Lipid Compounds, Lipid Nanoparticles, and Pharmaceutical Compositions

Abstract

The present application provides lipid compounds, such as compounds of formula (I), as well as lipid nanoparticles and pharmaceutical compositions, each comprising a lipid compound, such as a compound of formula (I). [Formula 1] JPEG2025537180000813.jpg28170

Description

Detailed Description of the Invention

[0001] [Technical field] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to international application PCT / CN2022 / 129490 filed on November 3, 2022, international application PCT / CN2023 / 083169 filed on March 22, 2023, and international application PCT / CN2023 / 102918 filed on June 27, 2023, the disclosures of each of which are incorporated herein by reference in their entirety.

[0002] 2. Related Sequence Listing This application incorporates by reference the Sequence Listing submitted herewith. The Sequence Listing is an XML file entitled "TFG00919PCT Sequence Listing.XML", created on November 2, 2023, and is 75,000 bytes in size.

[0003] 3.Technical Field The present invention provides lipid compounds, lipid nanoparticles, and pharmaceutical compositions thereof. 4.Background technology

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

[0005] The present application relates to a compound of formula (I): [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)N R1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c , -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1a C(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-40 alkyl, C1-40 heteroalkyl, C2-40 alkenyl, C2-40 heteroalkenyl, C2-40 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-20 alkylene group, a C1-20 heteroalkylene group, a C2-20 alkenylene group, or a C2-20 alkynylene group; A is -O- or -N(R1a)-; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; and each R, R, R, and R is independently hydrogen, deuterium, C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; wherein each of alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and 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) each is optionally further substituted by one or more, and in one embodiment 1, 2, 3, or 4, 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, = and -S(O)NRbRc, wherein each Ra, Rb, Rc, and Rd is independently selected from (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 optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Qa; Each Qa is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl.

[0006] The present application also relates to a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1- 6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)NR1bR1c, —C(NCN)NR1bR1c, —C(NOR1a )NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR 1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O) R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC (O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR 1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-10 alkylene group, a C1-10 heteroalkylene group, a C2-10 alkenylene group, or a C2-10 alkynylene group; A is -O- or -N(R1a)-; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; and each R, R, R, and R is independently hydrogen, deuterium, C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; wherein each of alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 6 alkynyl, C 3 alkyl, C 6 alkynyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkynyl, C 3 alkyl, C 6 alkynyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkynyl, C 3 alkyl, C 3 alkyl, C 4 alkyl, C 5 ... -10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; 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)Ra, —OS(O)NRbRc, —OS(O)N RbRc, -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)Rd, -NRaS(O)NRbRc, -NRaS(O)NRbRc, =NORa, -SRa, -S(O)Ra, -S(O)Ra, -S(O)NRbRc and -S(O)NRbRc (wherein each Ra, Rb, Rc and Rd is independently (i) hydrogen or or deuterium; (ii) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Qa; Each Qa is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl.

[0007] The present application also provides lipid nanoparticles comprising a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0008] The present application further provides lipid nanoparticles comprising (i) a nucleic acid and (ii) a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0009] The present application provides a pharmaceutical composition comprising lipid nanoparticles comprising (i) a nucleic acid and (ii) a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0010] 6. Exemplary Embodiments A compound having the structure of formula (I): [ka] wherein R and R are each independently (i) hydrogen; (ii) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R, —C(O)OR, —C(O)NR, —C(O)SR, —C(NR )NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR 1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a , -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1 aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR 1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-40 alkyl, C1-40 heteroalkyl, C2-40 alkenyl, C2-40 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-20 alkylene group, a C1-20 heteroalkylene group, a C2-20 alkenylene group, a C2-20 heteroalkenylene group, or a C2-20 alkynylene group; A is -O- or -N(R1a)-; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; and each R, R, R, and R is independently hydrogen, deuterium, C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; Here, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, aryl Each of the aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, each of which is optionally further substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa. and heterocyclyl; 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, -N RbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, ​​-NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, =NORa, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc and -S(O)2NRbRc, wherein each Ra, Rb, Rc and Rd is, independently: (i) hydrogen or heavy hydrogen; (ii) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Qa; Each Qa is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0011] In the compound of paragraph

[0010] , R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR 1a, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C (S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC (S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d , -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-10 alkylene group, a C1-10 heteroalkylene group, a C2-10 alkenylene group, or a C2-10 alkynylene group; A is -O- or -N(R1a)-; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; and each R, R, R, and R is independently hydrogen, deuterium, C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; wherein each of alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, and wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C heteroalkyl, each of which is optionally further substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa. , C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; 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)2NR bRc, =NORa, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc and -S(O)2NRbRc (where each Ra, Rb, Rc and Rd are each independently selected from (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 optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; Each Qa is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl.

[0012] In the compound of paragraph

[0010] , L1 is C1-6 alkylene optionally substituted with one or more substituents Q.

[0013] In the compound of paragraph

[0010] or

[0012] , L1 is -(CR2aR2b)a-, R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl optionally substituted with one or more substituents Q, and a is an integer of 1, 2, 3, 4, 5, or 6.

[0014] In any one of the compounds in paragraphs

[0010] to

[0013] , L1 is —(CH2)a—.

[0015] In the compound of any one of paragraphs

[0010] to

[0014] , L2 is C1-6 alkylene optionally substituted with one or more substituents Q.

[0016] In the compound of any one of paragraphs

[0010] to

[0015] , L2 is -(CR2aR2b)b-, and R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form a C3-10 cycloalkyl optionally substituted with one or more substituents Q, and b is an integer of 1, 2, 3, 4, 5, or 6.

[0017] In any one of the compounds in paragraphs

[0010] to

[0016] , L2 is —(CH2)b—.

[0018] In the compound of any one of paragraphs

[0010] to

[0017] , L3 is C1-10 alkylene optionally substituted with one or more substituents Q.

[0019] In the compound of any one of paragraphs

[0010] to

[0018] , L3 is -(CR2aR2b)c-, and R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form C3-10 cycloalkyl optionally substituted with one or more substituents Q, and c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0020] In any one of the compounds in paragraphs

[0010] to

[0019] , L3 is —(CH2)c—.

[0021] In the compound of any one of paragraphs

[0010] to

[0020] , L4 is C1-10 alkylene optionally substituted with one or more substituents Q.

[0022] In the compound of any one of paragraphs

[0010] to

[0021] , L4 is -(CR2aR2b)d-, and R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form a C3-10 cycloalkyl optionally substituted with one or more substituents Q, and d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0023] In the compound of any one of paragraphs

[0010] to

[0022] , L4 is —(CH2)d—.

[0024] A structure of formula (II): [ka] (wherein a and b are each independently an integer of 1, 2, 3, 4, 5, or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Any one of the compounds of paragraphs

[0010] to

[0023] , or an enantiomer, a mixture of enantiomers, a diastereomer, or a mixture of two or more diastereomers thereof a mixture, tautomer, a mixture of two or more tautomers, or isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0025] In the compound of any one of paragraphs

[0010] to

[0024] , E is —OC(O)N(R1a)—.

[0026] In any one of the compounds in paragraphs

[0010] to

[0025] , E is —OC(O)N(H)—.

[0027] In the compound of any one of paragraphs

[0010] to

[0024] , E is —NR1aC(O)N(R1b)—.

[0028] In the compound of any one of paragraphs

[0010] to

[0024] and

[0027] , E is —NHC(O)N(H)—.

[0029] A structure of formula (III): [ka] (Wherein, U is —O— or —N(R1a)—) or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0030] In the compound of any one of paragraphs

[0010] to

[0029] , A is —O—.

[0031] In the compound of any one of paragraphs

[0010] to

[0029] , A is —N(R1a)—.

[0032] In the compound of any one of paragraphs

[0010] to

[0029] and

[0031] , A is —N(H)—.

[0033] In the compound of any one of paragraphs

[0024] to

[0032] , U is —O—.

[0034] In the compound of any one of paragraphs

[0024] to

[0032] , U is —N(R1a)—.

[0035] In the compound of any one of paragraphs

[0024] to

[0032] and

[0034] , U is —N(H)—.

[0036] A structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0037] A structure of formula (V): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0038] A structure of formula (VI): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0039] A structure of formula (VII): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0040] In any one of the compounds in paragraphs

[0013] to

[0039] , a is an integer of 2.

[0041] In any one of the compounds in paragraphs

[0016] to

[0040] , b is an integer of 2.

[0042] In the compound of any one of paragraphs

[0010] to

[0041] , R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O) R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(N S(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O )NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d , -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R 1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c.

[0043] In the compound of any one of paragraphs

[0010] to

[0042] , R1 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)NR1bR1c, -OR1a or -S(O)2R1a.

[0044] In any one of the compounds in paragraphs

[0010] to

[0043] , R1 is methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, or 2-(3,3-dimethylthioureido)ethyl. , 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4- dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, carbamimidoyl, methylaminothiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylcarbamimidoyl, (Z)-N'-cyano-N,N-dimethylcarbamimidoyl, (E)-N'-methoxy-N,N-dimethylcarbamimidoyl, (Z)-N'-methoxy-N,N-dimethylcarbamimidoyl, (E)-N'-methylsulfonyl-N,N-dimethylcarbamimidoyl, (Z)-N'-methylsulfonyl-N,N-dimethylcarbamimidoyl, hydroxy, methoxy or methylsulfonyl.

[0045] In the compound of any one of paragraphs

[0010] to

[0043] , R1 is a C1-6 alkyl group optionally substituted with one or more substituents Q.

[0046] In the compound of any one of paragraphs

[0010] to

[0043] and

[0045] , R1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0047] In the compound of any one of paragraphs

[0010] to

[0046] , R2 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O) R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(N S(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O )NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d , -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R 1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c.

[0048] In the compound of any one of paragraphs

[0010] to

[0047] , R2 is (i) hydrogen; (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or (iii) -C(O)R1a or -C(O)OR1a.

[0049] In the compound of any one of paragraphs

[0010] to

[0048] , R2 is hydrogen, methyl, ethyl, isopropyl, acetyl, or methoxycarbonyl.

[0050] In the compound of any one of paragraphs

[0010] to

[0049] , R2 is hydrogen, methyl, ethyl, or isopropyl.

[0051] In any one of the compounds in paragraphs

[0010] to

[0041] , R1 and R2, together with the N atom to which they are attached, are each substituted with one or more substituents Q. Optionally, the heteroaryl or heterocyclyl forms a heteroaryl or heterocyclyl.

[0052] In the compound of any one of paragraphs

[0010] to

[0041] and

[0051] , R1 and R2, together with the N atom to which they are attached, form a heteroaryl optionally substituted with one or more substituents Q.

[0053] In the compound of any one of paragraphs

[0010] to

[0041] ,

[0051] , and

[0052] , R1 and R2, together with the N atom to which they are attached, form a monocyclic heteroaryl optionally substituted with one or more substituents Q.

[0054] In the compound of any one of paragraphs

[0010] to

[0041] and

[0051] to

[0053] , R1 and R2, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl optionally substituted with one or more substituents Q.

[0055] In any one of the compounds in paragraphs

[0010] to

[0041] and

[0051] to

[0054] , R1 and R2, together with the N atom to which they are attached, form 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridinium-1-yl, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

[0056] In the compound of any one of paragraphs

[0010] to

[0041] ,

[0051] and

[0052] , R1 and R2, together with the N atom to which they are attached, form a bicyclic heteroaryl optionally substituted with one or more substituents Q.

[0057] In the compound of any one of paragraphs

[0010] to

[0041] ,

[0051] ,

[0052] , and

[0056] , R1 and R2, together with the N atom to which they are attached, form a 5,5-, 5,6-, or 6,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q.

[0058] In the compound of any one of paragraphs

[0010] to

[0041] ,

[0051] ,

[0052] ,

[0056] , and

[0057] , R1 and R2, together with the N atom to which they are attached, form 6-aminopurin-9-yl or 2-amino-6-oxo-1,9-dihydropurin-9-yl.

[0059] In the compound of any one of paragraphs

[0010] to

[0041] and

[0051] , R1 and R2, together with the N atom to which they are attached, form a heterocyclyl optionally substituted with one or more substituents Q.

[0060] In the compound of any one of paragraphs

[0010] to

[0041] ,

[0051] , and

[0059] , R1 and R2, together with the N atom to which they are attached, form a monocyclic heterocyclyl optionally substituted with one or more substituents Q.

[0061] In the compound of any one of paragraphs

[0010] to

[0041] ,

[0051] ,

[0059] , and

[0056] , R1 and R2, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0062] In any one of the compounds in paragraphs

[0010] to

[0041] ,

[0051] , and

[0059] to

[0061] , R1 and R2 together with the N atom to which they are attached to form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2,5-dioxypyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(4-methoxybenzyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or 1,3-dioxoisoindolyl-2-yl.

[0063] In the compound of any one of paragraphs

[0010] to

[0062] , R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each of which is optionally substituted with one or more substituents Q.

[0064] In the compound of any one of paragraphs

[0010] to

[0063] , R3 is C1-25 alkyl optionally substituted with one or more substituents Q.

[0065] In any one of the compounds in paragraphs

[0010] to

[0064] , R3 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonane- 1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0066] In the compound of any one of paragraphs

[0010] to

[0063] , R3 is C1-25 alkenyl optionally substituted with one or more substituents Q.

[0067] In any one of the compounds in paragraphs

[0010] to

[0063] and

[0066] , R3 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-en-1-yl, yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-henicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

[0068] In the compound of any one of paragraphs

[0010] to

[0063] , R3 is a C3-10 cycloalkyl group optionally substituted with one or more substituents Q.

[0069] In the compound of any one of paragraphs

[0010] to

[0063] and

[0068] , R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

[0070] In the compound of any one of paragraphs

[0010] to

[0063] , R3 is C6-14 aryl optionally substituted with one or more substituents Q.

[0071] In the compound of any one of paragraphs

[0010] to

[0063] and

[0070] , R3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0072] In the compound of any one of paragraphs

[0010] to

[0071] , R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each of which is optionally substituted with one or more substituents Q.

[0073] In the compound of any one of paragraphs

[0010] to

[0072] , R4 is C1-25 alkyl optionally substituted with one or more substituents Q.

[0074] In any one of the compounds of paragraphs

[0010] to

[0073] , R4 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonane- 1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0075] In the compound of any one of paragraphs

[0010] to

[0072] , R4 is C1-25 alkenyl optionally substituted with one or more substituents Q.

[0076] In any one of the compounds of paragraphs

[0010] to

[0072] and

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

[0077] In the compound of any one of paragraphs

[0010] to

[0072] , R4 is a C3-10 cycloalkyl group optionally substituted with one or more substituents Q.

[0078] In the compound of any one of paragraphs

[0010] to

[0072] and

[0077] , R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

[0079] In the compound of any one of paragraphs

[0010] to

[0072] , R4 is C6-14 aryl optionally substituted with one or more substituents Q.

[0080] In any one of the compounds in paragraphs

[0010] to

[0072] and

[0079] , R4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl. It's Nil.

[0081] The structure below: [ka] TIFF2025537180000012.tif213170TIFF2025537180000013.tif207170TIFF2025537180000014.tif205170TIFF2025537180000015.tif202170TIFF2025537180000016.tif220170TIFF2025537180000017.tif214170TIFF2025537180000018.tif214170TIFF2025537180000019.tif214170TIFF2025537180000020.tif214170TIFF2025537180000021.tif206170TIFF2025537180000022.tif222170TIFF2025537180000023.tif214170TIFF2025537180000024.tif215170TIFF2025537180000025.tif210170TIFF2025537180000026.tif207170TIFF2025537180000027.tif208170TIFF2025537180000028.tif221170TIFF2025537180000029.tif213170TIFF2025537180000030.tif215170TIFF2025537180000031.tif209169TIFF2025537180000032.tif207170TIFF2025537180000033.tif203170TIFF2025537180000034.tif223170TIFF2025537180000035.tif214170TIFF2025537180000036.tif215170TIFF2025537180000037.tif208170TIFF2025537180000038.tif208170TIFF2025537180000039.tif203170TIFF2025537180000040.tif222170TIFF2025537180000041.tif213169TIFF2025537180000042.tif218170TIFF2025537180000043.tif208170TIFF2025537180000044.tif209170TIFF2025537180000045.tif203170TIFF2025537180000046.tif222170TIFF20255371800000 47.tif215170TIFF2025537180000048.tif215170TIFF2025537180000049.tif209170TIFF20255371800 00050.tif209170TIFF2025537180000051.tif201169TIFF2025537180000052.tif222170TIFF2025537180000053.tif214170TIFF2025537180000054.tif41170 (wherein e and f are each independently an integer of 0, 1, 2, 3, 4, or 5, and g. and h are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; i and j are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; k and m are each independently an integer of 0, 1, 2, 3, 4, or 5; and each n is each independently an integer of 1, 2, 3, 4, 5, or 6. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0082] In the compound of any one of paragraphs

[0019] to

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

[0083] In the compound of any one of paragraphs

[0022] to

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

[0084] In the compound of any one of paragraphs

[0010] to

[0083] , X is a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-.

[0085] In the compound of any one of paragraphs

[0010] to

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

[0086] In the compound of any one of paragraphs

[0010] to

[0085] , Z is a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-.

[0087] In any one of the compounds in paragraphs

[0010] to

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

[0088] The structure below: [ka] TIFF2025537180000056.tif214169TIFF2025537180000057.tif230170TIFF2025537180000058.tif233170TIFF2025537180000059.tif219170TIFF2025537180000060.tif210170TIFF2025537180000061.tif229170TIFF2025537180000062.tif227170TIFF2025537180000063.tif232170TIFF2025537180000064.tif208170TIFF2025537180000065.tif211170TIFF2025537180000066.tif231169TIFF2025537180000067.tif224169TIFF2025537180000068.tif213169TIFF2025537180000069.tif221169TIFF2025537180000070.tif228170TIFF2025537180000071.tif227170TIFF2025537180000072.tif203170TIFF2025537180000073.tif218170TIFF2025537180000074.tif220170TIFF2025537180000075.tif221170TIFF2025537180000076.tif222169TIFF2025537180000077.tif217170TIFF2025537180000078.tif206169TIFF2025537180000079.tif226170TIFF2025537180000080.tif232170TIFF2025537180000081.tif212170TIFF2025537180000082.tif213170TIFF2025537180000083.tif214170TIFF2025537180000084.tif224170TIFF2025537180000085.tif217170TIFF2025537180000086.tif228170TIFF2025537180000087.tif214170TIFF2025537180000088.tif231170TIFF2025537180000089.tif223170TIFF2025537180000090.tif228170TIFF2025537180000091.tif230170TIFF2025537180000092.tif235170TIFF2025537180000093.tif235170TIFF2025537180000094.tif228169TIFF2025537180000095.tif229170TIFF2025537180000096.tif215170TIFF2025537180000097.tif204170TIFF2025537180000098.tif229170TIFF2025537180000099.tif233170TIFF2025537180000100.tif204170TIFF2025537180000101.tif218170TIFF2025537180000102.tif212170TIFF2025537180000103.tif223170TIFF2025537180000104.tif224170TIFF2025537180000105.tif230170TIFF2025537180000106.tif210170TIFF2025537180000107.tif228170TIFF2025537180000108.tif221170TIFF2025537180000109.tif211170TIFF2025537180000110.tif227170TIFF2025537180000111.tif223170TIFF2025537180000112.tif218170TIFF2025537180000113.tif212170TIFF2025537180000114.tif216170TIFF2025537180000115.tif209170TIFF2025537180000116.tif220170TIFF2025537180000117.tif219170TIFF2025537180000118.tif212170TIFF2025537180000119.tif206170TIFF2025537180000120.tif219170TIFF2025537180000121.tif233170TIFF2025537180000122.tif206170TIFF2025537180000123.tif219170TIFF2025537180000124.tif 212170TIFF2025537180000125.tif212170TIFF2025537180000126.tif226170TIFF2025537180000127.tif208 170TIFF2025537180000128.tif225170TIFF2025537180000129.tif230170TIFF2025537180000130.tif230170 TIFF2025537180000131.tif235170TIFF2025537180000132.tif226170TIFF2025537180000133.tif212170TIF F2025537180000134.tif231170TIFF2025537180000135.tif229170TIFF2025537180000136.tif230170TIFF20 25537180000137.tif233170TIFF2025537180000138.tif229170TIFF2025537180000139.tif226170TIFF20255 37180000140.tif207170TIFF2025537180000141.tif144170, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0089] 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyldihexanoate 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyldihexanoate 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)carbamoyl)oxy)heptane-1,7-diyldihexanoate 3; 4-(3-(2-((2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyldihexanoate or 7-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)tridecane-1,13-diyl-bis(2-hexyldecanoate)5, or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0090] The structure below: [ka] TIFF2025537180000143.tif220170TIFF2025537180000144.tif56170, or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0091] Lipid nanoparticles comprising any one of the compounds set forth in paragraphs

[0010] to

[0089] , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0092] A pharmaceutical composition comprising lipid nanoparticles, the lipid nanoparticles comprising: (i) a nucleic acid; (ii) any one of the compounds of paragraphs

[0010] to

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

[0093] The pharmaceutical composition of paragraph

[0092] further comprises a conjugated lipid.

[0094] In the pharmaceutical composition of paragraph

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

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

[0092] to

[0094] , the nucleic acid is mRNA.

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

[0092] to

[0095] , the nucleic acid is a circular RNA.

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

[0092] to

[0096] , the pharmaceutical composition is preferentially distributed to a target organ of a subject in need thereof.

[0098] In the pharmaceutical composition of paragraph

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

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

[0092] to

[0096] , the pharmaceutical composition is preferentially distributed to liver cells.

[0100] In the pharmaceutical composition of paragraph

[0099] , the liver cells are hepatocytes.

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

[0092] to

[0096] , The substance distributes preferentially to splenocytes.

[0102] In the pharmaceutical composition of paragraph

[0101] , the spleen cell is a splenocyte.

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

[0092] to

[0102] , the nucleic acid encodes a biologically active protein or enzyme.

[0104] In the pharmaceutical composition of paragraph

[0103] , the biologically active protein or enzyme is produced by hepatocytes or secreted systemically from hepatocytes.

[0105] In the pharmaceutical composition of paragraph

[0103] , the biologically active protein or enzyme is produced or systemically secreted from cells of the lung, heart, or eye, or the central nervous system. 7. Brief description of the drawings [Brief explanation of the drawings]

[0106] [Figure 1] Figure 1 shows the in vitro evaluation of luciferase expression of luciferase-encoding circular RNA. Human embryonic kidney 293T cells (HEK 293T cells), a non-small cell lung cancer cell line (A549), a human hepatoma cell line (HepG2), and a mouse myoblast cell line (C2C12) were used in this experiment. The figures were processed by calculating the corresponding mean LNP expression values. To ensure uniformity of the data, the relative LNP expression values ​​were divided by the mean expression value of the reference 1. [Figure 2] With further reference to FIG. 1, FIG. 2 shows the in vitro expression of cationic liposomes with different tail types. [Figure 3]Figure 3 shows the in vivo expression of cationic liposomes with different tail types. Circular RNA encoding luciferase encapsulated in LNPs was administered systemically to 6-8 week-old female BALB / cJ mice via tail vein injection or intramuscular injection. Two groups of mice received a given dose via tail vein injection. One group of mice received a given dose via intramuscular injection into the left and right legs. Six and 24 hours later, the mice were placed on the imaging platform. Bioluminescence imaging was performed using an IVIS Spectrum. This figure was processed by calculating the mean value of the corresponding LNP expression. [Figure 4] With further reference to FIG. 3, FIG. 4 shows expression with five cationic liposomes. DETAILED DESCRIPTION OF THE INVENTION

[0107] 8. MODE FOR CARRYING OUT THE INVENTION 8.1 Definition To facilitate understanding of the disclosure contained herein, several terms are defined below.

[0108] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those known and commonly used 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.

[0109] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as a human. In one embodiment, the subject is a human.

[0110] The term "treat / treating / treatment" is intended to include alleviating or eliminating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition, or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0111] The terms "prevent / preventing / prevention" are intended to include methods of delaying and / or eliminating the onset of a disorder, disease, or condition, and / or its complications, preventing a subject from developing a disorder, disease, or condition, or reducing a subject's risk of developing a disorder, disease, or condition.

[0112] The term "alleviate / alleviating" refers to alleviating or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms may also refer to reducing side effects associated with the active ingredient. The beneficial effects that a subject derives from a prophylactic or therapeutic agent may not cure the disorder, disease, or condition.

[0113] The term "contacting" refers to bringing a therapeutic agent into contact with a biological molecule (such as a protein, enzyme, RNA, DNA, etc.), cell, or tissue, such that a physiological and / or chemical effect occurs as a result of such contact. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro, and the effect of the therapeutic agent on the biological molecule is determined. In another embodiment, a therapeutic agent is contacted with cells in cell culture (in vitro), and the effect of the therapeutic agent on the cells is determined. In yet another embodiment, contacting a therapeutic agent with a biological molecule, cell, or tissue comprises administering the therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.

[0114] The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound that, upon administration, is sufficient to prevent or alleviate to some extent one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response in a biomolecule (such as a protein, enzyme, RNA, DNA), cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, medical doctor, or clinician.

[0115] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of a pharmaceutical formulation, suitable for use in contact with the tissues or organs of a subject (e.g., human) without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press,2020;Handbook of Pharmaceutical Excipients,9th ed.;Sheskey et al.,Eds.;Pharmaceutical Press,2020;Handbook of Pharmaceutical Additives, 3rd ed.;Ash and As h Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015.

[0116] The term "about" or "approximately" refers to the tolerance of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" refers to within 1, 2, or 3 standard deviations. In some embodiments, the term "about" or "approximately" refers to within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0117] As used herein, the term "a / an" may refer to one or more. As used in the claims, the term "a / an," when used with the word "comprising," may refer to one or more.

[0118] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group, where the alkyl group is optionally substituted with one or more substituents Q as described herein. For example, a C alkyl group refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, an alkyl group is a linear saturated monovalent hydrocarbon group having 1 to 20 (C), 1 to 15 (C), 1 to 10 (C), or 1 to 6 (C) carbon atoms, or a branched saturated monovalent hydrocarbon group having 3 to 20 (C), 3 to 15 (C), 3 to 10 (C), or 3 to 6 (C) carbon atoms. Herein, linear C alkyl groups and branched C alkyl groups are also referred to as "lower alkyl groups." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomers such as n-propyl, isopropyl), butyl (including all isomers such as n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (including all isomers such as n-pentyl, isopentyl, sec-pentyl, neopentyl, tert-pentyl), and hexyl (including all isomers such as n-hexyl, isohexyl, sec-hexyl).

[0119] As used herein, the terms "alkylene" and "alkanediyl" are used interchangeably to refer to a linear or branched saturated divalent hydrocarbon radical, which alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical having 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In some embodiments, the alkanediyl group is a straight-chain saturated divalent hydrocarbon group having 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 a branched-chain saturated divalent hydrocarbon group having 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. Herein, straight-chain C1-6 and branched C3-6 alkanediyl groups are also referred to as "lower alkanediyl groups." Examples of alkanediyl include methanediyl, ethanediyl (including all isomers such as ethane-1,1-diyl and ethane-1,2-diyl), propylenediyl (including all isomers such as propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), butanediyl (including all isomers such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl and butane-1,4-diyl), pentanediyl (including all isomers such as pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl and pentane-1,5-diyl), and hexanediyl. (including all isomers such as hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, -C(O)CH-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)(CH)-, -C(O)CHC(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, or -C(O)(CH)C(O)-.

[0120] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon group containing one or more heteroatoms in the main chain, each heteroatom independently selected from O, S, and N. Heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C heteroalkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, the heteroalkyl group is a linear saturated monovalent hydrocarbon group having 1 to 20 (C), 1 to 15 (C), 1 to 10 (C), or 1 to 6 (C) carbon atoms, or a branched saturated monovalent hydrocarbon group having 3 to 20 (C), 3 to 15 (C), 3 to 10 (C), or 3 to 6 (C) carbon atoms. As used herein, straight-chain C1-6 and straight-chain C3-6 heteroalkyl groups are also referred to as "lower heteroalkyl groups." Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CHOCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.

[0121] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein and refer to a linear or branched saturated divalent hydrocarbon group containing one or more heteroatoms (each independently selected from O, S, and N) in the main chain. The heteroalkylene group may be optionally substituted with one or more substituents Q as described herein. For example, C heteroalkylene refers to a linear saturated divalent hydrocarbon group having 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, the heteroalkylene is a straight-chain saturated divalent hydrocarbon group having 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or a branched-chain saturated divalent hydrocarbon group having 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Herein, straight-chain C1-6 and branched-chain C3-6 heteroalkylene groups are also referred to as "lower heteroalkylene." Examples of heteroalkylene include, but are not limited to, —CHO—, —(CH)O—, —(CH)O—, —(CH)O—, —(CH)O—, —(CH)O—, —(CH)O—, —(CH)O—, —(CH)O—, —(CH)O—, —CHOCH—, —CHCHO—, —(CHCHO)—, —(CHCHO)—, —(CHCHO)—, —(CHCHO)—, —CHNH—, —CHNHCH—, —CHCHNH—, —CHS—, —CHSCH—, and CHCHS—. Examples of substituted heteroalkylene groups include -C(O)CHO-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)OCHCHO-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)4, -C(O)C Examples include, but are not limited to, H2O(CH2CH2O)5-, -CH2NHC(O)CH2-, or -CH2CH2C(O)NH-.

[0122] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bonds. The alkenyl may be optionally substituted with one or more substituents Q as described herein. As will be understood by one of ordinary skill in the art, the term "alkenyl" includes groups having the "cis" or "trans" configuration, or mixtures thereof, or groups having the "Z" or "E" configuration, or mixtures thereof. For example, C2-6 alkenyl refers to a straight-chain unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms, or a branched-chain unsaturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In some embodiments, the alkenyl group is a straight-chain monovalent hydrocarbon group having 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-chain monovalent hydrocarbon group having 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 isomers such as propen-1-yl, propen-2-yl, allyl), and butenyl (including all isomers such as buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0123] The terms "alkenylene" and "alkenediyl" are used interchangeably herein and refer to a straight-chain or branched-chain divalent hydrocarbon group containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bonds. The alkenediyl may be optionally substituted with one or more substituents Q as described herein. As will be understood by those of skill in the art, the term "alkenediyl" includes groups having the "cis" or "trans" configuration or mixtures thereof, or groups having the "Z" or "E" configuration or mixtures thereof. For example, C2-6 alkenediyl refers to a straight-chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms, or a branched-chain unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, the alkenediyl group is a straight-chain divalent hydrocarbon group having 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-chain divalent hydrocarbon group having 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 ethylenediyl (including all isomers such as ethylene-1,1-diyl and ethylene-1,2-diyl), propylenediyl (including all isomers such as 1-propylene-1,1-diyl, 1-propylene-1,2-diyl and 1-propylene-1,3-diyl), butenediyl (including all isomers such as 1-butene-1,1-diyl, 1-butene-1,2-diyl and 1-butene-1,4-diyl), pentaerythritol, benzophenone, benzophenone, benzophenone- ... Examples include, but are not limited to, enediyl (including all isomers such as 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomers such as 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).

[0124] The term "heteroalkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more, in one embodiment 1, 2, 3, or 4, and in another embodiment 1, carbon-carbon double bonds, and containing one or more heteroatoms in the hydrocarbon chain (each independently selected from O, S, and N). The heteroalkenyl may be optionally substituted with one or more substituents Q as described herein. The term "heteroalkenyl" includes any of the following meanings known to those skilled in the art: Thus, groups having a "cis" or "trans" configuration or mixtures thereof, or groups having a "Z" or "E" configuration or mixtures thereof, are included. For example, C heteroalkenyl refers to a linear unsaturated monovalent hydrocarbon group having from 2 to 6 carbon atoms, or a branched unsaturated monovalent hydrocarbon group having from 3 to 6 carbon atoms. In some embodiments, the heteroalkenyl group is a linear monovalent hydrocarbon group having from 2 to 20 (C), 2 to 15 (C), 2 to 10 (C), or 2 to 6 (C) carbon atoms, or a branched monovalent hydrocarbon group having from 3 to 20 (C), 3 to 15 (C), 3 to 10 (C), or 3 to 6 (C) carbon atoms.

[0125] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bonds. An alkynyl group does not contain a carbon-carbon double bond. The alkynyl group may be optionally substituted with one or more substituents Q as described herein. For example, a C2-6 alkynyl group refers to a linear unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms, or a branched unsaturated monovalent hydrocarbon group having 4 to 6 carbon atoms. In some embodiments, the alkynyl group is a linear monovalent hydrocarbon group having from 2 to 20 (C2-20), from 2 to 15 (C2-15), from 2 to 10 (C2-10), or from 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon group having from 4 to 20 (C4-20), from 4 to 15 (C4-15), from 4 to 10 (C4-10), or from 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomers such as 1-propynyl (-C≡CCH) and propargyl (-CHC≡CH)), butynyl (including all isomers such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomers such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomers such as 1-hexyn-1-yl and 2-hexyn-1-yl).

[0126] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a straight-chain or branched-chain divalent hydrocarbon containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bonds. Alkynylene does not contain carbon-carbon double bonds. The alkynediyl may be substituted with one or more substituents Q as described herein. For example, C2-6 alkynediyl refers to a straight-chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms, or a branched-chain unsaturated divalent hydrocarbon group having 4 to 6 carbon atoms. In some embodiments, the alkynediyl is a linear divalent hydrocarbon group having from 2 to 30 (C2-30), from 2 to 20 (C2-20), from 2 to 15 (C2-15), from 2 to 10 (C2-10), or from 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon group having from 4 to 30 (C4-30), from 4 to 20 (C4-20), from 4 to 15 (C4-15), from 4 to 10 (C4-10), or from 4 to 6 (C4-6) carbon atoms. Examples of alkynediyl include, but are not limited to, ethynediyl, propynediyl (including all isomers such as 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomers such as 1-butyne-1,3-diyl, 1-butyne-1,4-diyl and 2-butyne-1,1-diyl), pentynediyl (including all isomers such as 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl and 2-pentyne-1,1-diyl), and hexynediyl (including all isomers such as 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl and 2-hexyne-1,1-diyl).

[0127] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group, optionally substituted with one or more substituents Q as defined herein. In one embodiment, the cycloalkyl is saturated or unsaturated, but not aromatic, and / or bridged or unbridged, and / or It is a fused bicyclic group. In some embodiments, the cycloalkyl has 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In another embodiment, the cycloalkyl is tricyclic. In another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl 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.

[0128] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbocyclic ring. In some embodiments, the aryl has 6 to 20 (C), 6 to 15 (C), or 6 to 10 (C) ring carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring in which one ring is aromatic and the remaining rings can be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In another embodiment, the aryl is tricyclic. In another embodiment, the aryl is polycyclic. In some embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0129] The terms "aralkyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In some embodiments, the aralkyl group has 7 to 30 (C7-30), 7 to 20 (C7-20), or 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomers such as 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomers such as 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0130] The term "heteroaryl" refers to a monovalent monocyclic aromatic or polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more heteroatoms in the ring, the heteroatoms being independently selected from O, S, and N. In the case of heteroaryl groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not attached to the remainder of the molecule through the non-aromatic heterocyclic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic. Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, benzo ...isoxazolyl, benzoisoxazolyl, benzoisoxazolyl, benzoisoxazolyl, benzoisoxazolyl, benzobenzotriazolyl, benzoxazolyl, furopyridinyl (including all isomers such as 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 isomers such as imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl) ), imidazothiazolyl (including all isomers of imidazo[2,1-b]thiazolyl, imidazo[4,5-d]thiazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothiophenyl (i.e., benzo[c]thiophenyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomers of 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl) ), oxazolopyridinyl (including all isomers such as oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridinyl (including all isomers such as pyrrolo[2,3-b]pyridinyl, pyrrolo[2-3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl and pyrrolo[3,2-c]pyridinyl), quinoline In another embodiment, the heteroaryl is a tricyclic heteroaryl. Examples of heteroaryls include, but are not limited to, thiadiazopyrimidinyl (including all isomers of [1,2,5]thiadiazo[3,4-d]pyrimidinyl, [1,2,3]thiadiazo[4,5-d]pyrimidinyl, and the like), and thienopyridinyl (including all isomers of thieno[2,3-b]pyridinyl, thieno[2-3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In another embodiment, the heteroaryl is a tricyclic heteroaryl.Examples of tricyclic heteroaryls include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, phenanthridinyl, phenanthrolinyl, phenanthridinyl (including all isomers such as 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenopyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0131] The term "heterocyclyl" or "heterocyclic" refers to a monovalent, monocyclic, non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. In the case of heterocyclyls containing heteroaromatic and non-aromatic rings, the heterocyclyl is not connected to the rest of the molecule by a heteroaromatic ring. In some embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, the nitrogen or sulfur atoms may be optionally oxidized, the 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 will result in the creation of a stable compound. Examples of heterocyclyl and heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolanyl, benzofuranonyl, chromanyl, decahydroisoquinolyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomers of 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothiophenyl, dihydroisobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, and dihydropyrrolyl. , dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl and isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiazolidinyl, dihydrobenzothiopyranyl (thiochromanyl), tetrahydroquinolinyl, and 1,3,5-trithianyl. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0132] The terms "halogen", "halogenated" or "halo" refer to fluoro, chloro, bromo and / or iodo.

[0133] The term "optionally substituted" refers to a group or substituent, such as alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, that may be substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, each independently selected from, for example, (a) deuterium (-D), cyano (-CN), halogen, imino (=NH), , nitro (—NO), and oxo (═O); (b) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, and heterocyclyl, each of which is optionally further substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —C(NRa) NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S) ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC (O)NRbRc, -NRaC(O)SRd, ​​-NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, =NORa, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc and -S(O)2NRbRc, where each Ra, Rb, Rc and Rd is, independently: (i) hydrogen or deuterium;(ii) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc, together with the N atom to which they are attached, form a heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all substitutable groups are "optionally substituted."

[0134] In one embodiment, each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)R e, -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)2NR fRg, -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)2R and (iii) R and R taken together with the N atom to which they are attached form a heterocyclyl.

[0135] In some embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In some embodiments, an optically active compound contains about 95% or greater of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In some embodiments, an optically active compound contains about 98% or greater of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In some embodiments, an optically active compound contains about 99% or greater of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture.

[0136] When describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the compound about its chiral center. The prefixes (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction in which the optically active compound rotates the plane of polarized light. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light right or clockwise. However, the sign of optical rotation (+) and (-) is independent of the absolute configuration of the compound, R or S.

[0137] The term "isotopically enriched" refers to a compound that contains an isotope in an unnatural proportion at one or more atoms that constitute the compound. In some embodiments, the isotope-enriched compound is selected from the group consisting of hydrogen (H), deuterium (H), tritium (H), carbon-11 (C), carbon-12 (C), carbon-13 (C), carbon-14 (C), nitrogen-13 (N), nitrogen-14 (N), nitrogen-15 (N), oxygen-14 (O), oxygen-15 (O), oxygen-16 (O), oxygen-17 (O), oxygen-18 (O), fluorine-17 (F), fluorine-18 (F), phosphorus-31 (P), phosphorus-32 (P), phosphorus- The isotopically enriched compounds may contain one or more isotopes in unnatural proportions, including, but not limited to, iodine-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 some embodiments, the isotopically enriched compounds are in a stable form, i.e., non-radioactive. In some embodiments, the isotopically enriched compound is hydrogen (H), deuterium (H), carbon-12 (C), carbon-13 The isotope-enriched compound may contain one or more isotopes in unnatural proportions, including, but not limited to, (C), nitrogen-14 (N), nitrogen-15 (N), oxygen-16 (O), oxygen-17 (O), oxygen-18 (O), fluorine-17 (F), phosphorus-31 (P), sulfur-32 (S), sulfur-33 (S), sulfur-34 (S), sulfur-36 (S), chlorine-35 (Cl), chlorine-37 (Cl), bromine-79 (Br), bromine-81 (Br), and iodine-127 (I). In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotopically enriched compounds contain one or more isotopes in unnatural proportions, including, but not limited to, tritium (H), carbon-11 (C), carbon-14 (C), nitrogen-13 (N), oxygen-14 (O), oxygen-15 (O), fluorine-18 (F), phosphorus-32 (P), phosphorus-33 (P), sulfur-35 (S), chlorine-36 (Cl), iodine-123 (I), iodine-125 (I), iodine-129 (I), and iodine-131 (I). It should be understood that in the compounds of the present application, where possible, for example, any hydrogen may be replaced with H, for example, any carbon with C, for example, any nitrogen with N, or any oxygen with O, according to the judgment of one of ordinary skill in the art.

[0138] The terms "nucleic acid," "polynucleotide," and "oligonucleotide" are used interchangeably herein to refer to a polymer or oligomer of nucleotides of any length. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides (such as methylated, hydroxymethylated, or glycosylated), non-naturally occurring nucleotides, non-nucleotide building blocks (i.e., "nucleotide analogs") that exhibit similar structure and / or function to natural nucleotides, and / or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. Nucleic acids or polynucleotides can be heterogeneous or homogeneous in composition, isolated from natural sources, or artificially or synthetically produced. Furthermore, nucleic acids can be DNA, RNA, or mixtures thereof, and can exist permanently or transiently in single- or double-stranded form, including homoduplexes, heteroduplexes, and hybrid states. Nucleic acid structures also include, for example, DNA / RNA helices, peptide nucleic acids (PNAs), morpholino nucleic acids (see, e.g., Braasch and Corey, Biochemistry 2002, 4, 4503-10; and U.S. Pat. No. 5,034,506), locked nucleic acids (LNAs; see, e.g., Wahlestedt et al., Proc. Natl. Acad. Sci. USA 2000, 97, 5633-8), cyclohexenyl nucleic acids (see, e.g., Wang, Am. Chem. Soc. 2000, 122, 8595-602), and / or ribozymes.

[0139] As used herein, "substantially free" of a particular component means that the particular component is not intentionally incorporated into the composition and / or is present only as a contaminant or in trace amounts. Thus, the total amount of the particular component resulting from incidental contamination of the composition is much less than 0.1%, preferably less than 0.05%, and more preferably less than 0.01%. Most preferred are compositions in which the amount of the particular component is undetectable by standard analytical methods.

[0140] The terms "substantially pure" and "substantially homogeneous" refer to a material that is sufficiently homogeneous and free of readily detectable impurities as detected by standard analytical methods used by those of 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 a material that is sufficiently pure such that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties of the material, such as enzymatic and biological activity. In some embodiments, "substantially pure" refers to a material that is sufficiently homogeneous and free of readily detectable impurities as detected by standard analytical methods used by those of 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). "Qualitatively pure" or "substantially homogeneous" refers to a collection of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single enantiomer, a racemic mixture, or a single compound containing a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular, less common isotope, the presence of other isotopes at that particular position makes the molecule an impurity relative to the isotopically enriched compound. Thus, for a deuterated compound in which a particular position is designated as deuterium, a compound containing protium at the same position is an impurity.

[0141] The term "solvate" refers to a complex or aggregate formed by the presence of one or more solute molecules (e.g., a compound of the present application) and one or more solvent molecules in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0142] For divalent groups described herein, the direction of the divalent group does not imply any orientation. For example, the formula -C(O)O- represents both -C(O)O- and -OC(O)-, unless a specific direction is specified.

[0143] The term "enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof" has the same meaning as the following terms: "(i) an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant of a compound described herein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of a compound described herein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate of an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant of a compound described herein."

[0144] 8.2 Lipid compounds In one embodiment, the present application provides a compound of formula (I):

[0145] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1- 6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)NR1bR1c, —C(NCN)NR1bR1c, —C(NOR1a )NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR 1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O) R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC (O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR 1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-40 alkyl, C1-40 heteroalkyl, C2-40 alkenyl, C2-40 heteroalkenyl, C2-40 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-20 alkylene group, a C1-20 heteroalkylene group, a C2-20 alkenylene group, or a C2-20 alkynylene group; A is -O- or -N(R1a)-; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; and each R, R, R, and R is independently hydrogen, deuterium, C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; wherein each of alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C 6 alkyl, C 6 aryl, each of which is optionally further substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa; heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SRa, —OC(NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OP( O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, ​​-NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS( O)2NRbRc, =NORa, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc and -S(O)2NRbRc (where each Ra, R b, Rc, and Rd are each independently selected from (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 optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; Each Qa is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl.

[0146] In another embodiment, the present application provides a compound of formula (I):

[0147] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocycloalkyl. or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(NCN) NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1 c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S )R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1b R, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-10 alkylene group, a C1-10 heteroalkylene group, a C2-10 alkenylene group, or a C2-10 alkynylene group; A is -O- or -N(R1a)-; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; and each R, R, R, and R is independently hydrogen, deuterium, C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl; wherein each of alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, each of which is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa; and heterocyclyl; 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, —O C(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O )2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, ​​-NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, =NORa, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc and -S(O)2NRbRc, where each Ra, Rb, Rc and Rd are each independently: (i) hydrogen or deuterium; (ii) one or more, in one embodiment one, two, three or four or (iii) Rb and Rc together with the N atom to which they are attached form a heterocyclyl optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; Each Qa is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl.

[0148] In some embodiments, in Formula (I), L is C alkylene optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L is -(CRR)-, where R and R are each independently (i) hydrogen, or (ii) C alkyl optionally substituted with one or more substituents Q, or R and R together with the C atom to which they are attached form a C cycloalkyl optionally substituted with one or more substituents Q, and a is an integer of 1, 2, 3, 4, 5, or 6. In some embodiments, in Formula (I), L is -(CH)-, where a is an integer of 1, 2, 3, 4, 5, or 6. In some embodiments, in Formula (I), L is -(CH)-, where a is an integer of 2, 3, or 4. In some embodiments, in Formula (I), L is -(CH)-.

[0149] In some embodiments, in Formula (I), L2 is C1-6 alkylene optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L2 is -(CR2aR2b)b-, where b is an integer of 1, 2, 3, 4, 5, or 6, and each R2a and R2b is as defined herein. In some embodiments, in Formula (I), L2 is -(CH2)b-, where b is an integer of 1, 2, 3, 4, 5, or 6. In some embodiments, in Formula (I), L2 is -(CH2)b-, where b is an integer of 2, 3, or 4. In some embodiments, in Formula (I), L2 is -(CH2)2-.

[0150] In some embodiments, in Formula (I), L3 is C1-10 alkylene optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L3 is -(CR2aR2b)c-, where c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and each R2a and R2b is as defined herein. In some embodiments, in Formula (I), L3 is -(CH2)c-, where c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, in Formula (I), L3 is -(CH2)2-. In some embodiments, in Formula (I), L3 is -(CH2)3-.

[0151] In some embodiments, in Formula (I), L4 is C1-10 alkylene optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L4 is -(CR2aR2b)d-, where d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and each R2a and R2b is as defined herein. In some embodiments, in Formula (I), L4 is -(CH2)d-, where d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, in Formula (I), L4 is -(CH2)2-. In some embodiments, in Formula (I), L4 is -(CH2)3-.

[0152] In yet another embodiment, the present specification provides a compound of formula (II):

[0153] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1, R2, R3, R4, A, E, X, Z, a, b, c, and d are each as defined herein.

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

[0155] In yet another embodiment, the present specification provides a compound of formula (III):

[0156] [ka] or its enantiomer, mixture of enantiomers, diastereomer, two or more diastereomers A mixture of an asteromer, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein R1, R2, R3, R4, A, U, X, Z, a, b, c and d are each as defined herein.

[0157] In some embodiments, in any one of Formulas (I) to (III), A is -O-. In some embodiments, in any one of Formulas (I) to (III), A is -N(R1a)-, where R1a is as defined herein. In some embodiments, in any one of Formulas (I) to (III), A is -N(H)-.

[0158] In some embodiments, in any one of Formulas (I) to (III), U is -O-. In some embodiments, in any one of Formulas (I) to (III), U is -N(R1a)-, where R1a is as defined herein. In some embodiments, in any one of Formulas (I) to (III), U is -N(H)-.

[0159] In yet another embodiment, the present specification provides a compound of formula (IV):

[0160] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1, R2, R3, R4, X, Z, a, b, c, and d are each as defined herein.

[0161] In yet another embodiment, the present description provides a compound of formula (V):

[0162] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1, R2, R3, R4, X, Z, a, b, c, and d are each as defined herein.

[0163] In yet another embodiment, the present specification provides a compound of formula (VI):

[0164] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1, R2, R3, R4, X, Z, a, b, c, and d are each as defined herein.

[0165] In yet another embodiment, the present specification provides a compound of formula (VII):

[0166] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1, R2, R3, R4, X, Z, a, b, c, and d are each as defined herein.

[0167] In some embodiments, in any one of formulas (I)-(VII), R is (i) hydrogen; (ii) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R, —C( O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1 bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(N R1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR 1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1 and R is selected from the group consisting of C(S)R, -NRC(S)OR, -NRC(S)NRR, -NRS(O)R, -NRS(O)R, -NRS(O)NRR, -NRS(O)NRR, -S(O)R, -S(O)R, -S(O)NRR, and -S(O)NRR, where each R, R, R, R, and R are as defined herein. In some embodiments, in any one of formulas (I) to (VII), R is selected from the group consisting of (i) C alkyl, C alkenyl, C cycloalkyl, C aryl, C aralkyl, or heteroaryl, each of which is optionally substituted with one or more substituents Q. aryl; or (ii) —C(O)R, —C(O)OR, —C(O)NR, —C(NR)NR, —C(NCN)NR, —C(NOR, —C(NS(O)R, —NR, —C(S)NR, —OR, or —S(O)R, where each R, R, and R is as defined herein.

[0168] In some embodiments, in any one of formulas (I) to (VII), R 1 is C 1-6 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R is C alkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C cycloalkyl, C aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, ═NO, —SR, or —NRS(O)R, where each R, R, R, and R is as defined herein.

[0169] In some embodiments, in any one of formulas (I)-(VII), R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0170] In some embodiments, in any one of formulas (I)-(VII), R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0171] In some embodiments, in any one of formulas (I) to (VII), R is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3, 3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0172] In some embodiments, in any one of formulas (I) to (VII), R 1 is C 2-6 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R is C alkenyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C cycloalkyl, C aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, ═NO, —SR, or —NRS(O)R, where each R, R, R, and R is as defined herein. In some embodiments, in any one of formulas (I)-(VII), R1 is 1-(dimethylamino)-2-nitrovinyl.

[0173] In some embodiments, in any one of formulas (I) to (VII), R 1 is C 3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R is C cycloalkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C cycloalkyl, C aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, ═NO, —SR, or —NRS(O)R, where each R, R, R, and R is as defined herein.

[0174] In some embodiments, in any one of formulas (I) to (VII), R1 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R is a monocyclic C cycloalkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C cycloalkyl, C aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, ═NO, —SR, or —NRS(O)R, where each R, R, R, and R is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, in any of Formulas (I)-(VII), R1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl.

[0175] In some embodiments, in any one of Formulas (I)-(VII), R1 is C6-14 aryl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 is C6-14 aryl optionally substituted with one, two, or three substituents Q, each Q independently being selected from the group consisting of: (i) cyano, halogen, nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heteroaryl, each optionally substituted with one or more substituents Qa. or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, -SRa, or -NRaS(O)Rd, where each Ra, Rb, Rc, and Rd are as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is 4-dimethylaminophenyl.

[0176] In some embodiments, in any one of formulas (I) to (VII), R 1 is a C 7-15 aralkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R is a C aralkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) a C cycloalkyl, C aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, —SR, or —NRS(O)R, where each R, R, R, and R are as defined herein. In some embodiments, in any of Formulas (I)-(VII), R is 4-methoxybenzyl.

[0177] In some embodiments, in any one of Formulas (I)-(VII), R is heteroaryl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R is heteroaryl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, nitro; (ii) C cycloalkyl, C aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, —SR, or —NRS(O)R, where each R, R, R, and R is as defined herein.

[0178] In some embodiments, in any one of formulas (I) to (VII), R 1 is a monocyclic heteroaryl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R is a monocyclic heteroaryl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) a C cycloalkyl, a C aryl, a heteroaryl, or a heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)OR, —C(O)NRR, —C(O)SR, —OR, —NRR, —NRC(O)NRR, —NRC(NR)NRR, —NRC(S)NRR, —SR, or —NRS(O)R, where each R, R, R, and R is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R1 is a 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 is an imidazolyl, thiazolyl, or pyridinyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 is an imidazolyl, thiazolyl, pyridin-2-yl, or pyridin-3-yl.

[0179] In some embodiments, in any one of formulas (I)-(VII), R is -C (O)R1a, where R1a is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R1 is -C(O)-C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 is -C(O)-C1-6 alkyl, wherein the alkyl is optionally substituted with -ORa, and R1 is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, in any one of Formulas (I)-(VII), R1 is -C(O)OR1a, and R1a is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is —C(O)OC1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any of Formulas (I)-(VII), R1 is methoxycarbonyl. In some embodiments, in any of Formulas (I)-(VII), R1 is —C(O)NR1bR1c, wherein R1b and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is methylaminocarbonyl or dimethylaminocarbonyl. In some embodiments, in any of Formulas (I)-(VII), R1 is —C(NR1a)NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is carbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R1 is -C(NCN)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is N'-cyano-N,N-dimethylcarbamimidoyl.In some embodiments, in any of Formulas (I)-(VII), R1 is -C(NOR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is N'-methoxy-N,N-dimethylcarbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R1 is -C(NS(O2)R1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is N'-methylsulfonyl-N,N-dimethyl-carbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R1 is -C(S)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is methylaminothiocarbonyl or dimethylaminothiocarbonyl. In some embodiments, in any of Formulas (I)-(VII), R1 is -OR1a, where R1a is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is hydroxy or methoxy. In some embodiments, in any of Formulas (I)-(VII), R1 is -S(O)2R1a, where R1a is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R1 is methylsulfonyl.

[0180] In some embodiments, in any one of formulas (I) to (VII), R is methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, or 2-(3,3-dimethylthioureido). Ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4-dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl , pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, carbamimidoyl, methylaminothiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylcarbamimidoyl, (Z)-N'-cyano-N,N-dimethylcarbamimidoyl, (E)-N'-methoxy-N,N-dimethylcarbamimidoyl, (Z)-N'-methoxy-N,N-dimethylcarbamimidoyl, (E)-N'-methylsulfonyl-N,N-dimethylcarbamimidoyl, (Z)-N'-methylsulfonyl-N,N-dimethylcarbamimidoyl, hydroxy, methoxy or methylsulfonyl. In some embodiments, in any one of formulas (I) to (VII), R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0181] In some embodiments, in any one of formulas (I)-(VII), R2 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C( O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1 bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(N R1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR 1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1 aC(S)Rld, -NR1aC(S)ORld, -NR1aC(S)NR1bRlc, -NR1aS(O)Rld, -NR1aS(O)2Rld, -NR1aS(O)NR1bRlc, -NR1aS(O)2NR1bRlc, -S(O)R1a, -S(O)2R1a, -S(O)NR1bRlc or -S(O)2NR1bRlc, wherein each R1a, R1b, R1c and R1d are as defined herein.In some embodiments, in any one of formulas (I)-(VII), R2 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)NR1bR1c, -OR1a, or -S(O)2R1a, where each R1a, R1b, and R1c is as defined herein.

[0182] In some embodiments, in any one of formulas (I) to (VII), R2 is C1-6 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R2 is C1-6 alkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, =NORa, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd is as defined herein.

[0183] In some embodiments, in any one of formulas (I)-(VII), R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0184] In some embodiments, in any one of formulas (I)-(VII), R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.

[0185] In some embodiments, in any one of formulas (I)-(VII), R2 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3, 3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0186] In some embodiments, in any one of Formulas (I)-(VII), R2 is C2-6 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R2 is C1-6 alkenyl optionally substituted with one, two, or three substituents Q, each Q being independently selected from: (i) cyano, halogen, nitro; (ii) each substituted with one or more substituents Q; or (iii) —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —ORa, —NRbRc, —NRaC(O)NRbRc, —NRaC(NRd)NRbRc, —NRaC(S)NRbRc, ═NORa, —SRa, or —NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd are as defined herein. In some embodiments, in any one of formulas (I)-(VII), R2 is 1-(dimethylamino)-2-nitrovinyl.

[0187] In some embodiments, in any one of formulas (I) to (VII), R2 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R2 is C3-10 cycloalkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, =NORa, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd is as defined herein.

[0188] In some embodiments, in any one of formulas (I) to (VII), R2 is a monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R2 is monocyclic C3-10 cycloalkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, =NORa, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, in any of Formulas (I)-(VII), R2 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl.

[0189] In some embodiments, in any one of formulas (I) to (VII), R2 is C6-14 aryl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R2 is C6-14 aryl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd are as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is 4-dimethylaminophenyl.

[0190] In some embodiments, in any one of formulas (I) to (VII), R2 is a C7-15 aralkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R2 is C7-15 aralkyl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd are as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is 4-methoxybenzyl.

[0191] In some embodiments, in any one of Formulas (I)-(VII), R2 is heteroaryl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R2 is heteroaryl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd is as defined herein.

[0192] In some embodiments, in any one of formulas (I) to (VII), R2 is a monocyclic heteroaryl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R2 is a monocyclic heteroaryl optionally substituted with one, two, or three substituents Q, and each Q is independently (i) cyano, halogen, or nitro; (ii) a C3-10 cycloalkyl, a C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R2 is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R2 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.

[0193] In some embodiments, in any one of Formulas (I)-(VII), R2 is -C(O)R1a, where R1a is as defined herein. In some embodiments, in any one of Formulas (I)-(VII), R2 is -C(O)-C1-6 alkyl, where the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(O)-C1-6 alkyl, where the alkyl is optionally substituted with -ORa, where Ra is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(O)-C1-6 alkyl, where the alkyl is optionally substituted with -ORa, where Ra is as defined herein. wherein R2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, in any of Formulas (I)-(VII), R2 is —C(O)OR1a, where R1a is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is —C(O)OC1-6alkyl, where the alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any of Formulas (I)-(VII), R2 is methoxycarbonyl. In some embodiments, in any of Formulas (I)-(VII), R2 is —C(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is methylaminocarbonyl or dimethylaminocarbonyl. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(NR)NRR, where R, R, and R are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is carbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(NCN)NRR, where R and R are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is N'-cyano-N,N-dimethylcarbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(NOR)NRR, where R, R, and R are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is N'-methoxy-N,N-dimethylcarbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(NS(O2)R1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein.In some embodiments, in any of Formulas (I)-(VII), R2 is N'-methylsulfonyl-N,N-dimethyl-carbamimidoyl. In some embodiments, in any of Formulas (I)-(VII), R2 is -C(S)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is methylaminothiocarbonyl or dimethylaminothiocarbonyl. In some embodiments, in any of Formulas (I)-(VII), R2 is -OR1a, where R1a is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is hydroxy or methoxy. In some embodiments, in any of Formulas (I)-(VII), R2 is -S(O)2R1a, where R1a is as defined herein. In some embodiments, in any of Formulas (I)-(VII), R2 is methylsulfonyl.

[0194] In some embodiments, in any one of Formulas (I)-(VII), R2 is methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, or 2-(3,3-dimethylureido)ethyl. ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclohexyl propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4-dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, carboxymethyl, methylaminocarbonyl ... In some embodiments, in any one of Formulas (I)-(VII), R2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0195] In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a monocyclic heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 5-membered heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 6-membered heteroaryl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form 1,2,3-triazol-1-yl, pyridin-1-iumyl, or pyrimidin-1-yl, each of which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

[0196] In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a bicyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. R1 and R2, together with the N atom to which they are attached, form a 5,6-fused heteroaryl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 6,6-fused heteroaryl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a purin-9-yl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R1 and R2, together with the N atom to which they are attached, form a 6-aminopurin-9-yl or 2-amino-6-oxo-1,9-dihydropurin-9-yl.

[0197] In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a heterocyclyl that may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a monocyclic heterocyclyl that may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 3-membered heterocyclyl that may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 4-membered heterocyclyl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 5-membered heterocyclyl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 6-membered heterocyclyl, which may be substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form a 7-membered heterocyclyl, which may be substituted with one or more substituents Q.

[0198] In some embodiments, in any one of formulas (I) to (VII), R1 and R2, together with the N atom to which they are attached, form aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, oxazolidinon-3-yl, imidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, piperazin-1-yl, or isoindolin-2-yl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R and R, together with the N atom to which they are attached, form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(4-methoxybenzyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or 1,3-dioxoisoindolin-2-yl.

[0199] In some embodiments, in any one of formulas (I)-(VII),

[0200] [ka] The moiety can be dimethylamino, (2-cyanoethyl)(methyl)amino, (cyclopropylmethyl)(methyl)amino, (cyclobutylmethyl)(methyl)amino, (cyclopentylmethyl)(methyl)amino, (cyclohexylmethyl)(methyl)amino, (cycloheptylmethyl)(methyl)amino, (pyridin-2-ylmethyl)(methyl)amino, (pyridin-3-ylmethyl)(methyl)amino, (pyridin-4-ylmethyl)(methyl)amino, (dimethylaminomethyl)(methyl)amino, (ethyl)(methyl)amino, (2-hydroxyethyl) (2-methyl)amino, (2-acetamidoethyl)(methyl)amino, (2-guanidinoethyl)(methyl)amino, (2-methylsulfonamidoethyl)(methyl)amino, (2-(3-methylureido)ethyl)(methyl)amino, (2-(3,3-dimethylureido)ethyl)(methyl)amino), (2-(3-methylthioureido)ethyl)(methyl)amino, (2-(3,3-dimethylthioureido)ethyl)(methyl)amino, diethylamino, (1,3-dihydroxypropan-2-yl)amino, (isopropyl)(methyl)amino, (R)-(2-hydroxypropyl)(methyl)amino, (S)-(2-hydroxypropyl)(methyl)amino, (3-hydroxypropyl)(methyl)amino, (1,3-dihydroxypropan-2-yl)(methyl)amino, (ethyl)(isopropyl)amino, diisopropylamino, (4-hydroxybutyl)(methyl)amino, (R)-(2-hydroxybutyl)(methyl)amino, (S)-(2-hydroxybutyl)(methyl)amino, (5-hydroxypentyl)(methyl)amino, (4-(2-hydroxyethoxy)butyl)(methyl)amino )amino, 4-(methoxyimino)butylamino, (4-(methoxyimino)butyl)(methyl)amino, (5-hydroxy-5-carboxypentyl)(methyl)amino, (6-hydroxyhexyl)(methyl)amino, 1-(methylamino)-2-nitrovinylamino, (cyclopropyl)(methyl)amino, (cyclobutyl)(methyl)amino, (cyclopentyl)(methyl)amino, (cyclohexyl)(methyl)amino, (cycloheptyl)(methyl)amino, (2-hydroxycycloheptyl)(methyl)amino, 2-dimethylamino-3,4-Dioxo-1-cyclobutenyl, (4-dimethylaminophenyl)amino, (4-methoxybenzyl)(methyl)amino, imidazol-2-ylamino, thiazol-2-ylamino, (pyridin-2-yl)(methyl)amino, (pyridin-3-yl)(methyl)amino, methoxyformamide, methylaminoformamide, dimethylaminoformamide, methylaminothioformamide, dimethylaminothioformamide, acetamide, N-(methyl)acetamide, N-(2-hydroxy )acetamide, N-(2-methoxy)acetamide, N-(2-benzyloxy)acetamide, propionamide, isobutyramide, guanidinyl, 2-cyano-3,3-dimethylguanidinyl, 2-methoxy-3,3-dimethylguanidinyl, 2-methylsulfonyl-3,3-dimethylguanidinyl, N-(methyl)hydroxyamino, N-(methoxy)acetamide, N-(methoxy)methoxyformamide, methylsulfonamide, or N-(methoxy)(methylsulfonamide).

[0201] In some embodiments, in any one of formulas (I)-(VII),

[0202] [ka] The moieties include 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, 4-amino-2-oxopyrimidin-1-yl, 6-aminopurin-9-yl, 2-amino-6-oxo-1,9-dihydropurin-9-yl, 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2-methyl-2-oxopyrrimidin-1-yl, 2-methyl-6-oxo-1,9-dihydropurin-9-yl, 2-methyl-6-oxo-1,9-dihydropurin-9-yl, 2-methyl-6-oxo-1,9-dihydropurin-1 ... yl, 1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(4-methoxybenzyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or 1,3-dioxoisoindolin-2-yl.

[0203] In some embodiments, in any one of formulas (I)-(VII),

[0204] [ka] The moiety has the following structure:

[0205] [ka] wherein e and f are each independently an integer of 0, 1, 2, 3, 4, or 5; k and m are each independently an integer of 0, 1, 2, 3, 4, or 5; n is an integer of 0, 1, 2, 3, 4, 5, or 6; and each R is as defined herein; and in one embodiment, each R is independently C alkyl optionally substituted with one or more substituents Q; and in another embodiment, each R is methyl.

[0206] In some embodiments, in any one of formulas (I)-(VII), R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q. ... -30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, or C6-14 aryl.

[0207] In some embodiments, in any one of Formulas (I)-(VII), R3 is C1-30 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is C1-25 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is C1-20 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nona- and 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0208] In some embodiments, in any one of Formulas (I) to (VII), R3 is C1-30 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R3 is C1-25 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R3 is C1-20 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R3 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, or pentacosenyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R3 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, ( (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-henedecen-1-yl, (8Z,11Z)-heptadecene-8,11-dien-1-yl, (9Z,12Z)-octadecane-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadecene-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadecene-8,11,14-trien-1-yl.

[0209] In some embodiments, in any one of formulas (I) to (VII), R3 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In embodiments, in any one of Formulas (I)-(VII), R3 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is cyclohexyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

[0210] In some embodiments, in any one of Formulas (I) to (VII), R3 is C aryl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R3 is phenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0211] In some embodiments, in any one of Formulas (I)-(VII), R3 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, yl, decan-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, heneicosan-1-yl, 2-(dodecan-1-yldisulfanyl)ethyl, (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, ( Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methylocten-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8- henedecen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexylcyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0212] In some embodiments, in any one of formulas (I)-(VII), R3 is

[0213] [ka] TIFF2025537180000158.tif221170TIFF2025537180000159.tif210170.

[0214] In some embodiments, in any one of formulas (I)-(VII), R3 is

[0215] [ka] and wherein each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0216] In some embodiments, in any one of formulas (I)-(VII), R3 is

[0217] [ka] and wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0218] In some embodiments, in any one of formulas (I)-(VII), R3 is

[0219] [ka] TIFF2025537180000163.tif227170TIFF2025537180000164.tif225170TIFF2025537180000165.tif67170.

[0220] In some embodiments, in any one of Formulas (I)-(VII), R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, or C6-14 aryl, each of which is optionally substituted with one or more substituents Q.

[0221] In some embodiments, in any one of Formulas (I)-(VII), R4 is C1-30 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R4 is C1-25 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R4 is C1-20 alkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R4 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonane -1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0222] In some embodiments, in any one of formulas (I) to (VII), R4 is C1-30 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R4 is C1-25 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R4 is C1-25 alkenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I)-(VII), R4 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, or pentacosenyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I)-(VII), R4 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, ( (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-henedecen-1-yl, (8Z,11Z)-heptadecene-8,11-dien-1-yl, (9Z,12Z)-octadecane-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadecene-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadecene-8,11,14-trien-1-yl.

[0223] In some embodiments, in any one of Formulas (I) to (VII), R4 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R4 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R4 is cyclohexyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

[0224] In some embodiments, in any one of Formulas (I) to (VII), R4 is C aryl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R4 is phenyl optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0225] In some embodiments, in any one of Formulas (I)-(VII), R4 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptane-1-yl, hex ... Butadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, heneicosan-1-yl, 2-(dodecan-1-yldisulfanyl)ethyl, (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3 -octen-1-yl, (E)-3-methylocten-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-henedecen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexylcyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0226] In some embodiments, in any one of formulas (I)-(VII), R4 is

[0227] [ka] TIFF2025537180000167.tif222170TIFF2025537180000168.tif222170.

[0228] In some embodiments, in any one of formulas (I)-(VII), R4 is

[0229] [ka] and wherein each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0230] In some embodiments, in any one of formulas (I)-(VII), R4 is

[0231] [ka] and wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0232] In some embodiments, in any one of formulas (I)-(VII), R4 is

[0233] [ka] TIFF2025537180000172.tif229170TIFF2025537180000173.tif221170TIFF2025537180000174.tif66170.

[0234] In one embodiment, the present description provides a compound of formula A1:

[0235] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein g and h are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, and X, Z, c, d, e, and f are each as defined herein.

[0236] In another embodiment, the present description provides a compound of formula A2:

[0237] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, and f are each as defined herein.

[0238] In another embodiment, the present description provides a compound of formula A3:

[0239] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, and f are each as defined herein.

[0240] In another embodiment, the present description provides a compound of formula A4:

[0241] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein i and j are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, and X, Z, c, d, e, and f are each as defined herein.

[0242] In another embodiment, the present description provides a compound of formula A5:

[0243] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0244] In another embodiment, the present description provides a compound of formula A6:

[0245] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0246] In another embodiment, the present description provides a compound of formula A7:

[0247] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0248] In another embodiment, the present description provides a compound of formula A8:

[0249] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0250] In another embodiment, the present description provides a compound of formula A9:

[0251] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0252] In another embodiment, the present description provides a compound of formula A10:

[0253] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , where X, Z, c, d, i, and j are each as defined herein.

[0254] In another embodiment, the present description provides a compound of formula A11:

[0255] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0256] In another embodiment, the present description provides a compound of formula A12:

[0257] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0258] In another embodiment, the present description provides a compound of formula A13:

[0259] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0260] In another embodiment, the present description provides a compound of formula A14:

[0261] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0262] In another embodiment, the present description provides a compound of formula A15:

[0263] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0264] In another embodiment, the present description provides a compound of formula A16:

[0265] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0266] In another embodiment, the present description provides a compound of formula A17:

[0267] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0268] In another embodiment, the present description provides a compound of formula A18:

[0269] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0270] In another embodiment, the present description provides a compound of formula A19:

[0271] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0272] In another embodiment, the present description provides a compound of formula A20:

[0273] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0274] In another embodiment, the present description provides a compound of formula A21:

[0275] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0276] In another embodiment, the present description provides a compound of formula A22:

[0277] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0278] In another embodiment, the present description provides a compound of formula A23:

[0279] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0280] In another embodiment, the present description provides a compound of formula A24:

[0281] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0282] In another embodiment, the present description provides a compound of formula A25:

[0283] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0284] In another embodiment, the present description provides a compound of formula A26:

[0285] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0286] In another embodiment, the present description provides a compound of formula A27:

[0287] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0288] In another embodiment, the present description provides a compound of formula A28:

[0289] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0290] In another embodiment, the present description provides a compound of formula A29:

[0291] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0292] In another embodiment, the present description provides a compound of formula A30:

[0293] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0294] In another embodiment, the present description provides a compound of formula A31:

[0295] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0296] In another embodiment, the present description provides a compound of formula A32:

[0297] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0298] In another embodiment, the present description provides a compound of formula A33:

[0299] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0300] In another embodiment, the present description provides a compound of formula A34:

[0301] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, k, and m are each as defined herein. .

[0302] In another embodiment, the present description provides a compound of formula A35:

[0303] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0304] In another embodiment, the present description provides a compound of formula A36:

[0305] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0306] In another embodiment, the present description provides a compound of formula A37:

[0307] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0308] In another embodiment, the present description provides a compound of formula A38:

[0309] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0310] In another embodiment, the present description provides a compound of formula A39:

[0311] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0312] In another embodiment, the present description provides a compound of formula A40:

[0313] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0314] In another embodiment, the present description provides a compound of formula A41:

[0315] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0316] In another embodiment, the present description provides a compound of formula A42:

[0317] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0318] In another embodiment, the present description provides a compound of formula A43:

[0319] [ka] or its enantiomer, mixture of enantiomers, diastereomer, two or more diastereomers A mixture of an asteomer, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0320] In another embodiment, the present description provides a compound of formula A44:

[0321] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0322] In another embodiment, the present description provides a compound of formula A45:

[0323] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0324] In another embodiment, the present description provides a compound of formula A46:

[0325] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, and n are each as defined herein.

[0326] In another embodiment, the present description provides a compound of formula A47:

[0327] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0328] In another embodiment, the present description provides a compound of formula A48:

[0329] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0330] In another embodiment, the present description provides a compound of formula A49:

[0331] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0332] In another embodiment, the present description provides a compound of formula A50:

[0333] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0334] In another embodiment, the present description provides a compound of formula A51:

[0335] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0336] In another embodiment, the present description provides a compound of formula A52:

[0337] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0338] In another embodiment, the present description provides a compound of formula A53:

[0339] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0340] In another embodiment, the present description provides a compound of formula A54:

[0341] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0342] In another embodiment, the present specification provides a compound of formula B1:

[0343] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0344] In another embodiment, the present description provides a compound of formula B2:

[0345] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, and f are each as defined herein.

[0346] In another embodiment, the present description provides a compound of formula B3:

[0347] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, e and f are each as defined herein.

[0348] In another embodiment, the present description provides a compound of formula B4:

[0349] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, i, and j are each as defined herein.

[0350] In another embodiment, the present description provides a compound of formula B5:

[0351] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0352] In another embodiment, the present description provides a compound of formula B6:

[0353] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0354] In another embodiment, the present description provides a compound of formula B7:

[0355] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0356] In another embodiment, the present description provides a compound of formula B8:

[0357] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0358] In another embodiment, the present specification provides a compound of formula B9:

[0359] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0360] In another embodiment, the present description provides a compound of formula B10:

[0361] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0362] In another embodiment, the present description provides a compound of formula B11:

[0363] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0364] In another embodiment, the present description provides a compound of formula B12:

[0365] [ka] or its enantiomer, mixture of enantiomers, diastereomer, two or more diastereomers A mixture of an asteomer, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0366] In another embodiment, the present description provides a compound of formula B13:

[0367] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0368] In another embodiment, the present specification provides a compound of formula B14:

[0369] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0370] In another embodiment, the present description provides a compound of formula B15:

[0371] [ka] or its enantiomer, mixture of enantiomers, diastereomer, two or more diastereomers A mixture of an asteromer, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0372] In another embodiment, the present description provides a compound of formula B16:

[0373] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0374] In another embodiment, the present description provides a compound of formula B17:

[0375] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0376] In another embodiment, the present description provides a compound of formula B18:

[0377] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0378] In another embodiment, the present description provides a compound of formula B19:

[0379] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0380] In another embodiment, the present description provides a compound of formula B20:

[0381] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0382] In another embodiment, the present description provides a compound of formula B21:

[0383] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0384] In another embodiment, the present description provides a compound of formula B22:

[0385] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0386] In another embodiment, the present description provides a compound of formula B23:

[0387] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0388] In another embodiment, the present description provides a compound of formula B24:

[0389] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0390] In another embodiment, the present description provides a compound of formula B25:

[0391] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0392] In another embodiment, the present description provides a compound of formula B26:

[0393] [ka] or its enantiomer, mixture of enantiomers, diastereomer, two or more diastereomers A mixture of an asteromer, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0394] In another embodiment, the present description provides a compound of formula B27:

[0395] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0396] In another embodiment, the present description provides a compound of formula B28:

[0397] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0398] In another embodiment, the present specification provides a compound of formula B29:

[0399] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0400] In another embodiment, the present description provides a compound of formula B30:

[0401] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0402] In another embodiment, the present description provides a compound of formula B31:

[0403] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0404] In another embodiment, the present description provides a compound of formula B32:

[0405] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0406] In another embodiment, the present description provides a compound of formula B33:

[0407] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0408] In another embodiment, the present description provides a compound of formula B34:

[0409] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, k, and m are each as defined herein. .

[0410] In another embodiment, the present description provides a compound of formula B35:

[0411] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0412] In another embodiment, the present description provides a compound of formula B36:

[0413] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0414] In another embodiment, the present description provides a compound of formula B37:

[0415] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0416] In another embodiment, the present description provides a compound of formula B38:

[0417] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0418] In another embodiment, the present description provides a compound of formula B39:

[0419] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0420] In another embodiment, the present description provides a compound of formula B40:

[0421] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0422] In another embodiment, the present description provides a compound of formula B41:

[0423] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0424] In another embodiment, the present description provides a compound of formula B42:

[0425] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0426] In another embodiment, the present description provides a compound of formula B43:

[0427] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0428] In another embodiment, the present description provides a compound of formula B44:

[0429] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0430] In another embodiment, the present description provides a compound of formula B45:

[0431] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0432] In another embodiment, the present description provides a compound of formula B46:

[0433] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, and n are each as defined herein.

[0434] In another embodiment, the present description provides a compound of formula B47:

[0435] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0436] In another embodiment, the present description provides a compound of formula B48:

[0437] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0438] In another embodiment, the present description provides a compound of formula B49:

[0439] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0440] In another embodiment, the present description provides a compound of formula B50:

[0441] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0442] In another embodiment, the present description provides a compound of formula B51:

[0443] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0444] In another embodiment, the present description provides a compound of formula B52:

[0445] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0446] In another embodiment, the present description provides a compound of formula B53:

[0447] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0448] In another embodiment, the present description provides a compound of formula B54:

[0449] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0450] In another embodiment, the present description provides a compound of formula C1:

[0451] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0452] In another embodiment, the present specification provides a compound of formula C2:

[0453] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, and f are each as defined herein.

[0454] In another embodiment, the present description provides a compound of formula C3:

[0455] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, and f are each as defined herein.

[0456] In another embodiment, the present specification provides a compound of formula C4:

[0457] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, i, and j are each as defined herein.

[0458] In another embodiment, the present description provides a compound of formula C5:

[0459] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0460] In another embodiment, the present specification provides a compound of formula C6:

[0461] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0462] In another embodiment, the present specification provides a compound of formula C7:

[0463] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0464] In another embodiment, the present description provides a compound of formula C8:

[0465] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0466] In another embodiment, the present specification provides a compound of formula C9:

[0467] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0468] In another embodiment, the present specification provides a compound of formula C10:

[0469] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0470] In another embodiment, the present specification provides a compound of formula C11:

[0471] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0472] In another embodiment, the present specification provides a compound of formula C12:

[0473] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0474] In another embodiment, the present specification provides a compound of formula C13:

[0475] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0476] In another embodiment, the present specification provides a compound of formula C14:

[0477] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0478] In another embodiment, the present specification provides a compound of formula C15:

[0479] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0480] In another embodiment, the present specification provides a compound of formula C16:

[0481] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0482] In another embodiment, the present specification provides a compound of formula C17:

[0483] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0484] In another embodiment, the present specification provides a compound of formula C18:

[0485] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0486] In another embodiment, the present specification provides a compound of formula C19:

[0487] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0488] In another embodiment, the present specification provides a compound of formula C20:

[0489] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0490] In another embodiment, the present specification provides a compound of formula C21:

[0491] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0492] In another embodiment, the present specification provides a compound of formula C22:

[0493] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , where X, Z, c, d, i, and j are each as defined herein.

[0494] In another embodiment, the present specification provides a compound of formula C23:

[0495] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0496] In another embodiment, the present specification provides a compound of formula C24:

[0497] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0498] In another embodiment, the present description provides a compound of formula C25:

[0499] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0500] In another embodiment, the present specification provides a compound of formula C26:

[0501] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0502] In another embodiment, the present description provides a compound of formula C27:

[0503] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0504] In another embodiment, the present description provides a compound of formula C28:

[0505] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , where X, Z, c, d, i, and j are each as defined herein.

[0506] In another embodiment, the present description provides a compound of formula C29:

[0507] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0508] In another embodiment, the present specification provides a compound of formula C30:

[0509] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0510] In another embodiment, the present description provides a compound of formula C31:

[0511] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0512] In another embodiment, the present description provides a compound of formula C32:

[0513] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0514] In another embodiment, the present description provides a compound of formula C33:

[0515] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0516] In another embodiment, the present specification provides a compound of formula C34:

[0517] [ka] or its enantiomer, mixture of enantiomers, diastereomer, two or more diastereomers A mixture of an asteomer, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, k, and m are each as defined herein.

[0518] In another embodiment, the present description provides a compound of formula C35:

[0519] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0520] In another embodiment, the present description provides a compound of formula C36:

[0521] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0522] In another embodiment, the present description provides a compound of formula C37:

[0523] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0524] In another embodiment, the present description provides a compound of formula C38:

[0525] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0526] In another embodiment, the present description provides a compound of formula C39:

[0527] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0528] In another embodiment, the present specification provides a compound of formula C40:

[0529] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0530] In another embodiment, the present description provides a compound of formula C41:

[0531] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0532] In another embodiment, the present description provides a compound of formula C42:

[0533] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0534] In another embodiment, the present description provides a compound of formula C43:

[0535] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0536] In another embodiment, the present specification provides a compound of formula C44:

[0537] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0538] In another embodiment, the present description provides a compound of formula C45:

[0539] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0540] In another embodiment, the present description provides a compound of formula C46:

[0541] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, and n are each as defined herein.

[0542] In another embodiment, the present description provides a compound of formula C47:

[0543] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0544] In another embodiment, the present specification provides a compound of formula C48:

[0545] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0546] In another embodiment, the present description provides a compound of formula C49:

[0547] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0548] In another embodiment, the present description provides a compound of formula C50:

[0549] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0550] In another embodiment, the present description provides a compound of formula C51:

[0551] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0552] In another embodiment, the present description provides a compound of formula C52:

[0553] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0554] In another embodiment, the present description provides a compound of formula C53:

[0555] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0556] In another embodiment, the present description provides a compound of formula C54:

[0557] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0558] In another embodiment, the present description provides a compound of formula D1:

[0559] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0560] In another embodiment, the present description provides a compound of formula D2:

[0561] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, e and f are each as defined herein.

[0562] In another embodiment, the present description provides a compound of formula D3:

[0563] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, and f are each as defined herein.

[0564] In another embodiment, the present description provides a compound of formula D4:

[0565] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, i, and j are each as defined herein.

[0566] In another embodiment, the present description provides a compound of formula D5:

[0567] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0568] In another embodiment, the present description provides a compound of formula D6:

[0569] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, e, f, g, and h are each as defined herein.

[0570] In another embodiment, the present description provides a compound of formula D7:

[0571] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0572] In another embodiment, the present description provides a compound of formula D8:

[0573] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0574] In another embodiment, the present description provides a compound of formula D9:

[0575] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0576] In another embodiment, the present description provides a compound of formula D10:

[0577] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , where X, Z, c, d, i, and j are each as defined herein.

[0578] In another embodiment, the present description provides a compound of formula D11:

[0579] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0580] In another embodiment, the present description provides a compound of formula D12:

[0581] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0582] In another embodiment, the present description provides a compound of formula D13:

[0583] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0584] In another embodiment, the present description provides a compound of formula D14:

[0585] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0586] In another embodiment, the present description provides a compound of formula D15:

[0587] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0588] In another embodiment, the present description provides a compound of formula D16:

[0589] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0590] In another embodiment, the present description provides a compound of formula D17:

[0591] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0592] In another embodiment, the present description provides a compound of formula D18:

[0593] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0594] In another embodiment, the present description provides a compound of formula D19:

[0595] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0596] In another embodiment, the present description provides a compound of formula D20:

[0597] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0598] In another embodiment, the present description provides a compound of formula D21:

[0599] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0600] In another embodiment, the present description provides a compound of formula D22:

[0601] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0602] In another embodiment, the present description provides a compound of formula D23:

[0603] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0604] In another embodiment, the present description provides a compound of formula D24:

[0605] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0606] In another embodiment, the present description provides a compound of formula D25:

[0607] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0608] In another embodiment, the present description provides a compound of formula D26:

[0609] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0610] In another embodiment, the present description provides a compound of formula D27:

[0611] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0612] In another embodiment, the present description provides a compound of formula D28:

[0613] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0614] In another embodiment, the present description provides a compound of formula D29:

[0615] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , wherein X, Z, c, d, g, and h are each as defined herein.

[0616] In another embodiment, the present description provides a compound of formula D30:

[0617] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0618] In another embodiment, the present description provides a compound of formula D31:

[0619] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0620] In another embodiment, the present description provides a compound of formula D32:

[0621] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0622] In another embodiment, the present description provides a compound of formula D33:

[0623] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, k, and m are each as defined herein.

[0624] In another embodiment, the present description provides a compound of formula D34:

[0625] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, k, and m are each as defined herein.

[0626] In another embodiment, the present description provides a compound of formula D35:

[0627] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0628] In another embodiment, the present description provides a compound of formula D36:

[0629] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, k, and m are each as defined herein.

[0630] In another embodiment, the present description provides a compound of formula D37:

[0631] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0632] In another embodiment, the present description provides a compound of formula D38:

[0633] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0634] In another embodiment, the present description provides a compound of formula D39:

[0635] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0636] In another embodiment, the present description provides a compound of formula D40:

[0637] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , where X, Z, c, d, i, and j are each as defined herein.

[0638] In another embodiment, the present description provides a compound of formula D41:

[0639] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0640] In another embodiment, the present description provides a compound of formula D42:

[0641] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0642] In another embodiment, the present description provides a compound of formula D43:

[0643] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0644] In another embodiment, the present description provides a compound of formula D44:

[0645] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0646] In another embodiment, the present description provides a compound of formula D45:

[0647] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, and n are each as defined herein.

[0648] In another embodiment, the present description provides a compound of formula D46:

[0649] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, j, and n are each as defined herein.

[0650] In another embodiment, the present description provides a compound of formula D47:

[0651] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0652] In another embodiment, the present description provides a compound of formula D48:

[0653] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, h, and n are each as defined herein.

[0654] In another embodiment, the present description provides a compound of formula D49:

[0655] [ka] or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotope or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0656] In another embodiment, the present description provides a compound of formula D50:

[0657] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0658] In another embodiment, the present description provides a compound of formula D51:

[0659] [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, and d are each as defined herein.

[0660] In another embodiment, the present description provides a compound of formula D52:

[0661] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, i, and j are each as defined herein.

[0662] In another embodiment, the present description provides a compound of formula D53:

[0663] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0664] In another embodiment, the present description provides a compound of formula D54:

[0665] [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X, Z, c, d, g, and h are each as defined herein.

[0666] In any one of formulas (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, X is a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —NR1aC(O)N(R1b)—, —S—, or —SS-; in another embodiment, X is a bond; in yet another embodiment, and X is —C(O)O—; in yet another embodiment, X is —C(O)N(R1a)—; in yet another embodiment, X is —C(O)N(H)—; in yet another embodiment, X is —C(O)S—; in yet another embodiment, X is —O—; in yet another embodiment, X is —OC(O)O—; in yet another embodiment, X is —OC(O)N(R1a)—; in yet another embodiment, X is —OC(O)N(H)—; and in yet another embodiment, X is — In yet another embodiment, X is -OC(O)S-; in yet another embodiment, X is -N(R)-; in yet another embodiment, X is -N(H)-; in yet another embodiment, X is -NRC(O)N(R)-; in yet another embodiment, X is -NHC(O)N(H)-; in yet another embodiment, X is -S-; in yet another embodiment, X is -SS-; and in yet another embodiment, X is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -SS-, wherein each R and R are as defined herein.

[0667] In one embodiment, in any one of formulae (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, Z is a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —NR1aC(O)N(R1b)—, —S—, or is -SS-; in another embodiment Z is a bond; in yet another embodiment Z is -C(O)O-; in yet another embodiment Z is -C(O)N(R1a)-; in yet another embodiment Z is -C(O)N(H)-; in yet another embodiment Z is -C(O)S-; in yet another embodiment Z is -O-; in yet another embodiment Z is -OC(O)O-; In yet another embodiment, Z is -OC(O)N(R)-; in yet another embodiment, Z is -OC(O)N(H)-; in yet another embodiment, Z is -OC(O)S-; in yet another embodiment, Z is -N(R)-; in yet another embodiment, Z is -N(H)-; in yet another embodiment, Z is -NRC(O)N(R)-; in yet another embodiment, Z is -NHC(O)N(H)-; in yet another embodiment, Z is -S-; in yet another embodiment, Z is -SS-; and in yet another embodiment, Z is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -SS-, wherein each R and R are as defined herein.

[0668] In some embodiments, in any one of Formulas (II)-(VII), a is an integer of 1. In some embodiments, in any one of Formulas (II)-(VII), a is an integer of 2. In some embodiments, in any one of Formulas (II)-(VII), a is an integer of 3. In some embodiments, in any one of Formulas (II)-(VII), a is an integer of 4. In some embodiments, in any one of Formulas (II)-(VII), a is an integer of 5.

[0669] In some embodiments, in any one of Formulas (II)-(VII), b is an integer of 1. In some embodiments, in any one of Formulas (II)-(VII), b is an integer of 2. In some embodiments, in any one of Formulas (II)-(VII), b is an integer of 3. In some embodiments, in any one of Formulas (II)-(VII), b is an integer of 4. In some embodiments, in any one of Formulas (II)-(VII), b is an integer of 5.

[0670] In any one of formulas (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, c is an integer of 1, in another embodiment, c is an integer of 2, in yet another embodiment, c is an integer of 3, in yet another embodiment, c is an integer of 4, in yet another embodiment, c is an integer of 5, in yet another embodiment, c is an integer of 6, in yet another embodiment, c is an integer of 7, in yet another embodiment, c is an integer of 8, and in yet another embodiment, c is 2, 3, 4, 5, or 6.

[0671] In any one of formulas (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, d is an integer of 1, in another embodiment, d is an integer of 2, in yet another embodiment, d is an integer of 3, in yet another embodiment, d is an integer of 4, in yet another embodiment, d is an integer of 5, in yet another embodiment, d is an integer of 6, in yet another embodiment, d is an integer of 7, in yet another embodiment, d is an integer of 8, and in yet another embodiment, d is 2, 3, 4, 5, or 6.

[0672] In any one of A1 to A6, B1 to B6, C1 to C6, and D1 to D6, in one embodiment, e is an integer of 1, in another embodiment, e is an integer of 2, in yet another embodiment, e is an integer of 3, in yet another embodiment, e is an integer of 4, and in yet another embodiment, e is an integer of 5.

[0673] In any one of A1 to A6, B1 to B6, C1 to C6, and D1 to D6, in one embodiment, f is an integer of 1, in another embodiment, f is an integer of 2, in yet another embodiment, f is an integer of 3, in yet another embodiment, f is an integer of 4, and in yet another embodiment, f is an integer of 5.

[0674] Formula A1, A5~A7, A11~A13, A17~A19, A23~A25, A29~A31, A35~A37, A41~A43, A47~A49, A53, A54, B1, B5~B7, B11~B13, B17~B19, B23~B25, B29~B31, B 35~B37, B41~B43, B47~B49, B53, B54, C1, C5~C7, C11~C13, C17~C19, C2 3~C25, C29~C31, C35~C37, C41~C43, C47~C49, C53, C54, D1, D5~D7, D11~ In any one of D13, D17 to D19, D23 to D25, D29 to D31, D35 to D37, D41 to D43, D47 to D49, D53, and D54, in one embodiment, g is an integer of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in another embodiment, g is an integer of 1; in yet another embodiment, g is an integer of 2; in yet another embodiment, g is an integer of 3; in yet another embodiment, g is an integer of 4; , where g is an integer of 5, and in yet another embodiment g is an integer of 6, and in yet another embodiment g is an integer of 7, and in yet another embodiment g is an integer of 8, and in yet another embodiment g is an integer of 9, and in yet another embodiment g is an integer of 10, and in yet another embodiment g is an integer of 11, and in yet another embodiment g is an integer of 12, and in yet another embodiment g is an integer of 13, and in yet another embodiment g is an integer of 14, and in yet another embodiment g is an integer of 15, and in yet another embodiment g is an integer of 16, and in yet another embodiment g is an integer of 17, and in yet another embodiment g is an integer of 18, and in yet another embodiment g is an integer of 19, and in yet another embodiment g is an integer of 20, and in yet another embodiment g is an integer of 21, and in yet another embodiment g is an integer of 22, and in yet another embodiment g is an integer of 23, and in yet another embodiment g is an integer of 24, and in yet another embodiment g is an integer of 25.

[0675] Formula A1, A5~A7, A11~A13, A17~A19, A23~A25, A29~A31, A35~A37, A41~A43, A 47~A49, A53, A54, B1, B5~B7, B11~B13, B17~B19, B23~B25, B29~B31, B35~ B37, B41~B43, B47~B49, B53, B54, C1, C5~C7, C11~C13, C17~C19, C23~C25 , C29~C31, C35~C37, C41~C43, C47~C49, C53, C54, D1, D5~D7, D11~D13, D1 In any one of D7 to D19, D23 to D25, D29 to D31, D35 to D37, D41 to D43, D47 to D49, D53, and D54, in one embodiment, h is an integer of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in another embodiment, h is an integer of 1; in yet another embodiment, h is an integer of 2; in yet another embodiment, h is an integer of 3; in yet another embodiment, h is an integer of 4; in yet another embodiment, h is an integer of 5; in yet another embodiment, h is an integer of 6; in yet another embodiment, h is an integer of 7; in yet another embodiment, h is an integer of 8; in yet another embodiment, h is an integer of 9; and in yet another embodiment, h is an integer of 10. In yet another embodiment, h is an integer of 11, in yet another embodiment, h is an integer of 12, in yet another embodiment, h is an integer of 13, in yet another embodiment, h is an integer of 14, in yet another embodiment, h is an integer of 15, in yet another embodiment, h is an integer of 16, in yet another embodiment, h is an integer of 17, in yet another embodiment, h is an integer of 18, in yet another embodiment, h is an integer of 19, in yet another embodiment, h is an integer of 20, in yet another embodiment, h is an integer of 21, in yet another embodiment, h is an integer of 22, in yet another embodiment, h is an integer of 23, in yet another embodiment, h is an integer of 24, and in yet another embodiment, h is an integer of 25.

[0676] In any one of formulas A4, A10, A16, A22, A28, A34, A40, A46, A52, B4, B10, B16, B22, B28, B34, B40, B46, B52, C4, C10, C16, C22, C28, C34, C40, C46, ​​C52, D4, D10, D16, D22, D28, D34, D40, D46, and D52, in one embodiment i is an integer of 5, 7, 9, 11, or 13; in another embodiment i is an integer of 1; in yet another embodiment i is an integer of 2; in yet another embodiment i is an integer of 3; , where i is an integer of 4, in yet another embodiment i is an integer of 5, in yet another embodiment i is an integer of 6, in yet another embodiment i is an integer of 7, in yet another embodiment i is an integer of 8, in yet another embodiment i is an integer of 9, in yet another embodiment i is an integer of 10, in yet another embodiment i is an integer of 11, in yet another embodiment i is an integer of 12, in yet another embodiment i is an integer of 13, in yet another embodiment i is an integer of 14, and in yet another embodiment i is an integer of 15.

[0677] In any one of formulas A4, A10, A16, A22, A28, A34, A40, A46, A52, B4, B10, B16, B22, B28, B34, B40, B46, B52, C4, C10, C16, C22, C28, C34, C40, C46, ​​C52, D4, D10, D16, D22, D28, D34, D40, D46, and D52, in one embodiment j is an integer of 5, 7, 9, 11, or 13; in another embodiment j is an integer of 1; in yet another embodiment j is an integer of 2; in yet another embodiment j is an integer of 3; , where j is an integer of 4, in yet another embodiment j is an integer of 5, in yet another embodiment j is an integer of 6, in yet another embodiment j is an integer of 7, in yet another embodiment j is an integer of 8, in yet another embodiment j is an integer of 9, in yet another embodiment j is an integer of 10, in yet another embodiment j is an integer of 11, in yet another embodiment j is an integer of 12, in yet another embodiment j is an integer of 13, in yet another embodiment j is an integer of 14, and in yet another embodiment j is an integer of 15.

[0678] In any one of formulas A31 to A36, B31 to B36, C31 to C36, and D31 to D36, in one embodiment, k is an integer of 1, in another embodiment, k is an integer of 2, in yet another embodiment, k is an integer of 3, and in yet another embodiment, k is In yet another embodiment, k is an integer equal to 4; in yet another embodiment, k is an integer equal to 5.

[0679] In any one of formulas A31 to A36, B31 to B36, C31 to C36, and D31 to D36, in one embodiment, m is an integer of 1, in another embodiment, m is an integer of 2, in yet another embodiment, m is an integer of 3, in yet another embodiment, m is an integer of 4, and in yet another embodiment, m is an integer of 5.

[0680] In any one of formulas A43 to A48, B43 to B48, C43 to C48, and D43 to D48, in one embodiment, n is an integer of 1, in another embodiment, n is an integer of 2, in yet another embodiment, n is an integer of 3, in yet another embodiment, n is an integer of 4, in yet another embodiment, n is an integer of 5, and in yet another embodiment, n is an integer of 6.

[0681] In the formulae described herein, including formulae (I)-(VII), A1-A54, B1-B54, C1-C54, and D1-D54, each of the groups R1, R2, R3, R4, A, E, L1, L2, L3, L4, U, X, Z, a, b, c, and d is further defined in the embodiments described herein. For each group in these formulae described herein, including R1, R2, R3, R4, A, E, L1, L2, L3, L4, U, X, Z, a, b, c, d, e, f, g, h, i, j, k, m, n, p, s, and t, all combinations of these embodiments of the present application are within the scope of the present disclosure.

[0682] In yet another embodiment, the present application provides a compound of Formula E-1-0001 to E-1-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0683] In yet another embodiment, the present application provides a compound of Formula E-2-0001 to E-2-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0684] In yet another embodiment, the present application provides a compound of Formula E-3-0001 to E-3-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0685] In yet another embodiment, the present application provides a compound of Formula E-4-0001 to E-4-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0686] In some embodiments, R is hydrogen. In some embodiments, R is C alkyl optionally substituted with one or more substituents Q. In some embodiments, R is C alkyl optionally substituted with one, two, or three substituents Q, each Q independently being selected from the group consisting of (i) cyano, halogen, and nitro; (ii) C cycloalkyl, C aryl, each optionally substituted with one or more substituents Q. , heteroaryl, or heterocyclyl; or (iii) —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —ORa, —NRbRc, —NRaC(O)NRbRc, —NRaC(NRd)NRbRc, —NRaC(S)NRbRc, ═NORa, —SRa, or —NRaS(O)Rd, where each Ra, Rb, Rc, and Rd is as defined herein. In some embodiments, R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In some embodiments, R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.In some embodiments, R1 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethyl ... (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0687] In some embodiments, R1 is C1-6 heteroalkyl optionally substituted with one or more substituents Q. In some embodiments, R1 is C2-6 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R1 is 1-(dimethylamino)-2-nitrovinyl. In some embodiments, R1 is C2-6 alkynyl optionally substituted with one or more substituents Q. In some embodiments, R1 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R1 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, R1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl. In some embodiments, R1 is C6-14 aryl optionally substituted with one or more substituents Q. In some embodiments, R1 is 4-dimethylaminophenyl. In some embodiments, R1 is C7-15 aralkyl optionally substituted with one or more substituents Q. In some embodiments, R1 is 4-methoxybenzyl. In some embodiments, R1 is heteroaryl optionally substituted with one or more substituents Q. In some embodiments, R1 is and R1 is a monocyclic heteroaryl optionally substituted with one or more substituents Q above. In some embodiments, R1 is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R1 is an imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In some embodiments, R1 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl. In some embodiments, R1 is a heterocyclyl optionally substituted with one or more substituents Q. In some embodiments, R1 is a monocyclic heterocyclyl optionally substituted with one or more substituents Q.

[0688] In some embodiments, R is —C(O)R, where R is as defined herein. In some embodiments, R is —C(O)—C alkyl, where the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R is —C(O)—C alkyl, where the alkyl is optionally substituted with —OR, and R is as defined herein. In some embodiments, R is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, R is —C(O)OR, where R is as defined herein. In some embodiments, R is —C(O)OC alkyl, where the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R is methoxycarbonyl. In some embodiments, R is —C(O)NRR, where R and R are each as defined herein. In some embodiments, R1 is methylaminocarbonyl or dimethylaminocarbonyl. In some embodiments, R1 is —C(O)SR1a, where R1a is as defined herein. In some embodiments, R1 is —C(NR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is carbamimidoyl. In some embodiments, R1 is —C(NCN)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is N′-cyano-N,N-dimethylcarbamimidoyl. In some embodiments, R1 is —C(NOR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is N′-methoxy-N,N-dimethylcarbamimidoyl. In some embodiments, R is -C(NS(O)R)NR, where R, R, and R are each as defined herein. In some embodiments, R is N'-methylsulfonyl-N,N-dimethyl-carbamimidoyl.In some embodiments, R1 is -C(S)R1a, where R1a is as defined herein. In some embodiments, R1 is -C(S)OR1a, where R1a is as defined herein. In some embodiments, R1 is -C(S)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is methylaminothiocarbonyl or dimethylaminothiocarbonyl. In some embodiments, R1 is -OR1a, where R1a is as defined herein. In some embodiments, R1 is hydroxy or methoxy. In some embodiments, R1 is methoxy. In some embodiments, R1 is -OC(O)R1a, where R1a is as defined herein. In some embodiments, R1 is -OC(O)OR1a, where R1a is as defined herein. In some embodiments, R1 is -OC(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is -OC(O)SR1a, where R1a is as defined herein. In some embodiments, R1 is -OC(NR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is -OC(S)R1a, where R1a is as defined herein. In some embodiments, R1 is -OC(S)OR1a, where R1a is as defined herein. In some embodiments, R1 is -OC(S)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is -OS(O)R1a, where R1a is as defined herein. In some embodiments, R1 is -OS(O)2R1a, where R1a is as defined herein. In some embodiments, R1 is -OS(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is -OS(O)2NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is -NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is -NR1aC(O)R1d, where R1a and R1d are each as defined herein. In some embodiments, R1 is -NR1aC(O)OR1d, where R1a and R1d are each as defined herein. In some embodiments, R1 is -NR1aC(O)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is -NR1aC(O)SR1d, where R1a and R1d are each as defined herein. In some embodiments, R1 is -NR1aC(NR1d)NR1bR1c, where R1a, R1b, R1c, and R1d are each as defined herein. In some embodiments, R1 is -NR1aC(S)R1d, where R1a and R1d are each as defined herein. In some embodiments, R1 is -NR1aC(S)OR1d, where R1a and R1d are each as defined herein. In some embodiments, R1 is -NR1aC(S)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is -NR1aS(O)R1d, where R1a and R1d are each as defined herein.In some embodiments, R1 is -NR1aS(O)2R1d, where R1a and R1d are each as defined herein. In some embodiments, R1 is -NR1aS(O)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is -NR1aS(O)2NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R1 is -S(O)R1a, where R1a is as defined herein. In some embodiments, R1 is -S(O)2R1a, where R1a is as defined herein. In some embodiments, R1 is methylsulfonyl. In some embodiments, R1 is -S(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R1 is -S(O)2NR1bR1c, where R1b and R1c are each as defined herein.

[0689] In some embodiments, R2 is hydrogen. In some embodiments, R2 is C1-6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R2 is C1-6 alkyl optionally substituted with one, two, or three substituents Q, where each Q is independently (i) cyano, halogen, or nitro; (ii) C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Qa; or (iii) -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -ORa, -NRbRc, -NRaC(O)NRbRc, -NRaC(NRd)NRbRc, -NRaC(S)NRbRc, =NORa, -SRa, or -NRaS(O)2Rd, where each Ra, Rb, Rc, and Rd is as defined herein. In some embodiments, R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, or methyl. In some embodiments, R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, and each Q is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido. In some embodiments, R2 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethyl ... (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0690] In some embodiments, R2 is C1-6 heteroalkyl optionally substituted with one or more substituents Q. In some embodiments, R2 is C2-6 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R2 is 1-(dimethylamino)-2-nitrovinyl. In some embodiments, R2 is C2-6 alkynyl optionally substituted with one or more substituents Q. In some embodiments, R2 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R2 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R2 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q. In some embodiments, R2 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl. In some embodiments, R2 is C6-14 aryl, optionally substituted with one or more substituents Q. In some embodiments, R2 is 4-dimethylaminophenyl. In some embodiments, R2 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In some embodiments, R2 is 4-methoxybenzyl. In some embodiments, R2 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R2 is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R2 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q. In some embodiments, R2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl. In some embodiments, R2 is heterocyclyl optionally substituted with one or more substituents Q.In some embodiments, R2 is monocyclic heterocyclyl optionally substituted with one or more substituents Q.

[0691] In some embodiments, R2 is —C(O)R1a, where R1a is as defined herein. In some embodiments, R2 is —C(O)—C1-6 alkyl, where the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R2 is —C(O)—C1-6 alkyl, where the alkyl is optionally substituted with —ORa, where R1 is as defined herein. In some embodiments, R2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In some embodiments, R2 is —C(O)OR1a, where R1a is as defined herein. In some embodiments, R2 is —C(O)OC1-6 alkyl, where the alkyl is optionally substituted with one or more substituents Q. In some embodiments, R2 is methoxycarbonyl. In some embodiments, R2 is —C(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is methylaminocarbonyl or dimethylaminocarbonyl. In some embodiments, R2 is —C(O)SR1a, where R1a is as defined herein. In some embodiments, R2 is —C(NR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is carbamimidoyl. In some embodiments, R2 is —C(NCN)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is N′-cyano-N,N-dimethylcarbamimidoyl. In some embodiments, R2 is —C(NOR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is N′-methoxy-N,N-dimethylcarbamimidoyl. In some embodiments, R2 is -C(NS(O2)R1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is N'-methylsulfonyl-N,N-dimethyl-carbamimidoyl.In some embodiments, R2 is -C(S)R1a, where R1a is as defined herein. In some embodiments, R2 is -C(S)OR1a, where R1a is as defined herein. In some embodiments, R2 is -C(S)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is methylaminothiocarbonyl or dimethylaminothiocarbonyl. In some embodiments, R2 is -OR1a, where R1a is as defined herein. In some embodiments, R2 is hydroxy or methoxy. In some embodiments, R2 is methoxy. In some embodiments, R2 is -OC(O)R1a, where R1a is as defined herein. In some embodiments, R2 is -OC(O)OR1a, where R1a is as defined herein. In some embodiments, R2 is -OC(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is -OC(O)SR1a, where R1a is as defined herein. In some embodiments, R2 is -OC(NR1a)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is -OC(S)R1a, where R1a is as defined herein. In some embodiments, R2 is -OC(S)OR1a, where R1a is as defined herein. In some embodiments, R2 is -OC(S)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is -OS(O)R1a, where R1a is as defined herein. In some embodiments, R2 is -OS(O)2R1a, where R1a is as defined herein. In some embodiments, R2 is -OS(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is -OS(O)2NR1bR1c, where R1b and R1c are each as defined herein. and R1c are each as defined herein. In some embodiments, R2 is -NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is -NR1aC(O)R1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aC(O)OR1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aC(O)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is -NR1aC(O)SR1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aC(NR1d)NR1bR1c, where R1a, R1b, R1c, and R1d are each as defined herein. In some embodiments, R2 is -NR1aC(S)R1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aC(S)OR1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aC(S)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is -NR1aS(O)R1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aS(O)2R1d, where R1a and R1d are each as defined herein. In some embodiments, R2 is -NR1aS(O)NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is -NR1aS(O)2NR1bR1c, where R1a, R1b, and R1c are each as defined herein. In some embodiments, R2 is -S(O)R1a, where R1a is as defined herein. In some embodiments, R2 is -S(O)2R1a, where R1a is as defined herein. In some embodiments, R2 is methylsulfonyl.In some embodiments, R2 is -S(O)NR1bR1c, where R1b and R1c are each as defined herein. In some embodiments, R2 is -S(O)2NR1bR1c, where R1b and R1c are each as defined herein.

[0692] In some embodiments, R1 and R2, together with the N atom to which they are attached, form a heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 5-membered heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 6-membered heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 1,2,3-triazol-1-yl, pyridin-1-iumyl, or pyrimidin-1-yl, each optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

[0693] In some embodiments, R1 and R2, together with the N atom to which they are attached, form a bicyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a bicyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 5,5-, 5,6-, or 6,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 5,5-fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 5,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 6,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a purin-9-yl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 6-aminopurin-9-yl or 2-amino-6-oxo-1,9-dihydropurin-9-yl.

[0694] In some embodiments, R1 and R2, together with the N atom to which they are attached, form a heterocyclyl that is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a monocyclic heterocyclyl that is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 3-membered heterocyclyl that is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 4-membered heterocyclyl that is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 5-membered heterocyclyl that is optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form a 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R1 and R2, together with the N atom to which they are attached, form an aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, oxazolidinon-3-yl, imidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, piperazin-1-yl, or isoindolin-2-yl, each of which is optionally substituted with one or more substituents Q.In some embodiments, R and R, together with the N atom to which they are attached, form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(4-methoxybenzyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or 1,3-dioxoisoindolin-2-yl.

[0695] In some embodiments, R3 is C1-30 alkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is C1-25 alkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is C1-20 alkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, or the like, each optionally substituted with one or more substituents Q. The alkyl group may be cyclohexyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl. In some embodiments, R3 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0696] In some embodiments, R3 is C1-30 heteroalkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is 2-(dodec-1-yldisulfanyl)ethyl. In some embodiments, R3 is C1-30 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R3 is C1-25 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R3 is C1-20 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R3 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, or pentacosenyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R3 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen- 1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-henedecen-1-yl, (8Z,11Z)-heptadecene-8,11-dien-1-yl, (9Z,12Z)-octadecane-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadecene-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadecene-8,11,14-trien-1-yl.

[0697] In some embodiments, R3 is C2-30 alkynyl optionally substituted with one or more substituents Q. In some embodiments, R3 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is cyclohexyl optionally substituted with one or more substituents Q. In some embodiments, R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl. In some embodiments, R3 is C6-14 aryl optionally substituted with one or more substituents Q. In some embodiments, R3 is phenyl optionally substituted with one or more substituents Q. In some embodiments, R3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl. In some embodiments, R3 is C7-30 aralkyl optionally substituted with one or more substituents Q. In some embodiments, R3 is heteroaryl optionally substituted with one or more substituents Q. In some embodiments, R3 is heterocyclyl optionally substituted with one or more Q substituents.

[0698] In some embodiments, R4 is a C1- optionally substituted with one or more substituents Q. In some embodiments, R4 is C1-25 alkyl optionally substituted with one or more substituents Q. In some embodiments, R4 is C1-20 alkyl optionally substituted with one or more substituents Q. In some embodiments, R4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each optionally substituted with one or more substituents Q. In some embodiments, R4 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

[0699] In some embodiments, R4 is C1-30 heteroalkyl optionally substituted with one or more substituents Q. In some embodiments, R4 is 2-(dodec-1-yldisulfanyl)ethyl. In some embodiments, R4 is C1-30 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R4 is C1-25 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R4 is C1-20 alkenyl optionally substituted with one or more substituents Q. In some embodiments, R4 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, or pentacosenyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R4 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen- 1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-henedecen-1-yl, (8Z,11Z)-heptadecene-8,11-dien-1-yl, (9Z,12Z)-octadecane-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadecene-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadecene-8,11,14-trien-1-yl.

[0700] In some embodiments, R4 is C2-30 alkynyl optionally substituted with one or more substituents Q. In some embodiments, R4 is C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R4 is monocyclic C3-10 cycloalkyl optionally substituted with one or more substituents Q. In some embodiments, R4 is cyclohexyl optionally substituted with one or more substituents Q. In some embodiments, R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl. In some embodiments, R4 is C6-14 aryl optionally substituted with one or more substituents Q. In some embodiments, R4 is phenyl optionally substituted with one or more substituents Q. In some embodiments, R4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentyl In some embodiments, R4 is phenyl. In some embodiments, R4 is C7-30 aralkyl optionally substituted with one or more substituents Q. In some embodiments, R4 is heteroaryl optionally substituted with one or more substituents Q. In some embodiments, R4 is heterocyclyl optionally substituted with one or more substituents Q.

[0701] In some embodiments, A is -O-. In some embodiments, A is -N(R1a)-, where R1a is as defined herein. In some embodiments, A is -N(H)-.

[0702] In some embodiments, E is -UC(O)N(R)-, where R and U are each as defined herein. In some embodiments, E is -OC(O)N(R)-, where R is as defined herein. In some embodiments, E is -OC(O)N(H)-. In some embodiments, E is -N(R)C(O)N(R)-, where R and R are each as defined herein. In some embodiments, E is -N(H)C(O)N(H)-.

[0703] In some embodiments, L1 is a C1-6 alkylene group optionally substituted with one or more substituents Q. In some embodiments, L1 is -(CR2aR2b)a-, where each R2a, R2b, and a is as defined herein. In some embodiments, L1 is -(CH2)a-, where a is as defined herein. In some embodiments, L1 is -(CH2)-. In some embodiments, L1 is -(CH2)2-. In some embodiments, L1 is -(CH2)3-. In some embodiments, L1 is -(CH2)4-. In some embodiments, L1 is -(CH2)5-. In some embodiments, L1 is -(CH2)6-.

[0704] In some embodiments, L2 is a C1-6 alkylene group optionally substituted with one or more substituents Q. In some embodiments, L2 is -(CR2aR2b)b-, where each R2a, R2b, and b is as defined herein. In some embodiments, L2 is -(CH2)b-, where b is as defined herein. In some embodiments, L2 is -(CH2)-. In some embodiments, L2 is -(CH2)2-. In some embodiments, L2 is -(CH2)3-. In some embodiments, L2 is -(CH2)4-. In some embodiments, L2 is -(CH2)5-. In some embodiments, L2 is -(CH2)6-.

[0705] In some embodiments, L3 is a C1-10 alkylene group optionally substituted with one or more substituents Q. In some embodiments, L3 is -(CR2aR2b)c-, where each R2a, R2b, and c are as defined herein. In some embodiments, L3 is -(CH2)c-, where c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, L3 is -(CH2)2-. In some embodiments, L3 is -(CH2)3-. In some embodiments, L3 is -(CH2)4-. In some embodiments, L3 is -(CH2)5-. In some embodiments, L3 is -(CH2)6-. In some embodiments, L3 is a C1-10 heteroalkylene group optionally substituted with one or more substituents Q. In some embodiments, L3 is a C2-10 alkenylene group optionally substituted with one or more substituents Q. In some embodiments, L3 is a C2-10 alkynylene group optionally substituted with one or more Q substituents.

[0706] In some embodiments, L4 is a C1-10 alkylene group optionally substituted with one or more substituents Q. In some embodiments, L4 is -(CR2aR2b)d-, where each R2a, R2b, and d is as defined herein. In embodiments, L4 is -(CH2)d-, where d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, L4 is -(CH2)2-. In some embodiments, L4 is -(CH2)3-. In some embodiments, L4 is -(CH2)4-. In some embodiments, L4 is -(CH2)5-. In some embodiments, L4 is -(CH2)6-. In some embodiments, L4 is a C1-10 heteroalkylene group optionally substituted with one or more substituents Q. In some embodiments, L4 is a C2-10 alkenylene group optionally substituted with one or more substituents Q. In some embodiments, L4 is a C2-10 alkynylene group optionally substituted with one or more substituents Q.

[0707] In some embodiments, U is -O-. In some embodiments, U is -N(R1a)-, where R1a is as defined herein. In some embodiments, U is -N(H)-.

[0708] In some embodiments, X is a bond. In some embodiments, X is —C(O)O—. In some embodiments, X is —C(O)N(R)—, where R is as defined herein. In some embodiments, X is —C(O)N(H)—. In some embodiments, X is —C(O)S—. In some embodiments, X is —O—. In some embodiments, X is —OC(O)O—. In some embodiments, X is —OC(O)N(R)—. In some embodiments, X is —OC(O)N(H)—. In some embodiments, X is —OC(O)S—. In some embodiments, X is —N(R)—, where R is as defined herein. In some embodiments, X is —N(H)—. In some embodiments, X is —NRC(O)N(R)—, where R and R are each as defined herein. In some embodiments, X is -NHC(O)N(H)-. In some embodiments, X is -S-. In some embodiments, X is -SS-.

[0709] In some embodiments, Z is a bond. In some embodiments, Z is —C(O)O—. In some embodiments, Z is —C(O)N(R)—, where R is as defined herein. In some embodiments, Z is —C(O)N(H)—. In some embodiments, Z is —C(O)S—. In some embodiments, Z is —O—. In some embodiments, Z is —OC(O)O—. In some embodiments, Z is —OC(O)N(R)—. In some embodiments, Z is —OC(O)N(H)—. In some embodiments, Z is —OC(O)S—. In some embodiments, Z is —N(R)—, where R is as defined herein. In some embodiments, Z is —N(H)—. In some embodiments, Z is —NRC(O)N(R)—, where R and R are each as defined herein. In some embodiments, Z is -NHC(O)N(H)-. In some embodiments, Z is -S-. In some embodiments, Z is -SS-.

[0710] In some embodiments, a is an integer equal to 1. In some embodiments, a is an integer equal to 2. In some embodiments, a is an integer equal to 3. In some embodiments, a is an integer equal to 4. In some embodiments, a is an integer equal to 5. In some embodiments, a is an integer equal to 6.

[0711] In some embodiments, b is an integer equal to 1. In some embodiments, b is an integer equal to 2. In some embodiments, b is an integer equal to 3. In some embodiments, b is an integer equal to 4. In some embodiments, b is an integer equal to 5. In some embodiments, Now, b is an integer equal to 6.

[0712] In some embodiments, c is an integer equal to 1. In some embodiments, c is an integer equal to 2. In some embodiments, c is an integer equal to 3. In some embodiments, c is an integer equal to 4. In some embodiments, c is an integer equal to 5. In some embodiments, c is an integer equal to 6. In some embodiments, c is an integer equal to 7. In some embodiments, c is an integer equal to 8. In some embodiments, c is an integer equal to 9. In some embodiments, c is an integer equal to 10.

[0713] In some embodiments, d is an integer equal to 1. In some embodiments, d is an integer equal to 2. In some embodiments, d is an integer equal to 3. In some embodiments, d is an integer equal to 4. In some embodiments, d is an integer equal to 5. In some embodiments, d is an integer equal to 6. In some embodiments, d is an integer equal to 7. In some embodiments, d is an integer equal to 8. In some embodiments, d is an integer equal to 9. In some embodiments, d is an integer equal to 10.

[0714] In one embodiment, the present disclosure provides a compound: 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyldihexanoate 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyldihexanoate 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)carbamoyl)oxy)heptane-1,7-diyldihexanoate 3; 4-(3-(2-((2-(dimethylamino)ethyl)amino)ethyl)-ureido)heptane-1,7-diyldihexanoate 4; or 7-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)tridecane-1,13-diyl-bis(2-hexyldecanoate)5; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0715] In some embodiments, the compounds provided herein are isolated or purified, ie, the purity of the compounds provided herein is at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.

[0716] The compounds provided herein are intended to include all possible stereoisomers unless a particular stereochemistry is specified. When compounds of the present application contain an alkenyl group, the compounds may exist as one or a mixture of cis / trans (or Z / E) isomers. When structural isomers are interconvertible, the compounds may exist as a single tautomer or a mixture of tautomers. This can take the form of, for example, proton tautomerism in compounds containing imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. Thus, a single compound may exhibit multiple types of isomers.

[0717] The compounds provided by the present application may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or a stereoisomeric mixture, such as a mixture of enantiomers, such as a racemic mixture of two enantiomers, or a mixture of two or more diastereomers. Thus, those skilled in the art will understand that for compounds that undergo diastereoisomerization in vivo, administering the compound in the (R) form is equivalent to administering the compound in the (S) form. Conventional techniques for preparing / isolating single enantiomers include synthesis from appropriate optically pure precursors, asymmetric synthesis from non-chiral starting materials, and the like. or resolution of enantiomeric mixtures such as chiral chromatography, recrystallization, resolution, formation of diastereomeric salts, or derivatization to diastereomeric adducts followed by separation.

[0718] When the compounds provided in this application contain an acidic or basic moiety, they may be provided as pharmaceutically acceptable salts. Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical See Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0719] Suitable acids for preparing pharmaceutically acceptable salts of the compounds of the present application include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfonamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-ketobenzoic acid, ... These include, but are not limited to, glutaric 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-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0720] Suitable bases for preparing pharmaceutically acceptable salts of the compounds of the present application include inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, sodium hydroxide, and the like; and organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines (L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N- The hydroxybenzoates include, but are not limited to, methylglucamine, 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.

[0721] 8.3 Lipid nanoparticles In one embodiment, the present specification provides a lipid nanoparticle comprising a compound of the present application, 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. Particles are provided.

[0722] In another embodiment, the present specification provides lipid nanoparticles comprising: (i) a compound of the present application, 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.

[0723] In yet another embodiment, the present specification provides lipid nanoparticles comprising (i) a nucleic acid and (ii) a compound of the present application, 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.

[0724] In yet another embodiment, the present specification provides lipid nanoparticles comprising: (i) a nucleic acid; (ii) a compound of the present application, 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.

[0725] In some embodiments, the lipid nanoparticles described herein further comprise a conjugated lipid. In some embodiments, the conjugated lipid comprises a polyethylene glycol (PEG)-conjugated lipid. In some embodiments, the conjugated lipid is a PEG-conjugated lipid.

[0726] Thus, in one embodiment, the present specification provides lipid nanoparticles comprising: (i) a compound of the present application, 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.

[0727] In another embodiment, the present specification provides lipid nanoparticles comprising: (i) a nucleic acid; (ii) a compound of the present application, 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.

[0728] In some embodiments, the nucleic acid is DNA. In some embodiments, the nucleic acid is RNA. In some embodiments, the nucleic acid is mRNA. In some embodiments, the nucleic acid is a circular nucleic acid. In some embodiments, the...

Claims

1. A compound of formula (I) 【Chemistry 1】 wherein R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a )NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR 1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a , -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1 aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR 1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c or —S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-40 alkyl, C1-40 heteroalkyl, C2-40 alkenyl, C2-40 heteroalkenyl, C2-40 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-20 alkylene group, a C1-20 heteroalkylene group, a C2-20 alkenylene group, or a C2-20 alkynylene group; A is —O— or —N(R1a)—; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —S—S—; and each R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; Here, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, aryl Each of the aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C heteroalkyl, C alkenyl, C alkynyl, C cycloalkyl, C aryl, C aralkyl, heteroaryl, each of which is optionally further substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa; and heterocyclyl; 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)NRbR c, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -N RbRc, —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)Rd, —NRaS(O)NRbRc, —NRaS(O)NRbRc, ═NORa, —SRa, —S(O)Ra, —S(O)Ra, —S(O)NRbRc, and —S(O)NRbRc, wherein each Ra, Rb, Rc, and Rd is, independently: (i) hydrogen or deuterium; hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form a heterocyclyl optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Qa; Each Qa is independently (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. R1 and R2 are each independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)N R1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c , -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1a C(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1 aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c or —S(O)2NR1bR1c; or R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl; R3 and R4 are each independently C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-30 aralkyl, heteroaryl, or heterocyclyl; L1 and L2 are each independently a C1-6 alkylene group or a C1-6 heteroalkylene group; L3 and L4 are each independently a C1-10 alkylene group, a C1-10 heteroalkylene group, a C2-10 alkenylene group, or a C2-10 alkynylene group; A is —O— or —N(R1a)—; E is -UC(O)N(R1a)-, where U is -O- or -N(R1b)-; X and Z are each independently a bond, —C(O)O—, —C(O)N(R1a)—, —C(O)S—, —O—, —OC(O)O—, —OC(O)N(R1a)—, —OC(O)S—, —N(R1a)—, —NR1aC(O)N(R1b)—, —S—, or —S—S—; and each R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each of alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, and wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C alkyl, C heteroalkyl, each of which is optionally further substituted with one or more, and in one embodiment, one, two, three, or four, substituents Qa; , C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; 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, -N RaC(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)2NR bRc, =NORa, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc and -S(O)2NRbRc (where each Ra, Rb, Rc and Rd are each independently selected from (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 optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Qa; Each Qa is independently (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re , -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O )Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, - NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, =NORe, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg and -S(O) 2NRfRg, where Re, Rf, Rg, and Rh are each independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl. The compound of claim 1.

3. The compound according to claim 1, wherein L1 is C1-6 alkylene optionally substituted with one or more substituents Q.

4. The compound according to claim 1 or 2, wherein L1 is -(CR2aR2b)a-, R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form a C3-10 cycloalkyl optionally substituted with one or more substituents Q, and a is an integer of 1, 2, 3, 4, 5, or 6.

5. The compound according to any one of claims 1 to 4, wherein L1 is -(CH2)a-.

6. The compound according to any one of claims 1 to 5, wherein L2 is C1-6 alkylene optionally substituted with one or more substituents Q.

7. The compound according to any one of claims 1 to 6, wherein L2 is -(CR2aR2b)b-, R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form a C3-10 cycloalkyl optionally substituted with one or more substituents Q, and b is an integer of 1, 2, 3, 4, 5, or 6.

8. The compound according to any one of claims 1 to 7, wherein L2 is -(CH2)b-.

9. The compound according to any one of claims 1 to 8, wherein L3 is C1-10 alkylene optionally substituted with one or more substituents Q.

10. The compound according to any one of claims 1 to 9, wherein L3 is -(CR2aR2b)c-, R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form a C3-10 cycloalkyl optionally substituted with one or more substituents Q, and c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

11. The compound according to any one of claims 1 to 10, wherein L3 is -(CH2)c-.

12. The compound according to any one of claims 1 to 11, wherein L4 is C1-10 alkylene optionally substituted with one or more substituents Q.

13. The compound according to any one of claims 1 to 12, wherein L4 is -(CR2aR2b)d-, R2a and R2b are each independently (i) hydrogen, or (ii) C1-6 alkyl optionally substituted with one or more substituents Q, or R2a and R2b together with the C atom to which they are attached form a C3-10 cycloalkyl optionally substituted with one or more substituents Q, and d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

14. The compound according to any one of claims 1 to 13, wherein L4 is -(CH2)d-.

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

16. The compound of any one of claims 1 to 15, wherein E is -OC(O)N(R1a)-.

17. The compound of any one of claims 1 to 16, wherein E is -OC(O)N(H)-.

18. The compound of any one of claims 1 to 15, wherein E is -NR1aC(O)N(R1b)-.

19. 19. The compound of any one of claims 1 to 15 and 18, wherein E is -NHC(O)N(H)-.

20. A structure of formula (III): 【Transformation 3】 (Wherein, U is —O— or —N(R1a)—) or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

21. The compound of any one of claims 1 to 20, wherein A is -O-.

22. The compound of any one of claims 1 to 20, wherein A is -N(R1a)-.

23. 23. The compound of any one of claims 1 to 20 and 22, wherein A is -N(H)-.

24. The compound of any one of claims 15 to 23, wherein U is -O-.

25. The compound of any one of claims 15 to 23, wherein U is -N(R1a)-.

26. 26. The compound of any one of claims 15 to 23 and 25, wherein U is -N(H)-.

27. A structure of formula (IV): 【Chemistry 4】 21. The compound of claim 15 or 20, having the formula: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

28. A structure of formula (V): 【Transformation 5】 21. The compound of claim 15 or 20, having the formula: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

29. A structure of formula (VI): 【Transformation 6】 21. The compound of claim 15 or 20, having the formula: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

30. A structure of formula (VII): 【Transformation 7】 21. The compound of claim 15 or 20, having the formula: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

31. The compound according to any one of claims 4 to 30, wherein a is an integer of 2.

32. The compound according to any one of claims 7 to 31, wherein b is an integer of 2.

33. R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)NR1bR1c, —C(NCN)NR1bR1c, —C(NOR1a)NR1bR1c, —C(NS(O2)R1a)NR1bR1c, —C(S)R1a, —C(S)OR1a, —C(S)N R1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1b R1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, The compound according to any one of claims 1 to 32, which is -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c.

34. 34. The compound of any one of claims 1 to 33, wherein R1 is (i) C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)NR1bR1c, -OR1a, or -S(O)2R1a.

35. R1 is methyl, (E)-1-(dimethylamino)-2-nitrovinyl, (Z)-1-(dimethylamino)-2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, or ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxy) (imino)butyl, 5-hydroxypentyl, 6-hydroxyhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 2-dimethylamino-3,4-dioxo-1-cyclobutenyl, 4-dimethylaminophenyl, 4-methoxybenzyl, imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, isopropionyl , methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, carbamimidoyl, methylaminothiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylcarbamimidoyl, (Z)-N'-cyano-N,N-dimethylcarbamimidoyl, (E)-N'-methoxy-N,N-dimethylcarbamimidoyl, (Z)-N'-methoxy-N,N-dimethylcarbamimidoyl, (E)-N'-methylsulfonyl-N,N-dimethylcarbamimidoyl, (Z)-N'-methylsulfonyl-N,N-dimethylcarbamimidoyl,The compound according to any one of claims 1 to 34, which is N-dimethylcarbamimidoyl, hydroxy, methoxy, or methylsulfonyl.

36. The compound according to any one of claims 1 to 34, wherein R1 is a C1-6 alkyl group optionally substituted with one or more substituents Q.

37. The compound of any one of claims 1 to 34 and 36, wherein R1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

38. R2 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, — C(O)SR1a, -C(NR1a)NR1bR1c, -C(NCN)NR1bR1c, -C(NOR1a)NR1bR1c, -C(NS(O2)R1a)NR1bR1c, -C(S)R1a, - C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1 c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, - NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(NR1d)NR1bR1c, -NR The compound according to any one of claims 1 to 37, which is 1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c or -S(O)2NR1bR1c.

39. The compound of any one of claims 1 to 38, wherein R2 is (i) hydrogen; (ii) C1-6 alkyl optionally substituted with one or more substituents Q; or (iii) -C(O)R1a or -C(O)OR1a.

40. 40. The compound of any one of claims 1 to 39, wherein R2 is hydrogen, methyl, ethyl, isopropyl, acetyl, or methoxycarbonyl.

41. The compound of any one of claims 1 to 40, wherein R2 is hydrogen, methyl, ethyl, or isopropyl.

42. 33. The compound of any one of claims 1 to 32, wherein R1 and R2 together with the N atom to which they are attached form a heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

43. 43. The compound according to any one of claims 1 to 32 and 42, wherein R1 and R2 together with the N atom to which they are attached form a heteroaryl optionally substituted with one or more substituents Q.

44. The compound according to any one of claims 1 to 32, 42 and 43, wherein R1 and R2 together with the N atom to which they are attached form a monocyclic heteroaryl, optionally substituted with one or more substituents Q.

45. The compound according to any one of claims 1 to 32 and 42 to 44, wherein R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heteroaryl optionally substituted with one or more substituents Q.

46. The compound according to any one of claims 1 to 32 and 42 to 45, wherein R1 and R2 together with the N atom to which they are attached form 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

47. The compound according to any one of claims 1 to 32 and 42 to 43, wherein R1 and R2 together with the N atom to which they are attached form a bicyclic heteroaryl, optionally substituted with one or more substituents Q.

48. The compound according to any one of claims 1 to 32, 42 to 43 and 47, wherein R1 and R2, together with the N atom to which they are attached, form a 5,5-, 5,6-, or 6,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q.

49. The compound according to any one of claims 1 to 32, 42 to 43 and 47 to 48, wherein R1 and R2 together with the N atom to which they are attached form 6-aminopurin-9-yl or 2-amino-6-oxo-1,9-dihydropurin-9-yl.

50. 43. The compound according to any one of claims 1 to 32 and 42, wherein R1 and R2 together with the N atom to which they are attached form a heterocyclyl optionally substituted with one or more substituents Q.

51. The compound according to any one of claims 1 to 32, 42 and 50, wherein R1 and R2 together with the N atom to which they are attached form a monocyclic heterocyclyl optionally substituted with one or more substituents Q.

52. 52. The compound according to any one of claims 1 to 32, 42 and 50 to 51, wherein R1 and R2 together with the N atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q.

53. 53. The compound according to any one of claims 1 to 32, 42, and 50 to 52, wherein R1 and R2, together with the N atom to which they are attached, form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2,5-dioxypyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(4-methoxybenzyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or 1,3-dioxoisoindolyl-2-yl.

54. 54. The compound of any one of claims 1 to 53, wherein R3 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each of which is optionally substituted with one or more substituents Q.

55. The compound of any one of claims 1 to 54, wherein R3 is C1-25 alkyl optionally substituted with one or more substituents Q.

56. R3 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-thiazolinone, 1,2-dimethyloctan-1-yl ... The compound of any one of claims 1 to 55, which is trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecan-1-yl, dodecan-1-yl, 2-hydroxydodecan-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

57. The compound according to any one of claims 1 to 54, wherein R3 is C1-25 alkenyl optionally substituted with one or more substituents Q.

58. R3 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1 58. The compound according to any one of claims 1 to 54 and 57, wherein the compound is (8Z,11Z)-heptadecene-8,11-dien-1-yl, (9Z,12Z)-octadecane-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadecene-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadecene-8,11,14-trien-1-yl.

59. The compound according to any one of claims 1 to 54, wherein R3 is a C3-10 cycloalkyl group optionally substituted with one or more substituents Q.

60. 60. The compound of any one of claims 1 to 54 and 59, wherein R3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

61. The compound according to any one of claims 1 to 54, wherein R3 is a C6-14 aryl optionally substituted with one or more substituents Q.

62. 62. The compound of any one of claims 1 to 54 and 61, wherein R3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

63. 63. The compound of any one of claims 1 to 62, wherein R4 is C1-30 alkyl, C1-30 heteroalkyl, C2-30 alkenyl, C3-10 cycloalkyl, or C6-14 aryl, each of which is optionally substituted with one or more substituents Q.

64. The compound of any one of claims 1 to 63, wherein R4 is C1-25 alkyl optionally substituted with one or more substituents Q.

65. R4 is prop-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, heptan-1-yl, octan-1-yl, octan-3-yl, 3,7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, nonan-1-yl, 8-methylnonan-1-yl, 2-methoxynonan-1-yl, decan-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecan-1-yl, tridecane-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or heneicosan-1-yl.

65. The compound of any one of claims 1 to 64, wherein the compound is -yl.

66. The compound according to any one of claims 1 to 63, wherein R4 is C1-25 alkenyl optionally substituted with one or more substituents Q.

67. R4 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1 67. The compound according to any one of claims 1 to 63 and 66, wherein the compound is (8Z,11Z)-heptadecene-8,11-dien-1-yl, (9Z,12Z)-octadecane-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadecene-5,8,11-trien-1-yl, or (8Z,11Z,14Z)-heptadecene-8,11,14-trien-1-yl.

68. The compound according to any one of claims 1 to 63, wherein R4 is a C3-10 cycloalkyl group optionally substituted with one or more substituents Q.

69. 69. The compound of any one of claims 1 to 63 and 68, wherein R4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

70. The compound according to any one of claims 1 to 63, wherein R4 is a C6-14 aryl optionally substituted with one or more substituents Q.

71. 71. The compound of any one of claims 1 to 63 and 70, wherein R4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

72. The following structure: 【Transformation 8】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (In the formula, e and f each independently represent an integer of 0, 1, 2, 3, 4, or 5, and g and h each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; i and j are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; k and m are each independently an integer of 0, 1, 2, 3, 4, or 5; and each n is each independently an integer of 1, 2, 3, 4, 5, or 6. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

73. 73. The compound of any one of claims 10 to 72, wherein c is an integer of 2, 3, 4, 5, or 6.

74. 74. The compound of any one of claims 13 to 73, wherein b is an integer of 2, 3, 4, 5, or 6.

75. The compound according to any one of claims 1 to 74, wherein X is a bond, -C(O)O-, -C(O)N(R1a)-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R1a)-, -OC(O)S-, -N(R1a)-, -NR1aC(O)N(R1b)-, -S-, or -S-S-.

76. The compound according to any one of claims 1 to 75, wherein X is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-.

77. The compound according to any one of claims 1 to 76, wherein Z is a bond, -C(O)O-, -C(O)N(R1a)-, -C(O)S-, -O-, -OC(O)O-, -OC(O)N(R1a)-, -OC(O)S-, -N(R1a)-, -NR1aC(O)N(R1b)-, -S-, or -S-S-.

78. The compound according to any one of claims 1 to 77, wherein Z is a bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-.

79. The compound is 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1 , wherein:

80. Compound: 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyldihexanoate 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyldihexanoate 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)carbamoyl)oxy)heptane-1,7-diyldihexanoate 3; 4-(3-(2-((2-(dimethylamino)ethyl)amino)ethyl)-ureido)heptane-1,7-diyldihexanoate 4; or 7-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)tridecane-1,13-diyl-bis(2-hexyldecanoate)5; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

81. 81. A lipid nanoparticle comprising a compound according to any one of claims 1 to 80, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

82. (i) a nucleic acid, (ii) a compound according to any one of claims 1 to 80, or an ena thereof A pharmaceutical composition comprising lipid nanoparticles comprising: (i) an antimer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol, and a pharmaceutically acceptable excipient.

83. 83. The pharmaceutical composition of claim 82, further comprising a conjugated lipid.

84. 84. The pharmaceutical composition of claim 83, wherein the conjugated lipid comprises a polyethylene glycol-conjugated lipid.

85. The pharmaceutical composition of any one of claims 82 to 84, wherein the nucleic acid is mRNA.

86. The pharmaceutical composition of any one of claims 82 to 85, wherein the nucleic acid is a circular RNA.

87. 87. The pharmaceutical composition of any one of claims 82 to 86, wherein the pharmaceutical composition is preferentially distributed to a target organ of a subject in need thereof.

88. 88. The pharmaceutical composition of claim 87, wherein the target organ is the eye, heart, lung, kidney, liver, or spleen of a subject.

89. 87. The pharmaceutical composition of any one of claims 82 to 86, wherein the pharmaceutical composition is preferentially distributed to liver cells.

90. 90. The pharmaceutical composition of claim 89, wherein the liver cells are hepatocytes.

91. 87. The pharmaceutical composition of any one of claims 82 to 86, wherein the pharmaceutical composition is preferentially distributed to splenocytes.

92. 92. The pharmaceutical composition of claim 91, wherein the splenocyte is a spleen cell.

93. 93. The pharmaceutical composition of any one of claims 82 to 92, wherein the nucleic acid encodes a biologically active protein or enzyme.

94. 94. The pharmaceutical composition of claim 93, wherein the biologically active protein or enzyme is produced by or secreted systemically from hepatocytes.

95. 94. The pharmaceutical composition of claim 93, wherein the biologically active protein or enzyme is produced or systemically secreted from cells of the lung, heart, or eye, or central nervous system.

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