-bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A112; (2R,3S)-2,3-bis((3-(3-(hydroxymethyl)azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetra- methyl-17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A113; (2R,3S)-2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A114; (2R,3S)-2,3-bis((3-(piperidin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A115; (2R,3S)-2,3-bis((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)butane-1,4- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15- tetramethyl-17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A116; (2R,3S)-2,3-bis((3-(4-methylpiperazin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A117; or (2R,3S)-2,3-bis((3-morpholinopropanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A118;Attorney Docket No.277A003WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0214] In yet another embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2,3-bis(((4-(dimethylamino)butyl)carbamoyl)oxy)- succinate A151; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis(((4-(pyrrolidin-1-yl)butyl)- carbamoyl)oxy)succinate A152; bis(8-(octyloxy)-8-oxooctyl) 2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)- succinate A153; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)succinate A154; dipentadecyl 2,3-bis(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)- succinate A155; bis(7-(dodecanoyloxy)heptyl) 2,3-bis(((3-morpholinopropyl)carbamoyl)oxy)- succinate A156; bis(5-ethylnonyl) 2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)succinate A157; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis(((3-(pyrrolidin-1-yl)propyl)- carbamoyl)oxy)succinate A158; or di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)succinate A159; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0215] In yet another embodiment, provided herein is a compound of: 2,3-bis(((4-(dimethylamino)butyl)carbamoyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) A201; 4-(oleoyloxy)-2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)butyl (9Z,12Z)- octadeca-9,12-dienoate A202;Attorney Docket No.277A003WO01 4-(heptadecanoyloxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butyl oleate A203; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)butyl oleate A204; 2,3-bis(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) A205; 2,3-bis(((3-morpholinopropyl)carbamoyl)oxy)butane-1,4-diyl diheptadecanoate A206; 2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)butane-1,4-diyl bis(4,4-bis- (octyloxy)butanoate) A207; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)- carbamoyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A208; or 4-(heptadecanoyloxy)-2,3-bis(((3-(piperidin-1-yl)propyl)carbamoyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A209; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0216] In yet another embodiment, provided herein is a compound of: 1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl bis((4-(dimethylamino)- butyl)carbamate) A251; di((Z)-non-2-en-1-yl) 6,6'-((2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)- butane-1,4-diyl)bis(oxy))dihexanoate A252; dioctyl 8,8'-((2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl)- bis(oxy))dioctanoate A253; di(heptadecan-9-yl) 8,8'-((2,3-bis(((3-(piperidin-1-yl)propyl)carbamoyl)oxy)- butane-1,4-diyl)bis(oxy))dioctanoate A254; 1,4-bis(pentadecyloxy)butane-2,3-diyl bis((3-(4-methylpiperazin-1-yl)propyl)- carbamate) A255; ((2,3-bis(((3-morpholinopropyl)carbamoyl)oxy)butane-1,4-diyl)bis(oxy))- bis(heptane-7,1-diyl) didodecanoate A256; 1,4-bis((5-ethylnonyl)oxy)butane-2,3-diyl bis((4-(pyrrolidin-1-yl)butyl)-Attorney Docket No.277A003WO01 carbamate) A257; ((2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl)bis(oxy))- bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A258; or 1,4-bis(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane-2,3-diyl bis((3-(piperidin- 1-yl)propyl)carbamate) A259; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0217] In yet another embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2,3-bis(((4-(dimethylamino)butyl)carbamothioyl)- oxy)succinate A301; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis(((4-(pyrrolidin-1- yl)butyl)carbamothioyl)oxy)succinate A302; bis(8-(octyloxy)-8-oxooctyl) 2,3-bis(((4-(piperidin-1-yl)butyl)carbamothioyl)- oxy)succinate A303; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis(((3-(azetidin-1-yl)propyl)- carbamothioyl)oxy)succinate A304; dipentadecyl 2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamothioyl)oxy)succinate A305; bis(7-(dodecanoyloxy)heptyl) 2,3-bis(((3-(piperidin-1-yl)propyl)carbamothioyl)- oxy)succinate A306; or bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)succinate A307; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0218] In yet another embodiment, provided herein is a compound of: 2,3-bis(((4-(dimethylamino)butyl)carbamothioyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) A351; 2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4-diylAttorney Docket No.277A003WO01 (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) A352; 2,3-bis(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4-diyl dihepta- decanoate A353; 2,3-bis(((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)butane-1,4-diyl bis(4,4- bis(octyloxy)butanoate) A354; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamo- thioyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A355; 4-(heptadecanoyloxy)-2,3-bis(((3-(piperidin-1-yl)propyl)carbamothioyl)oxy)- butyl (9Z,12Z)-octadeca-9,12-dienoate A356; or 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)butyl oleate A357; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0219] In yet another embodiment, provided herein is a compound of: O,O'-(1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl) bis((4-(dimethyl- amino)butyl)carbamothioate) A401; di((Z)-non-2-en-1-yl) 6,6'-((2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamothioyl)- oxy)butane-1,4-diyl)bis(oxy))dihexanoate A402; dioctyl 8,8'-((2,3-bis(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4- diyl)bis(oxy))dioctanoate A403; di(heptadecan-9-yl) 8,8'-((2,3-bis(((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)- butane-1,4-diyl)bis(oxy))dioctanoate A404; O,O'-(1,4-bis(pentadecyloxy)butane-2,3-diyl) bis((3-(pyrrolidin-1-yl)propyl)- carbamothioate) A405; ((2,3-bis(((3-(piperidin-1-yl)propyl)carbamothioyl)oxy)butane-1,4-diyl)bis(oxy))- bis(heptane-7,1-diyl) didodecanoate A406; or ((2,3-bis(((3-(1-methylazetidin-3-yl)propyl)carbamothioyl)oxy)butane-1,4- diyl)bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A407; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; orAttorney Docket No.277A003WO01 a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0220] In yet another embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2-(4-(dimethylamino)butyl)-1,3-dioxolane-4,5- dicarboxylate A451; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-((1-methylpiperidin-4-yl)methyl)- 1,3-dioxolane-4,5-dicarboxylate A452; bis(8-(octyloxy)-8-oxooctyl) 2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolane- 4,5-dicarboxylate A453; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2-(2-(1-methylpiperidin-4-yl)ethyl)-1,3- dioxolane-4,5-dicarboxylate A454; dipentadecyl 2-(4-morpholinobutyl)-1,3-dioxolane-4,5-dicarboxylate A455; bis(7-(dodecanoyloxy)heptyl) 2-(3-(1-methylpiperidin-4-yl)propyl)-1,3- dioxolane-4,5-dicarboxylate A456; bis(5-ethylnonyl) 2-(3-(1-methylpyrrolidin-2-yl)propyl)-1,3-dioxolane-4,5- dicarboxylate A457; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(4-(2-methylpyrrolidin-1-yl)butyl)-1,3- dioxolane-4,5-dicarboxylate A458; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-(4-(ethyl(methyl)amino)butyl)-1,3- dioxolane-4,5-dicarboxylate A459; 4-(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 5-((Z)-octadec-9-en-1-yl) 2-(5-(ethyl- (methyl)amino)pentyl)-1,3-dioxolane-4,5-dicarboxylate A460; (Z)-4-(octadec-9-en-1-yl) 5-(8-(octyloxy)-8-oxooctyl) 2-(4-(dimethylamino)- butyl)-2-methyl-1,3-dioxolane-4,5-dicarboxylate A461; (Z)-4-(8-(heptadecan-9-yloxy)-8-oxooctyl) 5-(octadec-9-en-1-yl) 2-methyl-2-((1- methylpiperidin-4-yl)methyl)-1,3-dioxolane-4,5-dicarboxylate A462; (Z)-4-(octadec-9-en-1-yl) 5-pentadecyl 2-methyl-2-(3-(4-methylpiperazin-1-yl)- propyl)-1,3-dioxolane-4,5-dicarboxylate A463; (Z)-4-(7-(dodecanoyloxy)heptyl) 5-(octadec-9-en-1-yl) 2-methyl-2-(4-(pyrrolidin- 1-yl)butyl)-1,3-dioxolane-4,5-dicarboxylate A464; or 4-((Z)-octadec-9-en-1-yl) 5-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-(4-(ethyl- (methyl)amino)butyl)-2-methyl-1,3-dioxolane-4,5-dicarboxylate A465;Attorney Docket No.277A003WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0221] In yet another embodiment, provided herein is a compound of: 2-(4-(dimethylamino)butyl)-1,3-dioxolane-4,5-diyl)bis(methylene) (9Z,9'Z)- bis(hexadec-9-enoate) A501; (2-((1-methylpiperidin-4-yl)methyl)-5-((oleoyloxy)methyl)-1,3-dioxolan-4- yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A502; (5-((heptadecanoyloxy)methyl)-2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolan- 4-yl)methyl oleate A503; (5-(((4,4-bis(octyloxy)butanoyl)oxy)methyl)-2-(2-(1-methylpiperidin-4-yl)ethyl)- 1,3-dioxolan-4-yl)methyl oleate A504; (2-(4-morpholinobutyl)-1,3-dioxolane-4,5-diyl)bis(methylene) (9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate) A505; (2-(3-(1-methylpiperidin-4-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene) diheptadecanoate A506; (2-(3-(1-methylpyrrolidin-2-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene) bis(4,4-bis(octyloxy)butanoate) A507; (5-(((4,4-bis(octyloxy)butanoyl)oxy)methyl)-2-(4-(2-methylpyrrolidin-1-yl)- butyl)-1,3-dioxolan-4-yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A508; or (2-(4-(ethyl(methyl)amino)butyl)-5-((heptadecanoyloxy)methyl)-1,3-dioxolan-4- yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A509; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0222] In yet another embodiment, provided herein is a compound of: 4-(4,5-bis((((Z)-heptadec-9-en-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)-N,N- dimethylbutan-1-amine A551; di((Z)-non-2-en-1-yl) 6,6'-(((2-((1-methylpiperidin-4-yl)methyl)-1,3-dioxolane- 4,5-diyl)bis(methylene))bis(oxy))dihexanoate A552;Attorney Docket No.277A003WO01 dioctyl 8,8'-(((2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolane-4,5-diyl)bis- (methylene))bis(oxy))dioctanoate A553; di(heptadecan-9-yl) 8,8'-(((2-(2-(1-methylpiperidin-4-yl)ethyl)-1,3-dioxolane-4,5- diyl)bis(methylene))bis(oxy))dioctanoate A554; 4-(4-(4,5-bis((pentadecyloxy)methyl)-1,3-dioxolan-2-yl)butyl)morpholine A555; (((2-(3-(1-Methylpiperidin-4-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene))-bis(oxy))bis- (heptane-7,1-diyl) didodecanoate A556; 2-(3-(4,5-bis(((5-ethylnonyl)oxy)methyl)-1,3-dioxolan-2-yl)propyl)-1-methyl- pyrrolidine A557; (((2-(4-(2-methylpyrrolidin-1-yl)butyl)-1,3-dioxolane-4,5-diyl)bis(methylene))- bis(oxy))bis-(hexane-6,1-diyl) bis(2-hexyldecanoate) A558; 4-(4,5-bis((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)-N- ethyl-N-methylbutan-1-amine A559; (Z)-non-2-en-1-yl 6-((2-(5-(ethyl(methyl)amino)pentyl)-5-((((Z)-octadec-9-en-1- yl)oxy)methyl)-1,3-dioxolan-4-yl)methoxy)hexanoate A560; octyl (Z)-8-((2-(4-(dimethylamino)butyl)-2-methyl-5-((octadec-9-en-1-yloxy)- methyl)-1,3-dioxolan-4-yl)methoxy)octanoate A561; heptadecan-9-yl (Z)-8-((2-methyl-2-((1-methylpiperidin-4-yl)methyl)-5- ((octadec-9-en-1-yloxy)methyl)-1,3-dioxolan-4-yl)methoxy)octanoate A562; (Z)-1-methyl-4-(3-(2-methyl-4-((octadec-9-en-1-yloxy)methyl)-5-((pentadecyl- oxy)methyl)-1,3-dioxolan-2-yl)propyl)piperazine A563; (Z)-7-((2-methyl-5-((octadec-9-en-1-yloxy)methyl)-2-(4-(pyrrolidin-1-yl)butyl)- 1,3-dioxolan-4-yl)methoxy)heptyl dodecanoate A564; or N-ethyl-N-methyl-4-(2-methyl-4-((((Z)-octadec-9-en-1-yl)oxy)methyl)-5- ((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)butan-1-amine A565; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0223] In yet another embodiment, provided herein is a compound of didodecyl 2-((4- (dimethylamino)butanoyl)oxy)-3-hydroxysuccinate A601, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture ofAttorney Docket No.277A003WO01 two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0224] In yet another embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2-((3-(pyrrolidin-1-yl)propanoyl)oxy)malonate B001; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-((3-(azetidin-1-yl)propanoyl)oxy)- malonate B002; bis(8-(heptyloxy)-8-oxooctyl) 2-((4-(dimethylamino)butanoyl)oxy)malonate B003; 1-(8-(heptadecan-8-yloxy)-8-oxooctyl) 3-(8-(heptadecan-9-yloxy)-8-oxooctyl) 2- ((3-(piperidin-1-yl)propanoyl)oxy)malonate B004; dipentadecyl 2-((4-(azetidin-1-yl)butanoyl)oxy)malonate B005; bis(7-(dodecanoyloxy)heptyl) 2-((4-(pyrrolidin-1-yl)butanoyl)oxy)malonate B006; bis(5-ethylnonyl) 2-((4-(piperidin-1-yl)butanoyl)oxy)malonate B007; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-((5-(pyrrolidin-1-yl)pentanoyl)oxy)- malonate B008; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5-(piperidin-1-yl)pentanoyl)oxy)- malonate B009; or 1-((Z)-octadec-9-en-1-yl) 3-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5- morpholinopentanoyl)oxy)malonate B010; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0225] In yet another embodiment, provided herein is a compound of: dioctadecyl 2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)butanoyl)oxy)malonate B011; ditridecyl 2-((4-(4-methylpiperazin-1-yl)butanoyl)oxy)malonate B012; ditridecyl 2-((4-((2-hydroxyethyl)(methyl)amino)butanoyl)oxy)malonate B013; ditridecyl 2-((4-(3-hydroxyazetidin-1-yl)butanoyl)oxy)malonate B014; ditridecyl 2-((4-(azetidin-1-yl)butanoyl)oxy)malonate B015;Attorney Docket No.277A003WO01 ditridecyl 2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)butanoyl)oxy)malonate B016; ditridecyl 2-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B017; or ditridecyl 2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)oxy)malonate B018; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0226] In yet another embodiment, provided herein is a compound of: bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((4- (dimethylamino)butanoyl)oxy)malonate B021; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (azetidin-1-yl)propanoyl)oxy)malonate B022; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(3- hydroxyazetidin-1-yl)propanoyl)oxy)malonate B023; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (pyrrolidin-1-yl)propanoyl)oxy)malonate B024; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (piperidin-1-yl)propanoyl)oxy)malonate B025; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(4- (2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B026; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(4- methylpiperazin-1-yl)propanoyl)oxy)malonate B027; or bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-Attorney Docket No.277A003WO01 morpholinopropanoyl)oxy)malonate B028; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0227] In yet another embodiment, provided herein is a compound of: bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((4-(dimethylamino)butanoyl)oxy)malonate B031; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(azetidin-1-yl)propanoyl)oxy)malonate B032; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(3-hydroxyazetidin-1-yl)propanoyl)oxy)malonate B033; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(pyrrolidin-1-yl)propanoyl)oxy)malonate B034; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(piperidin-1-yl)propanoyl)oxy)malonate B035; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B036; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(4-methylpiperazin-1-yl)propanoyl)oxy)malonate B037; or bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-morpholinopropanoyl)oxy)malonate B038; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0228] In yet another embodiment, provided herein is a compound of di((Z)-octadec-9- en-1-yl) 2-(((3-(4-methylpiperazin-1-yl)propoxy)carbonyl)oxy)-malonate B051; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.Attorney Docket No.277A003WO01

[0229] In yet another embodiment, provided herein is a compound of dioctadecyl 2-(((3- (diethylamino)propoxy)carbonyl)oxy)malonate B052; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0230] In yet another embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2-(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)- malonate B101; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-(((4-(pyrrolidin-1-yl)butyl)- carbamoyl)oxy)malonate B102; bis(8-(octyloxy)-8-oxooctyl) 2-(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)- malonate B103; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2-(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)malonate B104; dipentadecyl 2-(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)malonate B105; bis(7-(dodecanoyloxy)heptyl) 2-(((3-morpholinopropyl)carbamoyl)oxy)malonate B106; 1-(5-ethyldecyl) 3-(5-ethylnonyl) 2-(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)- malonate B107; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(((3-(pyrrolidin-1-yl)propyl)carbamoyl)- oxy)malonate B108; or 1-((Z)-octadec-9-en-1-yl) 3-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5- morpholinopentanoyl)oxy)malonate B109; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0231] In yet another embodiment, provided herein is a compound of: di((Z)-octadec-9-en-1-yl) 2-(((4-(dimethylamino)butyl)carbamothioyl)oxy)- malonate B151;Attorney Docket No.277A003WO01 bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-(((4-(pyrrolidin-1-yl)butyl)- carbamothioyl)oxy)malonate B152; bis(8-(octyloxy)-8-oxooctyl) 2-(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)- malonate B153; 1-(8-(heptadecan-8-yloxy)-8-oxooctyl) 3-(8-(heptadecan-9-yloxy)-8-oxooctyl) 2- (((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)malonate B154; dipentadecyl 2-(((3-(pyrrolidin-1-yl)propyl)carbamothioyl)oxy)malonate B155; bis(7-(dodecanoyloxy)heptyl) 2-(((3-(piperidin-1-yl)propyl)carbamothioyl)oxy)- malonate B156; or bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)malonate B157; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0232] In yet another embodiment, provided herein is a compound of di((Z)-octadec-9- en-1-yl) 2-(3-(4-methylpiperazin-1-yl)propoxy)malonate B201; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0233] In yet another embodiment, provided herein is a compound of di((Z)-octadec-9- en-1-yl) 2-((3-(dimethylamino)propyl)(methyl)amino)malonate B251; or di((Z)-octadec-9-en-1- yl) 2-(pyrrolidin-1-yl)malonate B252; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0234] In yet another embodiment, provided herein is a compound of: 2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)propane-1,3-diyl dioleate B301; 2-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-Attorney Docket No.277A003WO01 amido)propane-1,3-diyl dioleate B302; or 2-(4-(11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl)-4-oxobutanamido)- propane-1,3-diyl dioleate B303; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;

[0235] In yet another embodiment, provided herein is 2-(azidomethyl)propane-1,3-diyl dioleate B351; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0236] In still another embodiment, provided herein is 2-(3-azidopropanamido)propane- 1,3-diyl dioleate B352; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0237] In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to,15N for nitrogen;17O or18O for oxygen, and34S,35S, or36S for sulfur.

[0238] In certain embodiments, a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes. The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.Attorney Docket No.277A003WO01

[0239] In certain embodiments, a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one of the atoms of a compound provided herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.

[0240] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.

[0241] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cis / trans (or Z / E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0242] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture ofAttorney Docket No.277A003WO01 enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0243] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci.1977, 66, 1- 19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate.

[0244] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid.Attorney Docket No.277A003WO01

[0245] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethyl- amino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl- glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine. Lipid Nanoparticles

[0246] In one embodiment, provided herein is a lipid nanoparticle comprising a compound provided herein, e.g., 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.

[0247] In another embodiment, provided herein is a lipid nanoparticle comprising (i) a compound provided herein, e.g., 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; (ii) a phospholipid; and (iii) cholesterol.

[0248] In yet another embodiment, provided herein is a lipid nanoparticle comprising (i) a nucleic acid and (ii) a compound provided herein, e.g., 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.

[0249] In still another embodiment, provided herein is a lipid nanoparticle comprising (i)Attorney Docket No.277A003WO01 a nucleic acid; (ii) a compound provided herein, e.g., 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; (iii) a phospholipid; and (iv) cholesterol.

[0250] In certain embodiments, the lipid nanoparticle provided herein further comprises a conjugated lipid. In certain embodiments, the conjugated lipid comprises a polyethylene glycol (PEG)-conjugated lipid. In certain embodiments, the conjugated lipid is a PEG-conjugated lipid.

[0251] Thus, in one embodiment, provided herein is a lipid nanoparticle comprising (i) a compound provided herein, e.g., 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; (ii) a phospholipid; (iii) cholesterol; and (iv) a PEG-conjugated lipid.

[0252] In another embodiment, provided herein is a lipid nanoparticle comprising (i) a nucleic acid; (ii) a compound provided herein, e.g., 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; (iii) a phospholipid; (iv) cholesterol; and (v) a PEG-conjugated lipid.

[0253] In certain embodiments, the nucleic acid is a DNA. In certain embodiments, the nucleic acid is an RNA. In certain embodiments, the nucleic acid is an mRNA. In certain embodiments, the nucleic acid is an siRNA. In certain embodiments, the nucleic acid is an antisense oligonucleotide.

[0254] In certain embodiments, the phospholipid is dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), 1,2-dielaidoylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine (DMPE), dioleoylphosphatidylethanolamine (DOPE), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), palmitoyloleoylphosphatidylethanolamine (POPE), 1-stearoyl-2-oleoylphosphatidyethanolamineAttorney Docket No.277A003WO01 (SOPE), 1,2-dipalmitoylphosphatidyl-N-methylethanolamine, 1,2-dipalmitoylphosphatidyl-N,N- dimethylethanolamine, dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), palmitoyloleoylphosphatidylcholine (POPC), or a combination thereof.

[0255] In certain embodiments, the PEG-conjugated lipid is a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide, or a combination thereof. In certain embodiments, the PEG-conjugated lipid is 2-(polyethylene glycol)-N,N-ditetradecylacetamide (ALC-0159), 1,2-dimyristoyl-sn-glycero-3-methoxy- polyethylene glycol (PEG-DMG), PEG-c-DMG, PEG-DSG, PEG-DSPE, or a combination thereof. Pharmaceutical Compositions

[0256] In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, e.g., 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; and a pharmaceutically acceptable excipient.

[0257] In another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle that comprises a compound provided herein, e.g., 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; and a pharmaceutically acceptable excipient.

[0258] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a compound provided herein, e.g., 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; (ii) a phospholipid; and (iii)Attorney Docket No.277A003WO01 cholesterol.

[0259] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a therapeutic agent and (ii) a compound provided herein, e.g., 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.

[0260] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a therapeutic agent; (ii) a compound provided herein, e.g., 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; (iii) a phospholipid; and (iv) cholesterol.

[0261] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a nucleic acid and (ii) a compound provided herein, e.g., 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.

[0262] In still another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a nucleic acid; (ii) a compound provided herein, e.g., 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; (iii) a phospholipid; and (iv) cholesterol.

[0263] In certain embodiments, the pharmaceutical composition provided herein furtherAttorney Docket No.277A003WO01 comprises a conjugated lipid. In certain embodiments, the conjugated lipid comprises a PEG- conjugated lipid.

[0264] Thus, in one embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a compound provided herein, e.g., 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; (ii) a phospholipid; (iii) cholesterol; and (iv) PEG-conjugated lipid.

[0265] In another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) a nucleic acid; (ii) a compound provided herein, e.g., 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; (iii) a phospholipid; (iv) cholesterol; and (v) PEG-conjugated lipid.

[0266] In certain embodiments, the therapeutic agent is a nucleic acid. In certain embodiments, the nucleic acid is a DNA. In certain embodiments, the nucleic acid is an RNA. In certain embodiments, the nucleic acid is an mRNA. In certain embodiments, the nucleic acid is an siRNA. In certain embodiments, the nucleic acid is an antisense oligonucleotide.

[0267] In certain embodiments, the phospholipid is DPPG, DMPE, DOPE, DPPE, DSPE, POPE, SOPE, 1,2-dipalmitoylphosphatidyl-N-methylethanolamine, 1,2-dipalmitoylphosphatidyl- N,N-dimethylethanolamine, DOPC, DPPC, DSPC, POPC, or a combination thereof.

[0268] In certain embodiments, the PEG-conjugated lipid is a DAG, DAA, PEG- phospholipid, PEG-ceramide, or a combination thereof. In certain embodiments, the PEG- conjugated lipid is ALC-0159, PEG-DMG, PEG-c-DMG, PEG-DSG, PEG-DSPE, or a combination thereof.

[0269] The disclosure will be further understood by the following non-limiting examples.Attorney Docket No.277A003WO01 EXAMPLES

[0270] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); ^L (microliters); mM (millimolar); ^M (micromolar); mmol (millimoles); min (minute or minutes); h (hour or hours); DCC (N,N’-dicyclohexylcarbodiimide); DCM (dichloromethane); DIPEA (diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (dimethylformamide); EDCI (1-methyl-3-(3-dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate); Me (methyl); NeOH (methanol); TEA (triethylamine); TFA (trifluoroacetic acid); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep-HPLC (preparative high performance liquid chromatography).

[0271] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ºC (degrees Centigrade). All reactions are conducted at room temperature unless otherwise specified. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure. Example 1A Preparation of di((Z)-octadec-9-en-1-yl) 2,3-bis((4-(dimethylamino)butanoyl)oxy)succinate A001

[0272] Compound A001 is prepared as shown in Scheme 1A.Attorney Docket No.277A003WO01Preparation of didodecyl 2,3-bis((4-(dimethylamino)butanoyl)oxy)succinate A011

[0273] Compound A011 was prepared as shown in Scheme 1B.

[0274] Preparation of didodecyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate 1.2b. To a mixture of potassium 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate 1.1b (3.1 g) in dry toluene (30 mL) at 0 ºC was added oxalyl chloride (2.25 mL) dropwise. The mixture was refluxed for 1 h and then stirred at 22 °C overnight. Dodecan-1-ol (4.88 g) was added, followed by addition of TEA (4 mL). After stirring for 1 h, the reaction mixture was washed with saturated brine (2 xAttorney Docket No.277A003WO01 150 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography eluting with EtOAc / hexanes to afford compound 1.2b (4.5 g) in 57% yield. MS (ESI) m / z: 528.2 [M+H]+. Scheme 1B O O O 1. (CO)2Cl2O O1.2b (3.58 g) in TFA (10 mL) and DCM (40 mL) was stirred at 22 °C overnight and then concentrated to afford compound 1.3b (3.1 g) in 92% yield. MS (ESI) m / z: 487.6 [M+H]+.

[0276] Preparation of didodecyl 2,3-bis((4-(dimethylamino)butanoyl)oxy)succinate A011. A mixture of compound 1.3b (3.58g), EDCI (3.45 g), and DMAP (0.54 g) in DMF (40 mL) was stirred at 70 °C for 15 days. The mixture was concentrated and purified by silica gel column chromatography eluting with MeOH / DCM to afford compound A011 (104 mg) in 2% yield. MS (ESI) m / z: 714.0 [M+H]+. Example 2A Preparation of 2,3-bis((4-(dimethylamino)butanoyl)oxy)butane-1,4-diyl (9Z,9'Z)-bis(hexadec-9-Attorney Docket No.277A003WO01 enoate) A051

[0277] Preparation of (2R,3S)-2,3-bis((3-(3-(hydroxymethyl)azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A061

[0278] Compound A061 was prepared as shown in Scheme 2B.Attorney Docket No.277A003WO01 Scheme 2B HO OH O +EDCIOH

[0279] - - 9- enoate) 2.3b. A mixture of erythritol 2.1b (6.11 g, 50 mmol), palmitoleic acid 2.2b (31.8 g, 125 mmol), EDCI ^HCl (24 g, 125 mmol), and DMAP (2.52 g, 20 mmol) in DMF (250 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with hexanes (3 x 200 mL). The combined organic layers were concentrated and purified by silica gel column chromatography eluting with acetone / hexanes to afford compound 2.3b (9.86 g) in 33% yield. MS (ESI) m / z: 612.8 [M+H3O]+.

[0280] Preparation of (2R,3S)-2,3-bis(acryloyloxy)butane-1,4-diyl (9Z,9'Z)-bis(hexadec- 9-enoate) 2.4b. A mixture of compound 2.3b (4 g, 6.7 mmol), acryloyl chloride (2.73 mL, 33.6 mmol), and DIPEA (5.21 g, 40.3 mmol) in DCM (100 mL) was stirred at room temperature for 16 h. The reaction mixture was then concentrated, diluted with EtOAc, and washed with water (3 x 100 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with acetone / hexanes to afford compound 2.4b (2.11 g) in 45% yield.Attorney Docket No.277A003WO01 MS (ESI) m / z: 720.1 [M+H3O]+.

[0281] Preparation of (2R,3S)-2,3-bis((3-(3-(hydroxymethyl)azetidin-1-yl)propanoyl)- oxy)butane-1,4-diyl (9Z,9'Z)-bis(hexadec-9-enoate) A061. A mixture of compound 2.4b (1 g, 1.4 mmol), azetidine-3-yl methanol hydrochloride (1.41 g, 11.4 mmol), and potassium hydroxide (641 mg, 11.4 mmol) in isopropyl alcohol (50 mL) was stirred overnight. The mixture was concentrated and purified by silica gel column chromatography eluting with MeOH / DCM to afford compound A061 (112 mg) in 9% yield. MS (ESI) m / z: 878.5 [M+H]+. Example 2C Preparation of (2R,3S)-2,3-bis((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A064was as

[0283] Preparation of (2R,3S)-2,3-bis((6-bromohexanoyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) 2.1c. A mixture of 6-bromohexanoic acid (3.90 g, 20 mmol), thionyl chloride (1.45 mL, 20 mmol), and 0.5 mL DMF in DCM (50 mL) was heated to a gentle reflux and then cooled slowly to room temperature over 30 min, followed by addition of pyridine (4.03 mL, 50 mmol) and compound 2.3b (2.97 g, 5.0 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The organic layer was washed with water three times, concentrated, and purified by silica gel column chromatography eluting with acetone / hexanes to afford compound 2.1c (6 g).

[0284] Preparation of (2R,3S)-2,3-bis((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)- oxy)butane-1,4-diyl (9Z,9'Z)-bis(hexadec-9-enoate) A064. A mixture of compound 2.1c (1.5 g, 1.6 mmol), N-(2-hydroxyethyl)piperazine (1.03 mg, 7.9 mmol), and potassium iodide (262 mg, 1.6 mmol) in DMF (50 mL) was stirred overnight. The mixture was concentrated and purifiedAttorney Docket No.277A003WO01 by silica gel column chromatography eluting with MeOH / DCM to afford compound A064 (66 mg) in 4% yield. MS (ESI) m / z: 1047.6 [M+H]+. Scheme 2C O OPreparation of 1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl bis(4-(dimethylamino)- butanoate) A101

[0285] Compound A101 is prepared as shown in Scheme 3.Attorney Docket No.277A003WO01Preparation of di((Z)-octadec-9-en-1-yl) 2,3-bis(((4-(dimethylamino)butyl)carbamoyl)- oxy)succinate A151 H N O N O

[0286] as Scheme 4 O NCO NAttorney Docket No.277A003WO01 Example 5 Preparation of 2,3-bis(((4-(dimethylamino)butyl)carbamoyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) A201 H N O N O

[0287] Example 6 Preparation of 1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl bis((4-(dimethylamino)- butyl)carbamate) A251

[0288] Compound A251 is prepared as shown in Scheme 6.Attorney Docket No.277A003WO01Preparation of di((Z)-octadec-9-en-1-yl) 2,3-bis(((4-(dimethylamino)butyl)carbamothioyl)- oxy)succinate A301 H N S N O

[0289] as Scheme 7 O NCS NExample 8 Preparation of 2,3-bis(((4-(dimethylamino)butyl)carbamothioyl)oxy)butane-1,4-diyl (9Z,9'Z)-Attorney Docket No.277A003WO01 bis(hexadec-9-enoate) A351 H N S N O

[0290] Preparation of O,O'-(1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl) bis((4-(dimethyl- amino)butyl)carbamothioate) A401

[0291] Compound A401 is prepared as shown in Scheme 9.Attorney Docket No.277A003WO01Preparation of di((Z)-octadec-9-en-1-yl) 2-(4-(dimethylamino)butyl)-1,3-dioxolane-4,5- dicarboxylate A451

[0292] (9Z,9'Z)-Attorney Docket No.277A003WO01 bis(hexadec-9-enoate) A501

[0293] Scheme 11 O2-yl)-N,N- dimethylbutan-1-amine A551

[0294] Compound A551 is prepared as shown in Scheme 12.Attorney Docket No.277A003WO01Preparation of di((Z)-octadec-9-en-1-yl) 2-((3-(pyrrolidin-1-yl)propanoyl)oxy)malonate B001

[0295] asExample 13BAttorney Docket No.277A003WO01 Preparation of dioctadecyl 2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)butanoyl)oxy)malonate B011Scheme 13B O OH TsOH +of compound 13.3b (a crude product prepared from compound 13.1b (3.13 g, 5 mmol)), DCC (1.44 g, 7 mmol), 4-bromobutyric acid (1 g, 6 mmol), and DMAP (126 mg, 1 mmol) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, resuspended in EtOAc (100 mL), and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography eluting with acetone / hexanes to afford compound 13.4b.

[0298] Preparation of dioctadecyl 2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)butanoyl)- oxy)malonate B011. A mixture of compound 13.4b (1.16 g, 1.5 mmol), N-(2-hydroxyethyl)-Attorney Docket No.277A003WO01 piperazine (976 mg, 7.5 mmol), and potassium iodide (250 mg, 1.5 mmol) in DMF (50 mL) was stirred overnight. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with MeOH / DCM to compound B011 (37 mg) in 2.5% yield. MS (ESI) m / z: 824.3 [M+H]+. Example 13C Preparation of ditridecyl 2-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B017

[0299] Scheme 13C O

[0300] Preparation of ditridecyl 2-(acryloyloxy)malonate 13.2b. To a solution of compound 13.1c (485 mg, 1 mmol) in EtOAc (50 mL) were added acryloyl chloride (181 mg, 2 mmol) and DIPEA (523 µL, 3 mmol). After stirring at room temperature for 3 h, the reaction mixture was diluted with EtOAc and washed with water (3 x 100 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with acetone / hexanes to afford compound 13.2c (310 mg) in 58% yield. MS (ESI) m / z: 557.1 [M+H3O]+.Attorney Docket No.277A003WO01

[0301] Preparation of ditridecyl 2-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)- oxy)malonate B017. A mixture of compound 13.2c (310 mg, 0.6 mmol) and N-(2-hydroxy- ethyl)piperazine (375 mg, 2.9 mmol) in isopropyl alcohol (50 mL) was stirred overnight. The mixture was concentrated and purified by silica gel column chromatography eluting with MeOH / DCM to afford compound A017 (24 mg) in 6% yield. MS (ESI) m / z: 669.6 [M+H]+. Example 14A Preparation of di((Z)-octadec-9-en-1-yl) 2-(((3-(4-methylpiperazin-1-yl)propoxy)carbonyl)oxy)- malonate B051

[0302] Example 14B Preparation of dioctadecyl 2-(((3-(diethylamino)propoxy)carbonyl)oxy)malonate B052 O O O

[0303] Compound B052 was prepared as shown in Scheme 14B.Attorney Docket No.277A003WO01

[0304] Preparation of dioctadecyl 2-(((3-(diethylamino)propoxy)carbonyl)oxy)malonate B052. To a solution of compound 13.3b (625 mg, 1 mmol) in DCM (50 mL) was added bis(4- nitrophenyl) carbonate (304 mg, 1 mmol). After the mixture was stirred for 1 day, 3- diethylamino-1-propanol (131 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 1 day, and then concentrated and purified by silica gel column chromatography eluting with 2% TEA in DCM / Acetone to afford compound B052 (46 mg) in 6% yield. MS (ESI) m / z: 782.5 [M+H]+.Preparation of di((Z)-octadec-9-en-1-yl) 2-(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)- malonate B101

[0305] Compound B101 is prepared as shown in Scheme 15.Attorney Docket No.277A003WO01Preparation of di((Z)-octadec-9-en-1-yl) 2-(((4-(dimethylamino)butyl)carbamothioyl)oxy)- malonate B151

[0306] asExample 17Attorney Docket No.277A003WO01 Preparation of di((Z)-octadec-9-en-1-yl) 2-(3-(4-methylpiperazin-1-yl)propoxy)malonate B201

[0307] Scheme 17 O HO CBr4 / PPh3Example 18 Preparation of di((Z)-octadec-9-en-1-yl) 2-((3-(dimethylamino)propyl)(methyl)amino)malonate B251

[0308] Compound B251 is prepared as shown in Scheme 18.Attorney Docket No.277A003WO01Preparation of 2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)propane-1,3-diyl dioleate B301

[0309] was as

[0310] Preparation of 2-((tert-butoxycarbonyl)amino)propane-1,3-diyl dioleate 19.3. To a solution of tert-butyl 1,3-dihydroxypropan-2-ylcarbamate 19.1 (1.91 g) in DCM (50 mL) were sequentially added oleic acid 19.2 (7.06 g), DCC (6.2 g), and DMAP (0.5 g). After stirring at room temperature for 3 h, hexane (150 mL) was added. The resulting suspension was filtered, and the filtrate was concentrated and purified by silica gel column chromatography eluting with EtOAc / hexanes to afford compound 19.3 (5.4 g) in 76% yield. MS (ESI) m / z: 721.2 [M+H]+.

[0311] Preparation of 2-aminopropane-1,3-diyl dioleate 19.4. A solution of compound 19.3 (1.4 g) in DCM / TFA (4:1, 100 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated to afford compound 19.4, which was used directly in the next step without further purification. MS (ESI) m / z: 221.4 [M+H]+.Attorney Docket No.277A003WO01 Scheme 19 OH H N O Boc + DCC / DMAPpropane- 1,3-diyl dioleate B301. To a solution of compound 19.4 in DCM (50 mL) were sequentially added 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate 19.5 (0.64 g) and TEA (0.84 mL). After stirring at room temperature for 19 h, the reaction mixture was diluted with DCM (150 mL) and washed with water (150 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with hexane / acetone to afford compound B301 (0.8 g) in 52% yield.1H NMR (300 MHz, CDCl3) δ 6.70 (s, 2H), 5.91 (m, 1H), 5.34 (m, 4H), 4.42 (m, 1H), 4.20 (m, 2H), 4.09 (m, 2H), 3.83 (t, J = 6.9 Hz, 2H), 2.54 (t, J = 7.1 Hz, 2H), 2.32 (t, J = 6.8 Hz, 4H), 2.01 (m, 8H), 1.59 (m, 8H), 1.42-1.24 (m, 40H), 0.88 (t, J = 7.2 Hz, 6H). MS (ESI) m / z: 772.3 [M+H]+. Example 20 Preparation of 2-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-Attorney Docket No.277A003WO01 amido)propane-1,3-diyl dioleate B302Scheme 20 O

[0314] Preparation of 2-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxa- pentadecan-15-amido)propane-1,3-diyl dioleate B302. To a solution of compound 19.4, which was prepared from compound 19.3 (1.4 g) as described in Example 19, in DCM (50 mL) were sequentially added 2,5-dioxopyrrolidin-1-yl 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12- tetraoxapentadecan-15-oate 20.1 (0.885 g) and TEA (1.3 mL). After stirring at room temperature for 19 h, the reaction mixture was concentrated, redissolved in EtOAc (150 mL), and washed with water (3 x 50 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with hexane / acetone to afford compound B302 (1.1 g) inAttorney Docket No.277A003WO01 62% yield.1H NMR (400 MHz, CDCl3) δ 6.70 (s, 2H), 6.61 (d, J = 5.8 Hz, 1H), 5.34 (m, 4H), 4.45 (m, 1H), 4.18 (m, 2H), 4.08 (m, 2H), 3.73 (m, 4H), 3.61 (m, 14H), 2.47 (t, J = 6.6 Hz, 2H), 2.30 (t, J = 7.1 Hz, 4H), 2.01 (m, 8H), 1.56 (m, 4H), 1.39-1.23 (m, 40H), 0.87 (t, J = 7.2 Hz, 6H); MS (ESI) m / z: 948.4 [M+H]+. Example 21 Preparation of 2-(4-(11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl)-4-oxobutanamido)- propane-1,3-diyl dioleate B303

[0315] Scheme 21 O

[0316] Preparation of 2-(4-(11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl)-4-Attorney Docket No.277A003WO01 oxobutanamido)-propane-1,3-diyl dioleate B303. To a solution of compound 19.4, which was prepared from compound 19.3 (1.4 g) as described in Example 19, in DCM (50 mL) were sequentially added DBCO-NHS ester 21.1 (0.804 g) and TEA (1.3 mL). After stirring at room temperature for 19 h, the reaction mixture was concentrated, redissolved in EtOAc (150 mL), and washed with water (3 x 50 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with hexane / acetone to afford compound B303 (1.1 g) in 62% yield.1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 5.9 Hz, 1H), 7.48 (m, 1H), 7.46-7.22 (m, 6H), 6.13 (d, J = 5.8 Hz, 1H), 5.34 (m, 4H), 5.14 (d, J = 7.6 Hz, 1H), 4.32 (m, 1H), 4.11 (m, 1H), 4.08 (m, 1H), 4.00 (m, 1H), 3.84 (m, 1H), 3.68 (d, J = 7.6 Hz, 1H), 2.77 (m, 1H), 2.47 (m, 1H), 2.30 (m, 1H), 2.27 (m, 4H), 2.20 (m, 1H), 2.03 (m, 10H), 1.57 (m, 8H), 1.39-1.23 (m, 49H), 0.88 (t, J = 7.2 Hz, 6H). MS (ESI) m / z: 908.4 [M+H]+. Example 22 Preparation of 2-(azidomethyl)propane-1,3-diyl dioleate B352

[0317] Compound B351 was prepared as shown in Scheme 22.

[0318] Preparation of 2-(((methylsulfonyl)oxy)methyl)propane-1,3-diyl dioleate 22.2. To a solution of 2-(hydroxymethyl)propane-1,3-diyl dioleate 22.1 (16.4 g) and TEA (18 mL) in EtOAc (200 mL) was added MsCl (4 mL) dropwise over 20 min. After stirring at room temperature for 2 h, the reaction mixture was washed with water (3 x 150 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with hexane / acetone to afford compound 22.2 (15.7 g) in 85% yield. MS (ESI) m / z: 714.2 [M+H]+.

[0319] Preparation of 2-(azidomethyl)propane-1,3-diyl dioleate B351. To a solution of compound 22.2 (17.7 g) in DMF (50 mL) was added sodium azide (4 g). The reaciton mixture was stirred at 70oC for 3 h, and then diluted with hexane (350 mL) and washed with water (3 xAttorney Docket No.277A003WO01 100 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with hexane / acetone to afford compound B351 (13.1 g) in 90% yield.1H NMR (400 MHz, CDCl3) δ 5.34 (m, 4H), 4.11 (d, J = 6.2 Hz, 4H), 3.43 (d, J = 6.0 Hz, 2H), 2.29 (m, 5H0, 2.00 (m, 8H), 1.63 (m, 5H), 1.39-1.23 (m, 44H), 0.88 (t, J = 7.2 Hz, 6H). MS (ESI) m / z: 661.2 [M+H]+.Example 23 Preparation of 2-(3-azidopropanamido)propane-1,3-diyl dioleate B352

[0320] Compound B352 was prepared as shown in Scheme 23.

[0321] Preparation of 2-(3-azidopropanamido)propane-1,3-diyl dioleate B352. To aAttorney Docket No.277A003WO01 solution of compound 19.4, which was prepared from compound 19.3 (1.4 g) as described in Example 19, in DCM (50 mL) were sequentially added 2,5-dioxopyrrolidin-1-yl 3-azido- propanoate 23.1 (0.637 g) and TEA (1.3 mL). After stirring at room temperature for 19 h, the reaction mixture was concentrated, redissolved in EtOAc (150 mL), and washed with water (3 x 50 mL). The organic layer was concentrated and purified by silica gel column chromatography eluting with hexane / acetone to afford compound B352 (1.1 g) in 65% yield.1H NMR (400 MHz, CDCl3) δ 5.94 (d, J = 5.9 Hz, 1H), 5.34 (m, 4H), 4.51 (m, 1H), 4.32 (m, 1H), 4.25 (m, 2H), 4.10 (m, 2H), 3.62 (d, J = 7.1 Hz, 2H), 2.42 (d, J = 7.1 Hz, 2H), 2.32 (d, J = 7.4 Hz, 4H), 2.02 (m, 8H), 1.63 (m, 8H), 1.39-1.23 (m, 44H), 0.88 (t, J = 7.2 Hz, 6H). MS (ESI) m / z: 718.1 [M+H]+. Scheme 23

[0322] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein.

[0323] 1-(((9Z,12Z)-Octadeca-9,12-dienoyl)oxy)-4-(oleoyloxy)butane-2,3-diyl bis(3- (azetidin-1-yl)propanoate) A052. MS (ESI) m / z: 817.6 [M+H]+.Attorney Docket No.277A003WO01

[0324] butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A062. MS (ESI) m / z: 964.0 [M+H]+.

[0325] - - bis(hexadec-9-enoate) A063. MS (ESI) m / z: 817.6 [M+H]+.

[0326] Ditridecyl 2-((4-(4-methylpiperazin-1-yl)butanoyl)oxy)malonate B012.1H NMR (400 MHz, CDCl3) δ 5.53 (s, 1H), 4.21 (s, 4H), 2.53 (t, J = 6.8 Hz, 2H), 2.46 (m, 8H), 2.30 (t, J = 6.9 Hz, 2H), 1.86 (m, 2H), 1.65 (m, 4H), 1.40-1.25 (m, 40H), 0.87 (t, J = 7.2 Hz, 6H); MS (ESI) m / z: 654.1 [M+H]+.

[0327] Ditridecyl 2-((4-((2-hydroxyethyl)(methyl)amino)butanoyl)oxy)malonate B013. MS (ESI) m / z: 628.7 [M+H]+.Attorney Docket No.277A003WO01

[0328] B014. MS (ESI) m / z: 626.5 [M+H]+.

[0329] (ESI) m / z: 611.0 [M+H]+.

[0330] oxy)malonate B016.1H NMR (400 MHz, CDCl3) δ 5.53 (s, 1H), 4.21 (s, 4H), 3.62 (t, J = 6.9 Hz, 2H), 2.67-2.30 (m, 12H), 1.88 (m, 2H), 1.66 (m, 6H), 1.40-1.25 (m, 44H), 0.88 (t, J = 7.0 Hz, 6H); MS (ESI) m / z: 684.0 [M+H]+.

[0331] Ditridecyl 2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)oxy)malonate B018.1H NMR (400 MHz, CDCl3) δ 5.53 (s, 1H), 4.21 (s, 4H), 3.62 (t, J = 6.8 Hz, 2H), 2.70-2.27 (m, 12H), 1.66 (m, 6H), 1.52 (m, 2H), 1.46-1.19 (m, 42H), 0.88 (t, J = 7.0 Hz, 6H). MS (ESI) m / z: 711.5 [M+H]+; MS (ESI) m / z: 711.5 [M+H]+.Attorney Docket No.277A003WO01

[0332] The following compounds are prepared similarly according to the synthetic procedures or methodologies exemplified herein.

[0333] Bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis((3-(azetidin-1-yl)propanoyl)- oxy)succinate A002.

[0334] - oxy)- succinate A003.

[0335] Bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis((3-(piperidin-1-yl)propanoyl)- oxy)succinate A004.

[0336] Dipentadecyl 2,3-bis((4-(azetidin-1-yl)butanoyl)oxy)succinate A005.Attorney Docket No.277A003WO01

[0337] oxy)succinate A006.

[0338] A007.

[0339] Bis(6-( 1-yl)pentanoyl)oxy)- succinate A008.

[0340] Di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis((5-(piperidin-1-yl)pentanoyl)oxy)- succinate A009.Attorney Docket No.277A003WO01

[0341] ((5- morpholinopentanoyl)oxy)succinate A010.

[0342] 1-yl)- propanoate) A053.

[0343] - (3- (piperidin-1-yl)propanoate) A054.

[0344] 2,3-Bis((4-(azetidin-1-yl)butanoyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate) A055.Attorney Docket No.277A003WO01

[0345] A056.

[0346] (octyloxy)- butanoate) A057.

[0347] 1-( - - 9,12-dienoyl)oxy)- butane-2,3-diyl bis(5-(pyrrolidin-1-yl)pentanoate) A058.

[0348] 1-(Heptadecanoyloxy)-4-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)butane-2,3-diyl bis(5-(piperidin-1-yl)pentanoate) A059.Attorney Docket No.277A003WO01

[0349] diyl bis(5- morpholinopentanoate) A060.

[0350] -non- en- butane-1,4- diyl)bis(oxy))dihexanoate A102.

[0351] Dioctyl 8,8'-((2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)butane-1,4-diyl)- bis(oxy))dioctanoate A103.

[0352] Di(heptadecan-9-yl) 8,8'-((2,3-bis((3-(piperidin-1-yl)propanoyl)oxy)butane-1,4- diyl)bis(oxy))dioctanoate A104.Attorney Docket No.277A003WO01

[0353] A105.

[0354] ()bis(heptane- 7,1-diyl) didodecanoate A106.

[0355] A107.

[0356] ((2,3-Bis((5-(pyrrolidin-1-yl)pentanoyl)oxy)butane-1,4-diyl)bis(oxy))bis(hexane- 6,1-diyl) bis(2-hexyldecanoate) A108.Attorney Docket No.277A003WO01

[0357] (piperidin- 1-yl)pentanoate) A109.

[0358] oxy)butane- 2,3-diyl bis(5-morpholinopentanoate) A110.

[0359] - (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A111.

[0360] (2R,3S)-2,3-Bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4-diylAttorney Docket No.277A003WO01 (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A112.

[0361] butane-1,4- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetra- methyl-17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A113.

[0362] - (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A114.

[0363] (2R,3S)-2,3-Bis((3-(piperidin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A115.Attorney Docket No.277A003WO01

[0364] butane-1,4- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15- tetramethyl-17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A116.- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A117.

[0366] (2R,3S)-2,3-Bis((3-morpholinopropanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A118.Attorney Docket No.277A003WO01 O N O

[0367] 1-yl)butyl)- carbamoyl)oxy)succinate A152.

[0368] - oxy)- succinate A153. H N N O O O

[0369] - propyl)- carbamoyl)oxy)succinate A154. H

[0370] Dipentadecyl 2,3-bis(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)-Attorney Docket No.277A003WO01 succinate A155. N H N N O

[0371] oxy)- succinate A156.A157. H N O N O

[0373] Bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis(((3-(pyrrolidin-1-yl)propyl)- carbamoyl)oxy)succinate A158.

[0374] Di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis(((3-(piperidin-1-yl)propyl)-Attorney Docket No.277A003WO01 carbamoyl)oxy)succinate A159.

[0375] (9Z,12Z)- octadeca-9,12-dienoate A202. H N O N O

[0376] - oxy)butyl oleate A203.

[0377] - - carbamoyl)oxy)butyl oleate A204.

[0378] 2,3-Bis(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) A205.Attorney Docket No.277A003WO01

[0379] A206.

[0380] (4,4-bis- (octyloxy)butanoate) A207.

[0381] 4-((4,4-Bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)- carbamoyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A208.

[0382] 4-(Heptadecanoyloxy)-2,3-bis(((3-(piperidin-1-yl)propyl)carbamoyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A209.Attorney Docket No.277A003WO01

[0383] oxy)- butane-1,4-diyl)bis(oxy))dihexanoate A252.

[0384] butane-1,4- diyl)bis(oxy))dioctanoate A253.

[0385] oxy)- butane-1,4-diyl)bis(oxy))dioctanoate A254. H

[0386] 1,4-Bis(pentadecyloxy)butane-2,3-diyl bis((3-(4-methylpiperazin-1-yl)propyl)- carbamate) A255.Attorney Docket No.277A003WO01

[0387] (oxy))- bis(heptane-7,1-diyl) didodecanoate A256.- carbamate) A257.

[0389] ((2,3-Bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl)bis(oxy))- bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A258.

[0390] 1,4-Bis(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane-2,3-diyl bis((3-(piperidin- 1-yl)propyl)carbamate) A259.Attorney Docket No.277A003WO01

[0391] yl)butyl)carbamothioyl)oxy)succinate A302.

[0392] - oxy)succinate A303.

[0393] - - carbamothioyl)oxy)succinate A304.

[0394] Dipentadecyl 2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamothioyl)oxy)succinate A305.Attorney Docket No.277A003WO01 H N N S O

[0395] carbamothioyl)- oxy)succinate A306.propyl)- carbamothioyl)oxy)succinate A307.

[0397] (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) A352. H N S

[0398] 2,3-Bis(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4-diyl dihepta- decanoate A353.Attorney Docket No.277A003WO01

[0399] bis(4,4- bis(octyloxy)butanoate) A354.

[0400] 4-( - yl)propyl)carbamo- thioyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A355.

[0401] - oxy)- butyl (9Z,12Z)-octadeca-9,12-dienoate A356.

[0402] 4-((4,4-Bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)butyl oleate A357.Attorney Docket No.277A003WO01

[0403] - oxy)butane-1,4-diyl)bis(oxy))dihexanoate A402.

[0404] butane-1,4- diyl)bis(oxy))dioctanoate A403.

[0405] oxy)- butane-1,4-diyl)bis(oxy))dioctanoate A404.

[0406] O,O'-(1,4-Bis(pentadecyloxy)butane-2,3-diyl) bis((3-(pyrrolidin-1-yl)propyl)- carbamothioate) A405.Attorney Docket No.277A003WO01

[0407] diyl)bis(oxy))- bis(heptane-7,1-diyl) didodecanoate A406.diyl)bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A407.

[0409] -non- en- - 4-yl)methyl)- 1,3-dioxolane-4,5-dicarboxylate A452. N O O

[0410] Bis(8-(octyloxy)-8-oxooctyl) 2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolane- 4,5-dicarboxylate A453.Attorney Docket No.277A003WO01

[0411] 4-yl)ethyl)-1,3- dioxolane-4,5-dicarboxylate A454.

[0412] A455.

[0413] -1,3- dioxolane-4,5-dicarboxylate A456. O O

[0414] Bis(5-ethylnonyl) 2-(3-(1-methylpyrrolidin-2-yl)propyl)-1,3-dioxolane-4,5- dicarboxylate A457.Attorney Docket No.277A003WO01

[0415] Bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(4-(2-methylpyrrolidin-1-yl)butyl)-1,3- dioxolane-4,5-dicarboxylate A458. O

[0416] -1,3- dioxolane-4,5-dicarboxylate A459.

[0417] - - - 2-(5-(ethyl- (methyl)amino)pentyl)-1,3-dioxolane-4,5-dicarboxylate A460.

[0418] - en- - - butyl)-2-methyl-1,3-dioxolane-4,5-dicarboxylate A461.

[0419] (Z)-4-(8-(Heptadecan-9-yloxy)-8-oxooctyl) 5-(octadec-9-en-1-yl) 2-methyl-2-((1- methylpiperidin-4-yl)methyl)-1,3-dioxolane-4,5-dicarboxylate A462.Attorney Docket No.277A003WO01

[0420] 1-yl)- propyl)-1,3-dioxolane-4,5-dicarboxylate A463. O O

[0421] (4- (pyrrolidin-1-yl)butyl)-1,3-dioxolane-4,5-dicarboxylate A464.

[0422] - en- - (methyl)amino)butyl)-2-methyl-1,3-dioxolane-4,5-dicarboxylate A465.

[0423] (2-((1-Methylpiperidin-4-yl)methyl)-5-((oleoyloxy)methyl)-1,3-dioxolan-4- yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A502.Attorney Docket No.277A003WO01

[0424] -1,3-dioxolan- 4-yl)methyl oleate A503.

[0425] 4-yl)ethyl)- 1,3-dioxolan-4-yl)methyl oleate A504. O

[0426] - - bis(octadeca-9,12-dienoate) A505. O

[0427] (2-(3-(1-Methylpiperidin-4-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene) diheptadecanoate A506.Attorney Docket No.277A003WO01

[0428] (methylene) bis(4,4-bis(octyloxy)butanoate) A507.

[0429] (5-(( - 1-yl)- butyl)-1,3-dioxolan-4-yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A508.

[0430] (2-(4-(Ethyl(methyl)amino)butyl)-5-((heptadecanoyloxy)methyl)-1,3-dioxolan-4- yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A509.

[0431] Di((Z)-non-2-en-1-yl) 6,6'-(((2-((1-methylpiperidin-4-yl)methyl)-1,3-dioxolane- 4,5-diyl)bis(methylene))bis(oxy))dihexanoate A552.Attorney Docket No.277A003WO01

[0432] 4,5-diyl)- bis(methylene))bis(oxy))dioctanoate A553.

[0433] - dioxolane- 4,5-diyl)bis(methylene))bis(oxy))dioctanoate A554.

[0434] - A555.

[0435] - (methylene))- bis(oxy))bis(heptane-7,1-diyl) didodecanoate A556.Attorney Docket No.277A003WO01

[0436] 2-(3-(4,5-Bis(((5-ethylnonyl)oxy)methyl)-1,3-dioxolan-2-yl)propyl)-1-methyl- pyrrolidine A557.

[0437] (((2-(4-diyl)bis(methylene))- bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A558.

[0438] - - 2-yl)-N- ethyl-N-methylbutan-1-amine A559.

[0439] - en- - - 9-en-1- yl)oxy)methyl)-1,3-dioxolan-4-yl)methoxy)hexanoate A560.

[0440] Octyl (Z)-8-((2-(4-(dimethylamino)butyl)-2-methyl-5-((octadec-9-en-1-yloxy)- methyl)-1,3-dioxolan-4-yl)methoxy)octanoate A561.Attorney Docket No.277A003WO01

[0441] Heptadecan-9-yl (Z)-8-((2-methyl-2-((1-methylpiperidin-4-yl)methyl)-5- ((octadec-9-en-1-yloxy)methyl)-1,3-dioxolan-4-yl)methoxy)octanoate A562.

[0442] - -5-((pentadecyl- oxy)methyl)-1,3-dioxolan-2-yl)propyl)piperazine A563.

[0443] - en- - 1-yl)butyl)- 1,3-dioxolan-4-yl)methoxy)heptyl dodecanoate A564.

[0444] N-Ethyl-N-methyl-4-(2-methyl-4-((((Z)-octadec-9-en-1-yl)oxy)methyl)-5- ((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)butan-1-amine A565.Attorney Docket No.277A003WO01

[0445] Didodecyl 2-((4-(dimethylamino)butanoyl)oxy)-3-hydroxysuccinate A601.

[0446] Bis(6-1-yl)propanoyl)oxy)- malonate B002.

[0447] - oxy)malonate B003.

[0448] - -8-oxooctyl) 2- ((3-(piperidin-1-yl)propanoyl)oxy)malonate B004.

[0449] Dipentadecyl 2-((4-(azetidin-1-yl)butanoyl)oxy)malonate B005.Attorney Docket No.277A003WO01

[0450] Bis(7-(dodecanoyloxy)heptyl) 2-((4-(pyrrolidin-1-yl)butanoyl)oxy)malonate B006.

[0451]

[0452] Bis(6-( yl)pentanoyl)oxy)- malonate B008.

[0453] - oxy)- malonate B009.

[0454] 1-((Z)-Octadec-9-en-1-yl) 3-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5- morpholinopentanoyl)oxy)malonate B010.Attorney Docket No.277A003WO01

[0455] 2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((4- (dimethylamino)butanoyl)oxy)malonate B021.

[0456] Bis(- - methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (azetidin-1-yl)propanoyl)oxy)malonate B022.

[0457] Bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(3- hydroxyazetidin-1-yl)propanoyl)oxy)malonate B023.Attorney Docket No.277A003WO01 H H

[0458] Bis2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (pyrrolidin-1-yl)propanoyl)oxy)malonate B024.

[0459] Bis( - - methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (piperidin-1-yl)propanoyl)oxy)malonate B025.Attorney Docket No.277A003WO01

[0460] Bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(4- (2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B026.

[0461] 2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(4- methylpiperazin-1-yl)propanoyl)oxy)malonate B027.

[0462] - - 2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- morpholinopropanoyl)oxy)malonate B028.Attorney Docket No.277A003WO01

[0463] Bischroman-6-yl) 2- ((4-(dimethylamino)butanoyl)oxy)malonate B031.

[0464] - - 6-yl) 2- ((3-(azetidin-1-yl)propanoyl)oxy)malonate B032.

[0465] Bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(3-hydroxyazetidin-1-yl)propanoyl)oxy)malonate B033.Attorney Docket No.277A003WO01

[0466] 6-yl) 2- ((3-(pyrrolidin-1-yl)propanoyl)oxy)malonate B034.

[0467] - - chroman-6-yl) 2- ((3-(piperidin-1-yl)propanoyl)oxy)malonate B035.

[0468] Bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B036.Attorney Docket No.277A003WO01

[0469] Bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(4-methylpiperazin-1-yl)propanoyl)oxy)malonate B037.

[0470] - - 6-yl) 2- ((3-morpholinopropanoyl)oxy)malonate B038. O

[0471] Bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-(((4-(pyrrolidin-1-yl)butyl)- carbamoyl)oxy)malonate B102.Attorney Docket No.277A003WO01

[0472] oxy)- malonate B103.

[0473] - carbamoyl)oxy)malonate B104. O O O H

[0474] malonate B105.

[0475] Bis(7-(dodecanoyloxy)heptyl) 2-(((3-morpholinopropyl)carbamoyl)oxy)malonate B106.Attorney Docket No.277A003WO01

[0476] 1-(5-Ethyldecyl) 3-(5-ethylnonyl) 2-(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)- malonate B107.

[0477] Bispropyl)carbamoyl)- oxy)malonate B108.

[0478] - - ((5- morpholinopentanoyl)oxy)malonate B109.

[0479] Bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-(((4-(pyrrolidin-1-yl)butyl)- carbamothioyl)oxy)malonate B152.

[0480] Bis(8-(octyloxy)-8-oxooctyl) 2-(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)- malonate B153.Attorney Docket No.277A003WO01

[0481] oxooctyl) 2- (((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)malonate B154.

[0482] B155.

[0483] oxy)- malonate B156. O

[0484] Bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)malonate B157.Attorney Docket No.277A003WO01

[0485] Di((Z)-octadec-9-en-1-yl) 2-(pyrrolidin-1-yl)malonate B252.

[0486] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

Attorney Docket No.277A003WO01 What is claimed is:

1. A compound of Formula (I): or an enantiomer, a mixture of of two or morediastereomers, a tautomer, a two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: A, A1, A2, and A3are: (i) A is C(H)–A4–L4–R4or CH(OH); A1and A4are each independently –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; (ii) A and A1together with the carbon atom to which they are attached form heterocyclyl; and A2and A3are each independently a bond, –C(O)O–, –C(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –CH2O–, or –CH2OC(O)–; or (iii) A is a bond; A1is a bond, –C(O)O–, –C(O)S–, –OC(O)O–, –OC(O)S–, –C(O)N(R1b)–, –C(S)N(R1b)–, –OC(O)N(R1b)–, –OC(S)N(R1b)–, –N(R1b)–, –N(R1a)C(O)N(R1d)–, or –N(R1a)C(S)N(R1d)–; and A2and A3are each independently –C(O)O–, –C(O)S–, –C(O)N(R1b)–, or –C(S)N(R1b)–; L1and L4are each independently a bond, C1-20alkylene, C1-20heteroalkylene, C2-20 alkenylene, or C2-20 alkynylene; L2and L3are each independently a bond, C1-20alkylene, C1-20heteroalkylene, C2-20alkenylene, C2-20alkynylene, C3-20cycloalkylene, heteroarylene, or heterocyclylene; R1and R4are each independently azido, heteroaryl, heterocyclyl, or –NR4aR4b;Attorney Docket No.277A003WO01 each R1a, R1b, R1c, and R1dis 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; R2aand R3aare each independently absent, hydrogen, C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R2band R3bare each independently C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C2-20 alkynyl, C3-10 cycloalkyl, C1-20 alkoxy, C1-20 heteroalkoxy, C2-20 alkenoxy, or C2-20 alkynoxy; R4aand R4bare each independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R4aand R4btogether with the N atom to which they are attached form heterocyclyl; and X and Z are each independently a bond, C(H), or N, with the proviso that, when X is a bond, R2ais absent; and when Z is a bond, R3ais absent; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene, alkoxy, heteroalkoxy, alkenoxy, and alkynoxy 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) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, 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) Rband Rctogether with the N atom to which they are attached formAttorney Docket No.277A003WO01 heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, 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, –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, and –S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, having the structure of Formula (II): or an enantiomer, a mixture ofof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. The compound of claim 1 or 2, wherein A2is –C(O)O–, –CH2O–, or –CH2OC(O)–.

4. The compound of any one of claims 1 to 3, wherein A3is –C(O)O–, –CH2O–, or –CH2OC(O)–.

5. The compound of any one of claims 1 to 4, having the structure of Formula (VI):Attorney Docket No.277A003WO01 or an enantiomer, a of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U1and U4are each independently O or S; and V1and V4are each independently a bond, O, or N(R1b).

6. The compound of any one of claims 1 to 4, having the structure of Formula (IX): or an enantiomer, aof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U1and U4are each independently O or S; and V1and V4are each independently a bond, O, or N(R1b).

7. The compound of any one of claims 1 to 4, having the structure of Formula (X): or an enantiomer, aof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U1and U4are each independently O or S; and V1and V4are each independently a bond, O, or N(R1b).

8. The compound of any one of claims 5 to 7, wherein U1is O.Attorney Docket No.277A003WO01 9. The compound of any one of claims 5 to 7, wherein U1is S.

10. The compound of any one of claims 5 to 9, wherein U4is O.

11. The compound of any one of claims 5 to 9, wherein U4is S.

12. The compound of any one of claims 5 to 11, wherein V1is a bond.

13. The compound of any one of claims 5 to 11, wherein V1is N(R1b).

14. The compound of any one of claims 5 to 13, wherein V4is a bond.

15. The compound of any one of claims 5 to 13, wherein V4is N(R1b).

16. The compound of any one of claims 5 to 7, wherein U1and U4are each O; and V1and V4are each a bond.

17. The compound of any one of claims 5 to 7, wherein U1and U4are each O; and V1and V4are each N(H).

18. The compound of any one of claims 5 to 7, wherein U1and U4are each S; and V1and V4are each N(H).

19. The compound of claim 1, wherein A and A1together with the carbon atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

20. The compound of claim 1 or 19, wherein A and A1together with the carbon atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

21. The compound of any one of claims 1, 19, and 20, wherein A and A1together with the carbon atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q.

22. The compound of any one of claims 1 and 19 to 21, having the structure of Formula (XV):Attorney Docket No.277A003WO01 or an enantiomer, a mixture of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R5is (i) hydrogen or deuterium; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.

23. The compound of claim 22, wherein A2is –C(O)O–, –CH2O–, or –CH2OC(O)–.

24. The compound of claim 22 to 23, wherein A3is –C(O)O–, –CH2O–, or –CH2OC(O)–.

25. The compound of any one of claims 22 to 24, having the structure of Formula (XVI): or an enantiomer, a mixtureof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

26. The compound of any one of claims 22 to 24, having the structure of Formula (XIX): or an enantiomer, a mixtureof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; orAttorney Docket No.277A003WO01 a pharmaceutically acceptable salt, solvate, or hydrate thereof.

27. The compound of any one of claims 22 to 24, having the structure of Formula (XXII): or an enantiomer, a of two or morediastereomers, a tautomer, a two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

28. The compound of any one of claims 22 to 27, wherein R5is (i) hydrogen or deuterium; or (ii) C1-6 alkyl or C1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

29. The compound of any one of claims 22 to 28, wherein R5is hydrogen.

30. The compound of any one of claims 22 to 28, wherein R5is C1-6 alkyl, optionally substituted with one or more substituents Q.

31. The compound of any one of claims 22 to 28 and 30, wherein R5is methyl.

32. The compound of claim 1, having the structure of Formula (XXV): R2aor an enantiomer, a mixtureof two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

33. The compound of claim 32, having the structure of Formula (XXVI):Attorney Docket No.277A003WO01 or an enantiomer, a mixture of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

34. The compound of claim 32 or 33, having the structure of Formula (XXVII): or an enantiomer, a of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U1is O or S; and V1is a bond, O, or N(R1b).

35. The compound of claim 34, wherein U1is O.

36. The compound of claim 34, wherein U1is S.

37. The compound of any one of claims 34 to 36, wherein V1is a bond.

38. The compound of any one of claims 34 to 36, wherein V1is N(R1b).

39. The compound of claim 34, wherein U1is O; and V1is a bond.

40. The compound of claim 34, wherein U1is O; and V1is N(H).

41. The compound of claim 34, wherein U1is S; and V1is N(H).

42. The compound of claim 32 or 33, having the structure of Formula (XXX):Attorney Docket No.277A003WO01 R1bO R2aN O L2X R2bor an enantiomer, a mixture of two or morediastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

43. The compound of claim 42, wherein R1bis (i) hydrogen; or (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q.

44. The compound of claim 42 or 43, wherein R1bis hydrogen.

45. The compound of claim 42 or 43, wherein R1bis C1-6alkyl, each optionally substituted with one or more substituents Q.

46. The compound of claim 42, 43, or 45, wherein R1bis methyl.

47. The compound of any one of claims 1 to 46, wherein R1is ionizable N-containing heterocyclyl, optionally substituted with one or more substituents Q.

48. The compound of any one of claims 1 to 47, wherein R1is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

49. The compound of any one of claims 1 to 48, wherein R1is 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q.

50. The compound of any one of claims 1 to 49, wherein R1is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q.

51. The compound of any one of claims 1 to 50, wherein R1is azetidin-1-yl, azetidin- 3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, morpholin-4- yl, or piperazin-1-yl, each optionally substituted with one or more substituents Q.Attorney Docket No.277A003WO01 52. The compound of any one of claims 1 to 51, wherein R1is azetidin-1-yl, 1- methylazetidin-3-yl, pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, piperidin- 1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-4-yl, or 4-methylpiperazin-1-yl.

53. The compound of any one of claims 1 to 46, wherein R1is (i) azido; (ii) heteroaryl, optionally substituted with one or more substituents Q; or (iii) –NR4aR4b.

54. The compound of claim 53, wherein R4aand R4bare each independently C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q.

55. The compound of any one of claims 1 to 48, 53, and 54, wherein R1is azido, maleimido, 11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl, dimethylamino, or ethyl(methyl)amino.

56. The compound of claim 53, wherein R4aand R4bare together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

57. The compound of claim 53 or 56, wherein R4aand R4bare together with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

58. The compound of claim 53, 56, or 57, wherein R4aand R4bare together with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q.

59. The compound of any one of claims 1 to 18 and 47 to 58, wherein R4is ionizable N-containing heterocyclyl, optionally substituted with one or more substituents Q.

60. The compound of any one of claims 1 to 18 and 47 to 59, wherein R4is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q.

61. The compound of any one of claims 1 to 18 and 47 to 60, wherein R4is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q.Attorney Docket No.277A003WO01 62. The compound of any one of claims 1 to 18 and 47 to 60, wherein R4is azetidin- 1-yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, morpholin-4-yl, or piperazin-1-yl, each optionally substituted with one or more substituents Q.

63. The compound of any one of claims 1 to 18 and 47 to 61, wherein R4is azetidin- 1-yl, 1-methylazetidin-3-yl, pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-4-yl, or 4-methyl- piperazin-1-yl.

64. The compound of any one of claims 1 to 18 and 47 to 58, wherein R4is (i) azido; (ii) heteroaryl, optionally substituted with one or more substituents Q; or (iii) –NR4aR4b.

65. The compound of claim 64, wherein R4aand R4bare each independently C1-6alkyl or C1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

66. The compound of any one of claims 1 to 18, 47 to 58, 64, and 65, wherein R4is azido, maleimido, 11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl, dimethylamino, or ethyl(methyl)amino.

67. The compound of claim 64, wherein R4aand R4bare together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

68. The compound of claim 64 or 67, wherein R4aand R4bare together with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

69. The compound of claim 64, 67, or 68, wherein R4aand R4bare together with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q.

70. The compound of any one of claims 1 to 69, wherein R2ais (i) absent or hydrogen; or (ii) C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20alkenoxy, each optionally substituted with one or more substituents Q.Attorney Docket No.277A003WO01 71. The compound of any one of claims 1 to 70, wherein R2ais absent, hydrogen, eth- 1-yl, but-1-yl, hex-1-yl, hept-1-yl, oct-1-yl, non-1-yl, undec-1-yl, pentadec-1-yl, hexadec-1-yl, heptadec-1-yl, (Z)-non-2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-heptadec-8- en-1-yl, (Z)-heptadec-9-en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (9Z,12Z)- octadec-9,12-dien-1-yl.

72. The compound of any one of claims 1 to 71, wherein R2ais absent.

73. The compound of any one of claims 1 to 71, wherein R2ais hydrogen.

74. The compound of any one of claims 1 to 73, wherein R2bis C1-20alkyl, C1-20heteroalkyl, C2-20alkenyl, C3-10cycloalkyl, C1-20alkoxy, C1-20heteroalkoxy, or C2-20alkenoxy, each optionally substituted with one or more substituents Q.

75. The compound of any one of claims 1 to 74, wherein R2bis C1-20 alkyl, C1-20 heteroalkyl, C2-20alkenyl, C1-20alkoxy, C1-20heteroalkoxy, or C2-20alkenoxy, each optionally substituted with one or more substituents Q.

76. The compound of any one of claims 1 to 74, wherein R2bis eth-1-yl, but-1-yl, hex-1-yl, hept-1-yl, 6-methylhept-2-yl, oct-1-yl, non-1-yl, undec-1-yl, 4,8,12-trimethyltridec-1- yl, pentadec-1-yl, hexadec-1-yl, heptadec-1-yl, (Z)-non-2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)- pentadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-heptadec-9-en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1-yl, (8Z,11Z,14Z)-heptadec- 8,11,14-trien-1-yl, (9Z,12Z)-octadec-9,12-dien-1-yl, or cyclohex-1-en-1-yl.

77. The compound of any one of claims 1 to 74 and 76, wherein R2bis 6-methylhept- 2-yl, 4,8,12-trimethyltridec-1-yl, or cyclohex-1-en-1-yl.

78. The compound of any one of claims 1 to 77, wherein R3ais (i) absent or hydrogen; or (ii) C1-20 alkyl, C1-20 heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q.

79. The compound of any one of claims 1 to 78, wherein R3ais absent, hydrogen, eth- 1-yl, but-1-yl, hex-1-yl, hept-1-yl, oct-1-yl, non-1-yl, undec-1-yl, pentadec-1-yl, hexadec-1-yl,Attorney Docket No.277A003WO01 heptadec-1-yl, (Z)-non-2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)-pentadec-8-en-1-yl, (Z)-heptadec-8- en-1-yl, (Z)-heptadec-9-en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1-yl, (8Z,11Z,14Z)-heptadec-8,11,14-trien-1-yl, or (9Z,12Z)- octadec-9,12-dien-1-yl.

80. The compound of any one of claims 1 to 79, wherein R3ais absent.

81. The compound of any one of claims 1 to 79, wherein R3ais hydrogen.

82. The compound of any one of claims 1 to 81, wherein R3bis C1-20alkyl, C1-20heteroalkyl, C2-20 alkenyl, C3-10 cycloalkyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q.

83. The compound of any one of claims 1 to 82, wherein R3bis C1-20alkyl, C1-20heteroalkyl, C2-20 alkenyl, C1-20 alkoxy, C1-20 heteroalkoxy, or C2-20 alkenoxy, each optionally substituted with one or more substituents Q.

84. The compound of any one of claims 1 to 82, wherein R3bis eth-1-yl, but-1-yl, hex-1-yl, hept-1-yl, 6-methylhept-2-yl, oct-1-yl, non-1-yl, undec-1-yl, 4,8,12-trimethyltridec-1- yl, pentadec-1-yl, hexadec-1-yl, heptadec-1-yl, (Z)-non-2-en-1-yl, (Z)-tridec-8-en-1-yl, (Z)- pentadec-8-en-1-yl, (Z)-heptadec-8-en-1-yl, (Z)-heptadec-9-en-1-yl, (Z)-octadec-9-en-1-yl, (8Z,11Z)-hexadec-8,11-dien-1-yl, (8Z,11Z)-heptadec-8,11-dien-1-yl, (8Z,11Z,14Z)-heptadec- 8,11,14-trien-1-yl, (9Z,12Z)-octadec-9,12-dien-1-yl, or cyclohex-1-en-1-yl.

85. The compound of any one of claims 1 to 82 and 84, wherein R3bis 6-methylhept- 2-yl, 4,8,12-trimethyltridec-1-yl, or cyclohex-1-en-1-yl.

86. The compound of any one of claims 1 to 85, wherein L1is C1-6 alkylene or C1-6 heteroalkylene, each optionally substituted with one or more substituents Q.

87. The compound of any one of claims 1 to 86, wherein L1is C1-6alkylene, optionally substituted with one or more substituents Q.

88. The compound of any one of claims 1 to 87, wherein L1is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted withAttorney Docket No.277A003WO01 one or more substituents Q.

89. The compound of any one of claims 1 to 88, wherein L1is methanediyl, ethane- 1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, or hexane-1,6-diyl, each optionally substituted with one or more substituents Q.

90. The compound of any one of claims 1 to 89, wherein L2is (i) a bond; or (ii) C1-20 alkylene, C1-20heteroalkylene, C2-20alkenylene, C3-20cycloalkylene, or heteroarylene, each optionally substituted with one or more substituents Q.

91. The compound of any one of claims 1 to 90, wherein L2is (i) a bond; or (ii) C1-20 alkylene, C1-20heteroalkylene, or C2-20alkenylene, each optionally substituted with one or more substituents Q.

92. The compound of any one of claims 1 to 91, wherein L2is a bond.

93. The compound of any one of claims 1 to 91, wherein L2is C1-20 alkylene, C1-20 heteroalkylene, or C2-20alkenylene, each optionally substituted with one or more substituents Q.

94. The compound of any one of claims 1 to 91 and 93, wherein L2is ethane-1,2-diyl, butane-1,4-diyl, petane-1,5-diyl, heptane-1,7-diyl, –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q.

95. The compound of any one of claims 1 to 90, wherein L2is C3-20cycloalkylene, optionally substituted with one or more substituents Q.

96. The compound of any one of claims 1 to 90 and 95, wherein L2is tetracyclic C6-20cycloalkylene, optionally substituted with one or more substituents Q.

97. The compound of any one of claims 1 to 90, wherein L2is heteroarylene, optionally substituted with one or more substituents Q.

98. The compound of any one of claims 1 to 90 and 97, wherein L2is bicyclic heteroarylene, optionally substituted with one or more substituents Q.

99. The compound of any one of claims 1 to 90, 97, and 98, wherein L2is 6,6-fusedAttorney Docket No.277A003WO01 heteroarylene, optionally substituted with one or more substituents Q.

100. The compound of any one of claims 1 to 90, wherein L2is (2Z,4E,6E,8E,10E,12E,14E,16E)-6,11,15-trimethylheptadeca-2,4,6,8,10,12,14,16-octaene-2,17- diyl 2,5,7,8-tetramethylchromane-2,6-diyl, (3S,8R,9S,13S,14S,17S)-10,13-dimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl, or 2,5,7,8-tetramethylchromane-2,6-diyl.

101. The compound of any one of claims 1 to 100, wherein L3is (i) a bond; or (ii) C1-20alkylene, C1-20 heteroalkylene, C2-20 alkenylene, C3-20 cycloalkylene, or heteroarylene, each optionally substituted with one or more substituents Q.

102. The compound of any one of claims 1 to 101, wherein L3is (i) a bond; or (ii) C1-20alkylene, C1-20 heteroalkylene, or C2-20 alkenylene, each optionally substituted with one or more substituents Q.

103. The compound of any one of claims 1 to 102, wherein L3is a bond.

104. The compound of any one of claims 1 to 102, wherein L3is C1-20 alkylene, C1-20 heteroalkylene, or C2-20 alkenylene, each optionally substituted with one or more substituents Q.

105. The compound of any one of claims 1 to 102 and 104, wherein L3is ethane-1,2- diyl, butane-1,4-diyl, petane-1,5-diyl, heptane-1,7-diyl, –OC(O)(CH2)5–, –OC(O)(CH2)7–, or –C(O)O(CH2)7–, each optionally substituted with one or more substituents Q.

106. The compound of any one of claims 1 to 101, wherein L3is C3-20cycloalkylene, optionally substituted with one or more substituents Q.

107. The compound of any one of claims 1 to 101 and 106, wherein L3is tetracyclic C6-20cycloalkylene, optionally substituted with one or more substituents Q.

108. The compound of any one of claims 1 to 101, wherein L3is heteroarylene, optionally substituted with one or more substituents Q.

109. The compound of any one of claims 1 to 101 and 108, wherein L3is bicyclicAttorney Docket No.277A003WO01 heteroarylene, optionally substituted with one or more substituents Q.

110. The compound of any one of claims 1 to 101, 108, and 109, wherein L3is 6,6- fused heteroarylene, optionally substituted with one or more substituents Q.

111. The compound of any one of claims 1 to 101, wherein L3is (2Z,4E,6E,8E,10E,12E,14E,16E)-6,11,15-trimethylheptadeca-2,4,6,8,10,12,14,16-octaene-2,17- diyl 2,5,7,8-tetramethylchromane-2,6-diyl, (3S,8R,9S,13S,14S,17S)-10,13-dimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl, or 2,5,7,8-tetramethylchromane-2,6-diyl.

112. The compound of any one of claims 1 to 18 and 47 to 111, wherein L4is C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q.

113. The compound of any one of claims 1 to 18 and 47 to 112, wherein L4is C1-6 alkylene, optionally substituted with one or more substituents Q.

114. The compound of any one of claims 1 to 18 and 47 to 113, wherein L4is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted with one or more substituents Q.

115. The compound of any one of claims 1 to 18 and 47 to 114, wherein L4is methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, or hexane-1,6- diyl, each optionally substituted with one or more substituents Q.

116. The compound of any one of claims 1 to 115, wherein X is a bond.

117. The compound of any one of claims 1 to 115, wherein X is N.

118. The compound of any one of claims 1 to 115, wherein X is C(H).

119. The compound of any one of claims 1 to 118, wherein Z is a bond.

120. The compound of any one of claims 1 to 118, wherein Z is N.

121. The compound of any one of claims 1 to 118, wherein Z is C(H).Attorney Docket No.277A003WO01 122. The of one of claims 1 to 121, wherein the124. The compound of any one of claims 1, 2, 19 to 22, 28 to 32, 47 to 69, 86 to 89, ,Attorney Docket No.277A003WO01 OO.19 to 22, 28 to 32, 47 to 69, 86 to 89, 112 122 ,di((Z)-octadec-9-en-1-yl) 2,3-bis((4-(dimethylamino)butanoyl)oxy)succinate A001; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis((3-(azetidin-1-yl)propanoyl)- oxy)succinate A002; bis(8-(heptyloxy)-8-oxooctyl) 2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)- succinate A003; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis((3-(piperidin-1-yl)propanoyl)- oxy)succinate A004; dipentadecyl 2,3-bis((4-(azetidin-1-yl)butanoyl)oxy)succinate A005; bis(7-(dodecanoyloxy)heptyl) 2,3-bis((4-(pyrrolidin-1-yl)butanoyl)oxy)succinate A006; bis(5-ethylnonyl) 2,3-bis((4-(piperidin-1-yl)butanoyl)oxy)succinate A007; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis((5-(pyrrolidin-1-yl)pentanoyl)oxy)- succinate A008; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis((5-(piperidin-1-yl)pentanoyl)oxy)-Attorney Docket No.277A003WO01 succinate A009; 1-((Z)-octadec-9-en-1-yl) 4-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis((5- morpholinopentanoyl)oxy)succinate A010; didodecyl 2,3-bis((4-(dimethylamino)butanoyl)oxy)succinate A011; 2,3-bis((4-(dimethylamino)butanoyl)oxy)butane-1,4-diyl (9Z,9'Z)-bis(hexadec-9- enoate) A051; 1-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)-4-(oleoyloxy)butane-2,3-diyl bis(3- (azetidin-1-yl)propanoate) A052; 1-(heptadecanoyloxy)-4-(oleoyloxy)butane-2,3-diyl bis(3-(pyrrolidin-1-yl)- propanoate) A053; 1-((4,4-bis(octyloxy)butanoyl)oxy)-4-(oleoyloxy)butane-2,3-diyl bis(3-(piperidin- 1-yl)propanoate) A054; 2,3-bis((4-(azetidin-1-yl)butanoyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)bis- (octadeca-9,12-dienoate) A055; 2,3-bis((4-(pyrrolidin-1-yl)butanoyl)oxy)butane-1,4-diyl diheptadecanoate A056; 2,3-bis((4-(piperidin-1-yl)butanoyl)oxy)butane-1,4-diyl bis(4,4-bis(octyloxy)- butanoate) A057; 1-((4,4-bis(octyloxy)butanoyl)oxy)-4-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)- butane-2,3-diyl bis(5-(pyrrolidin-1-yl)pentanoate) A058; 1-(heptadecanoyloxy)-4-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)butane-2,3-diyl bis(5-(piperidin-1-yl)pentanoate) A059; 1-((4,4-bis(octyloxy)butanoyl)oxy)-4-(heptadecanoyloxy)butane-2,3-diyl bis(5- morpholinopentanoate) A060; (2R,3S)-2,3-bis((3-(3-(hydroxymethyl)azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A061; (2R,3S)-2,3-bis((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A062; (2R,3S)-2,3-bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) A063; (2R,3S)-2,3-bis((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)oxy)butane-1,4- diyl (9Z,9'Z)-bis(hexadec-9-enoate) A064;Attorney Docket No.277A003WO01 1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl bis(4-(dimethylamino)- butanoate) A101; di((Z)-non-2-en-1-yl) 6,6'-((2,3-bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl)bis(oxy))dihexanoate A102; dioctyl 8,8'-((2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)butane-1,4-diyl)-bis- (oxy))dioctanoate A103; di(heptadecan-9-yl) 8,8'-((2,3-bis((3-(piperidin-1-yl)propanoyl)oxy)butane-1,4- diyl)bis(oxy))dioctanoate A104; 1,4-bis(pentadecyloxy)butane-2,3-diyl bis(4-(azetidin-1-yl)butanoate) A105; ((2,3-bis((4-(pyrrolidin-1-yl)butanoyl)oxy)butane-1,4-diyl)bis(oxy))bis(heptane- 7,1-diyl) didodecanoate A106; 1,4-bis((5-ethylnonyl)oxy)butane-2,3-diyl bis(4-(piperidin-1-yl)butanoate) A107; ((2,3-bis((5-(pyrrolidin-1-yl)pentanoyl)oxy)butane-1,4-diyl)bis(oxy))bis(hexane- 6,1-diyl) bis(2-hexyldecanoate) A108; 1,4-bis(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane-2,3-diyl bis(5-(piperidin-1- yl)pentanoate) A109; 1-(((Z)-octadec-9-en-1-yl)oxy)-4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane- 2,3-diyl bis(5-morpholinopentanoate) A110; (2R,3S)-2,3-bis((4-(dimethylamino)butanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A111; (2R,3S)-2,3-bis((3-(azetidin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A112; (2R,3S)-2,3-bis((3-(3-(hydroxymethyl)azetidin-1-yl)propanoyl)oxy)butane-1,4- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetra- methyl-17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A113; (2R,3S)-2,3-bis((3-(pyrrolidin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A114; (2R,3S)-2,3-bis((3-(piperidin-1-yl)propanoyl)oxy)butane-1,4-diylAttorney Docket No.277A003WO01 (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A115; (2R,3S)-2,3-bis((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)butane-1,4- diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15- tetramethyl-17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A116; (2R,3S)-2,3-bis((3-(4-methylpiperazin-1-yl)propanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A117; (2R,3S)-2,3-bis((3-morpholinopropanoyl)oxy)butane-1,4-diyl (2Z,2'Z,4E,4'E,6E,6'E,8E,8'E,10E,10'E,12E,12'E,14E,14'E,16E,16'E)-bis(2,6,11,15-tetramethyl- 17-(2,6,6-trimethylcyclohex-1-en-1-yl)heptadeca-2,4,6,8,10,12,14,16-octaenoate) A118; di((Z)-octadec-9-en-1-yl) 2,3-bis(((4-(dimethylamino)butyl)carbamoyl)oxy)-succinate A151; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis(((4-(pyrrolidin-1-yl)butyl)- carbamoyl)oxy)succinate A152; bis(8-(octyloxy)-8-oxooctyl) 2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)- succinate A153; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)succinate A154; dipentadecyl 2,3-bis(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)- succinate A155; bis(7-(dodecanoyloxy)heptyl) 2,3-bis(((3-morpholinopropyl)carbamoyl)oxy)- succinate A156; bis(5-ethylnonyl) 2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)succinate A157; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis(((3-(pyrrolidin-1-yl)propyl)- carbamoyl)oxy)succinate A158; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2,3-bis(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)succinate A159; 2,3-bis(((4-(dimethylamino)butyl)carbamoyl)oxy)butane-1,4-diyl (9Z,9'Z)bis- (hexadec-9-enoate) A201;Attorney Docket No.277A003WO01 4-(oleoyloxy)-2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)butyl (9Z,12Z)- octadeca-9,12-dienoate A202; 4-(heptadecanoyloxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butyl oleate A203; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)butyl oleate A204; 2,3-bis(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) A205; 2,3-bis(((3-morpholinopropyl)carbamoyl)oxy)butane-1,4-diyl diheptadecanoate A206; 2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)butane-1,4-diyl bis(4,4-bis- (octyloxy)butanoate) A207; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)- carbamoyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A208; 4-(heptadecanoyloxy)-2,3-bis(((3-(piperidin-1-yl)propyl)carbamoyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A209; 1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl bis((4-(dimethylamino)- butyl)carbamate) A251; di((Z)-non-2-en-1-yl) 6,6'-((2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)- butane-1,4-diyl)bis(oxy))dihexanoate A252; dioctyl 8,8'-((2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl)- bis(oxy))dioctanoate A253; di(heptadecan-9-yl) 8,8'-((2,3-bis(((3-(piperidin-1-yl)propyl)carbamoyl)oxy)- butane-1,4-diyl)bis(oxy))dioctanoate A254; 1,4-bis(pentadecyloxy)butane-2,3-diyl bis((3-(4-methylpiperazin-1-yl)propyl)- carbamate) A255; ((2,3-bis(((3-morpholinopropyl)carbamoyl)oxy)butane-1,4-diyl)bis(oxy))bis- (heptane-7,1-diyl) didodecanoate A256; 1,4-bis((5-ethylnonyl)oxy)butane-2,3-diyl bis((4-(pyrrolidin-1-yl)butyl)- carbamate) A257; ((2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)butane-1,4-diyl)bis(oxy))-Attorney Docket No.277A003WO01 bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A258; 1,4-bis(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)butane-2,3-diyl bis((3-(piperidin- 1-yl)propyl)carbamate) A259; di((Z)-octadec-9-en-1-yl) 2,3-bis(((4-(dimethylamino)butyl)carbamothioyl)oxy)- succinate A301; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2,3-bis(((4-(pyrrolidin-1-yl)butyl)- carbamothioyl)oxy)succinate A302; bis(8-(octyloxy)-8-oxooctyl) 2,3-bis(((4-(piperidin-1-yl)butyl)carbamothioyl)- oxy)succinate A303; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2,3-bis(((3-(azetidin-1-yl)propyl)- carbamothioyl)oxy)succinate A304; dipentadecyl 2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamothioyl)oxy)succinate A305; bis(7-(dodecanoyloxy)heptyl) 2,3-bis(((3-(piperidin-1-yl)propyl)carbamothioyl)- oxy)succinate A306; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2,3-bis(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)succinate A307; 2,3-bis(((4-(dimethylamino)butyl)carbamothioyl)oxy)butane-1,4-diyl (9Z,9'Z)- bis(hexadec-9-enoate) A351; 2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) A352; 2,3-bis(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4-diyl dihepta- decanoate A353; 2,3-bis(((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)butane-1,4-diyl bis(4,4- bis(octyloxy)butanoate) A354; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(pyrrolidin-1-yl)propyl)carbamo- thioyl)oxy)butyl (9Z,12Z)-octadeca-9,12-dienoate A355; 4-(heptadecanoyloxy)-2,3-bis(((3-(piperidin-1-yl)propyl)carbamothioyl)oxy)- butyl (9Z,12Z)-octadeca-9,12-dienoate A356; 4-((4,4-bis(octyloxy)butanoyl)oxy)-2,3-bis(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)butyl oleate A357;Attorney Docket No.277A003WO01 O,O'-(1,4-bis(((Z)-heptadec-9-en-1-yl)oxy)butane-2,3-diyl) bis((4-(dimethyl- amino)butyl)carbamothioate) A401; di((Z)-non-2-en-1-yl) 6,6'-((2,3-bis(((4-(pyrrolidin-1-yl)butyl)carbamothioyl)- oxy)butane-1,4-diyl)bis(oxy))dihexanoate A402; dioctyl 8,8'-((2,3-bis(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)butane-1,4- diyl)bis(oxy))dioctanoate A403; di(heptadecan-9-yl) 8,8'-((2,3-bis(((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)- butane-1,4-diyl)bis(oxy))dioctanoate A404; O,O'-(1,4-bis(pentadecyloxy)butane-2,3-diyl) bis((3-(pyrrolidin-1-yl)propyl)- carbamothioate) A405; ((2,3-bis(((3-(piperidin-1-yl)propyl)carbamothioyl)oxy)butane-1,4-diyl)bis(oxy))- bis(heptane-7,1-diyl) didodecanoate A406; ((2,3-bis(((3-(1-methylazetidin-3-yl)propyl)carbamothioyl)oxy)butane-1,4-diyl)- bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate) A407; di((Z)-octadec-9-en-1-yl) 2-(4-(dimethylamino)butyl)-1,3-dioxolane-4,5- dicarboxylate A451; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-((1-methylpiperidin-4-yl)methyl)- 1,3-dioxolane-4,5-dicarboxylate A452; bis(8-(octyloxy)-8-oxooctyl) 2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolane- 4,5-dicarboxylate A453; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2-(2-(1-methylpiperidin-4-yl)ethyl)-1,3- dioxolane-4,5-dicarboxylate A454; dipentadecyl 2-(4-morpholinobutyl)-1,3-dioxolane-4,5-dicarboxylate A455; bis(7-(dodecanoyloxy)heptyl) 2-(3-(1-methylpiperidin-4-yl)propyl)-1,3- dioxolane-4,5-dicarboxylate A456; bis(5-ethylnonyl) 2-(3-(1-methylpyrrolidin-2-yl)propyl)-1,3-dioxolane-4,5- dicarboxylate A457; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(4-(2-methylpyrrolidin-1-yl)butyl)-1,3- dioxolane-4,5-dicarboxylate A458; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-(4-(ethyl(methyl)amino)butyl)-1,3- dioxolane-4,5-dicarboxylate A459;Attorney Docket No.277A003WO01 4-(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 5-((Z)-octadec-9-en-1-yl) 2-(5-(ethyl- (methyl)amino)pentyl)-1,3-dioxolane-4,5-dicarboxylate A460; (Z)-4-(octadec-9-en-1-yl) 5-(8-(octyloxy)-8-oxooctyl) 2-(4-(dimethylamino)- butyl)-2-methyl-1,3-dioxolane-4,5-dicarboxylate A461; (Z)-4-(8-(heptadecan-9-yloxy)-8-oxooctyl) 5-(octadec-9-en-1-yl) 2-methyl-2-((1- methylpiperidin-4-yl)methyl)-1,3-dioxolane-4,5-dicarboxylate A462; (Z)-4-(octadec-9-en-1-yl) 5-pentadecyl 2-methyl-2-(3-(4-methylpiperazin-1-yl)- propyl)-1,3-dioxolane-4,5-dicarboxylate A463; (Z)-4-(7-(dodecanoyloxy)heptyl) 5-(octadec-9-en-1-yl) 2-methyl-2-(4-(pyrrolidin- 1-yl)butyl)-1,3-dioxolane-4,5-dicarboxylate A464; 4-((Z)-octadec-9-en-1-yl) 5-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-(4-(ethyl- (methyl)amino)butyl)-2-methyl-1,3-dioxolane-4,5-dicarboxylate A465; 2-(4-(dimethylamino)butyl)-1,3-dioxolane-4,5-diyl)bis(methylene) (9Z,9'Z)- bis(hexadec-9-enoate) A501; (2-((1-methylpiperidin-4-yl)methyl)-5-((oleoyloxy)methyl)-1,3-dioxolan-4-yl)- methyl (9Z,12Z)-octadeca-9,12-dienoate A502; (5-((heptadecanoyloxy)methyl)-2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolan- 4-yl)methyl oleate A503; (5-(((4,4-bis(octyloxy)butanoyl)oxy)methyl)-2-(2-(1-methylpiperidin-4-yl)ethyl)- 1,3-dioxolan-4-yl)methyl oleate A504; (2-(4-morpholinobutyl)-1,3-dioxolane-4,5-diyl)bis(methylene) (9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate) A505; (2-(3-(1-methylpiperidin-4-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene) diheptadecanoate A506; (2-(3-(1-methylpyrrolidin-2-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene) bis(4,4-bis(octyloxy)butanoate) A507; (5-(((4,4-bis(octyloxy)butanoyl)oxy)methyl)-2-(4-(2-methylpyrrolidin-1-yl)- butyl)-1,3-dioxolan-4-yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A508; (2-(4-(ethyl(methyl)amino)butyl)-5-((heptadecanoyloxy)methyl)-1,3-dioxolan-4- yl)methyl (9Z,12Z)-octadeca-9,12-dienoate A509; 4-(4,5-bis((((Z)-heptadec-9-en-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)-N,N-Attorney Docket No.277A003WO01 dimethylbutan-1-amine A551; di((Z)-non-2-en-1-yl) 6,6'-(((2-((1-methylpiperidin-4-yl)methyl)-1,3-dioxolane- 4,5-diyl)bis(methylene))bis(oxy))dihexanoate A552; dioctyl 8,8'-(((2-((1-methylpiperidin-3-yl)methyl)-1,3-dioxolane-4,5-diyl)bis- (methylene))bis(oxy))dioctanoate A553; di(heptadecan-9-yl) 8,8'-(((2-(2-(1-methylpiperidin-4-yl)ethyl)-1,3-dioxolane-4,5- diyl)bis(methylene))bis(oxy))dioctanoate A554; 4-(4-(4,5-bis((pentadecyloxy)methyl)-1,3-dioxolan-2-yl)butyl)morpholine A555; (((2-(3-(1-Methylpiperidin-4-yl)propyl)-1,3-dioxolane-4,5-diyl)bis(methylene))-bis(oxy))bis- (heptane-7,1-diyl) didodecanoate A556; 2-(3-(4,5-bis(((5-ethylnonyl)oxy)methyl)-1,3-dioxolan-2-yl)propyl)-1-methyl- pyrrolidine A557; (((2-(4-(2-methylpyrrolidin-1-yl)butyl)-1,3-dioxolane-4,5-diyl)bis(methylene))- bis(oxy))bis-(hexane-6,1-diyl) bis(2-hexyldecanoate) A558; 4-(4,5-bis((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)-N- ethyl-N-methylbutan-1-amine A559; (Z)-non-2-en-1-yl 6-((2-(5-(ethyl(methyl)amino)pentyl)-5-((((Z)-octadec-9-en-1- yl)oxy)methyl)-1,3-dioxolan-4-yl)methoxy)hexanoate A560; octyl (Z)-8-((2-(4-(dimethylamino)butyl)-2-methyl-5-((octadec-9-en-1-yloxy)- methyl)-1,3-dioxolan-4-yl)methoxy)octanoate A561; heptadecan-9-yl (Z)-8-((2-methyl-2-((1-methylpiperidin-4-yl)methyl)-5- ((octadec-9-en-1-yloxy)methyl)-1,3-dioxolan-4-yl)methoxy)octanoate A562; (Z)-1-methyl-4-(3-(2-methyl-4-((octadec-9-en-1-yloxy)methyl)-5-((pentadecyl- oxy)methyl)-1,3-dioxolan-2-yl)propyl)piperazine A563; (Z)-7-((2-methyl-5-((octadec-9-en-1-yloxy)methyl)-2-(4-(pyrrolidin-1-yl)butyl)- 1,3-dioxolan-4-yl)methoxy)heptyl dodecanoate A564; N-ethyl-N-methyl-4-(2-methyl-4-((((Z)-octadec-9-en-1-yl)oxy)methyl)-5- ((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)-1,3-dioxolan-2-yl)butan-1-amine A565; didodecyl 2-((4-(dimethylamino)butanoyl)oxy)-3-hydroxysuccinate A601; di((Z)-octadec-9-en-1-yl) 2-((3-(pyrrolidin-1-yl)propanoyl)oxy)malonate B001; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-((3-(azetidin-1-yl)propanoyl)oxy)-Attorney Docket No.277A003WO01 malonate B002; bis(8-(heptyloxy)-8-oxooctyl) 2-((4-(dimethylamino)butanoyl)oxy)malonate B003; 1-(8-(heptadecan-8-yloxy)-8-oxooctyl) 3-(8-(heptadecan-9-yloxy)-8-oxooctyl) 2- ((3-(piperidin-1-yl)propanoyl)oxy)malonate B004; dipentadecyl 2-((4-(azetidin-1-yl)butanoyl)oxy)malonate B005; bis(7-(dodecanoyloxy)heptyl) 2-((4-(pyrrolidin-1-yl)butanoyl)oxy)malonate B006; bis(5-ethylnonyl) 2-((4-(piperidin-1-yl)butanoyl)oxy)malonate B007; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-((5-(pyrrolidin-1-yl)pentanoyl)oxy)- malonate B008; di((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5-(piperidin-1-yl)pentanoyl)oxy)- malonate B009; 1-((Z)-octadec-9-en-1-yl) 3-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5- morpholinopentanoyl)oxy)malonate B010; dioctadecyl 2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)butanoyl)oxy)malonate B011; ditridecyl 2-((4-(4-methylpiperazin-1-yl)butanoyl)oxy)malonate B012; ditridecyl 2-((4-((2-hydroxyethyl)(methyl)amino)butanoyl)oxy)malonate B013; ditridecyl 2-((4-(3-hydroxyazetidin-1-yl)butanoyl)oxy)malonate B014; ditridecyl 2-((4-(azetidin-1-yl)butanoyl)oxy)malonate B015; ditridecyl 2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)butanoyl)oxy)malonate B016; ditridecyl 2-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B017; ditridecyl 2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanoyl)oxy)malonate B018; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((4- (dimethylamino)butanoyl)oxy)malonate B021; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (azetidin-1-yl)propanoyl)oxy)malonate B022; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-Attorney Docket No.277A003WO01 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(3- hydroxyazetidin-1-yl)propanoyl)oxy)malonate B023; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (pyrrolidin-1-yl)propanoyl)oxy)malonate B024; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- (piperidin-1-yl)propanoyl)oxy)malonate B025; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(4- (2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B026; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3-(4- methylpiperazin-1-yl)propanoyl)oxy)malonate B027; bis((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-((3- morpholinopropanoyl)oxy)malonate B028; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((4-(dimethylamino)butanoyl)oxy)malonate B031; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(azetidin-1-yl)propanoyl)oxy)malonate B032; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(3-hydroxyazetidin-1-yl)propanoyl)oxy)malonate B033; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(pyrrolidin-1-yl)propanoyl)oxy)malonate B034; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(piperidin-1-yl)propanoyl)oxy)malonate B035; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(4-(2-hydroxyethyl)piperazin-1-yl)propanoyl)oxy)malonate B036; bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-(4-methylpiperazin-1-yl)propanoyl)oxy)malonate B037;Attorney Docket No.277A003WO01 bis((R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl) 2- ((3-morpholinopropanoyl)oxy)malonate B038; di((Z)-octadec-9-en-1-yl) 2-(((3-(4-methylpiperazin-1-yl)propoxy)carbonyl)oxy)- malonate B051; dioctadecyl 2-(((3-(diethylamino)propoxy)carbonyl)oxy)malonate B052; di((Z)-octadec-9-en-1-yl) 2-(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)- malonate B101; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-(((4-(pyrrolidin-1-yl)butyl)- carbamoyl)oxy)malonate B102; bis(8-(octyloxy)-8-oxooctyl) 2-(((3-(pyrrolidin-1-yl)propyl)carbamoyl)oxy)- malonate B103; bis(8-(heptadecan-9-yloxy)-8-oxooctyl) 2-(((3-(piperidin-1-yl)propyl)- carbamoyl)oxy)malonate B104; dipentadecyl 2-(((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)oxy)malonate B105; bis(7-(dodecanoyloxy)heptyl) 2-(((3-morpholinopropyl)carbamoyl)oxy)malonate B106; 1-(5-ethyldecyl) 3-(5-ethylnonyl) 2-(((4-(pyrrolidin-1-yl)butyl)carbamoyl)oxy)- malonate B107; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(((3-(pyrrolidin-1-yl)propyl)carbamoyl)- oxy)malonate B108; 1-((Z)-octadec-9-en-1-yl) 3-((9Z,12Z)-octadeca-9,12-dien-1-yl) 2-((5- morpholinopentanoyl)oxy)malonate B109; di((Z)-octadec-9-en-1-yl) 2-(((4-(dimethylamino)butyl)carbamothioyl)oxy)- malonate B151; bis(6-(((Z)-non-2-en-1-yl)oxy)-6-oxohexyl) 2-(((4-(pyrrolidin-1-yl)butyl)- carbamothioyl)oxy)malonate B152; bis(8-(octyloxy)-8-oxooctyl) 2-(((4-(piperidin-1-yl)butyl)carbamothioyl)oxy)- malonate B153; 1-(8-(heptadecan-8-yloxy)-8-oxooctyl) 3-(8-(heptadecan-9-yloxy)-8-oxooctyl) 2- (((3-(azetidin-1-yl)propyl)carbamothioyl)oxy)malonate B154;Attorney Docket No.277A003WO01 dipentadecyl 2-(((3-(pyrrolidin-1-yl)propyl)carbamothioyl)oxy)malonate B155; bis(7-(dodecanoyloxy)heptyl) 2-(((3-(piperidin-1-yl)propyl)carbamothioyl)oxy)- malonate B156; bis(6-((2-hexyldecanoyl)oxy)hexyl) 2-(((3-(1-methylazetidin-3-yl)propyl)- carbamothioyl)oxy)malonate B157; di((Z)-octadec-9-en-1-yl) 2-(3-(4-methylpiperazin-1-yl)propoxy)malonate B201; di((Z)-octadec-9-en-1-yl) 2-((3-(dimethylamino)propyl)(methyl)amino)malonate B251; di((Z)-octadec-9-en-1-yl) 2-(pyrrolidin-1-yl)malonate B252; 2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)propane-1,3-diyl dioleate B301; 2-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15- amido)propane-1,3-diyl dioleate B302; 2-(4-(11,12-didehydro-5,6-dihydrodibenz[b,f]azocin-5-yl)-4-oxobutanamido)- propane-1,3-diyl dioleate B303; 2-(azidomethyl)propane-1,3-diyl dioleate B351; or 2-(3-azidopropanamido)propane-1,3-diyl dioleate B352; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

127. A lipid nanoparticle comprising a compound of any one of claims 1 to 126.

128. A pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) nucleic acid; (ii) a compound of any one of claims 1 to 126, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more 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.

129. The pharmaceutical composition of claim 128, further comprising a conjugated lipid.Attorney Docket No.277A003WO01 130. The pharmaceutical composition of claim 129, wherein the conjugated lipid comprises a polyethylene glycol-conjugated lipid.

131. The pharmaceutical composition of any one of claims 128 to 130, wherein the nucleic acid is an mRNA.

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