Lipid compound, lipid nanoparticle and pharmaceutical composition

By preparing lipid nanoparticles with specific lipid compounds, the problem of low efficiency in delivering highly charged nucleic acids is solved, and efficient nucleic acid delivery and therapeutic effects are achieved.

CN120659770APending Publication Date: 2025-09-16SHANGHAI CIRCODE BIOMED CO LTD
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Patent Information

Application Number
CN202480010207.9
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2023-03-22
Filing Date
2024-03-21
Publication Date
2025-09-16

AI Technical Summary

Technical Problem

Existing technologies make it difficult to effectively deliver highly charged nucleic acids as therapeutic agents, resulting in their inability to reach intracellular targets and affecting the therapeutic effect.

Method used

Provided are a series of lipid compounds, including compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and their derivatives, for use in preparing lipid nanoparticles to improve the delivery efficiency of nucleic acids. These compounds enhance the cell penetration ability of nucleic acids through specific linkers and connection methods.

Benefits of technology

The delivery efficiency of highly charged nucleic acids is improved, enabling them to reach intracellular targets more effectively and enhancing therapeutic effects.

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Abstract

Provided herein are lipid compounds, such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). Also provided are lipid nanoparticles and pharmaceutical compositions, each comprising a lipid compound, such as a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). # imgabs0 #
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Claims

1. A compound of formula (I), formula (II), formula (III), formula (IV) or formula (V): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: Each R 1 、R 2 、R 5 、R 6 and R 7 are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a , –C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d 、 –NR 1a C(O)OR 1d 、 –NR 1a C(O)NR 1b R 1c 、 –NR 1a C(O)SR 1d 、 –NR 1a C(NR 1d )NR 1b R 1c 、 –NR 1a C(S)R 1d 、 –NR 1a C(S)OR 1d 、 –NR 1a C(S)NR 1b R 1c 、 –NR 1a S(O)R 1d 、 –NR 1a S(O)2R 1d 、 –NR 1a S(O)NR 1b R 1c 、 –NR 1a S(O)2NR 1b R 1c 、 –S(O)R 1a 、 –S(O)2R 1a 、 –S(O)NR 1b R 1c 或 –S(O)2NR 1b R 1c ; Each R 3 and R 4 Independently C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or heterocyclic group; Each A is independently -O- or -N(R 1a )–; Each E 1 and E 2 are independently –C(O)– or –C(O)O–; Each L 1 and L 2 Independently C 1-6 Alkylene or C 1-6 heteroalkylene; Each L 3 and L 4 Independently C 1-10 Alkylene, C 1-10 Heteroalkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene; Each M 1 and M 2 independently a linker; Each U 1 and U 2 are independently -O- or -N(R 1b )–; Each X and Z is independently a chemical bond, –C(O)O–, –C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –S– or –S–S–; and Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NR b R c ,–C(S)R a ,–C(S)OR a , –C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b R c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halogen, nitro, imino and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e , –C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h ,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group.

2. The compound according to claim 1, which has the structure of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a , –C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR 1a C(O)NR 1b R 1c 、–NR 1a C(O)SR 1d 、–NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a C(S)R 1d 、–NR 1a C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR 1a S(O)R 1d 、–NR 1a S(O)2R 1d 、–NR 1a S(O)NR 1b R 1c 、–NR 1a S(O)2NR 1b R 1c 、–S(O)R 1a 、–S(O)2R 1a 、–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 3 and R 4 Each independently is C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or heterocyclic group; E 1 and E 2 each independently represents –C(O)– or –C(O)O–; L 1 and L 2 Each independently is C 1-6 Alkylene or C 1-6 heteroalkylene; L 3 and L 4 Each independently is C 1-10 Alkylene, C 1-10 Heteroalkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene; M 1 and M 2 each independently a linker; U 1 and U 2 are each independently -O- or -N(R 1b )-;as well as Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (in one embodiment, 1, 2, 3, or 4) substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NR b R c ,–C(S)R a ,–C(S)OR a , –C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b R c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halogen, nitro, imino and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e , –C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h ,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group.

3. The compound according to claim 1 or 2, wherein M 1 A cleavable linker.

4. The compound according to claim 1 or 2, wherein M 1 For the products containing –C(O)O–, –C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –N=N–, –S–, or –S–S– linkers.

5. The compound according to any one of claims 1 to 4, wherein M 1 is –C(O)O–, –C(O)N(H)–, –C(O)S–, –OC(O)O–, –OC(O)N(H)–, –OC(O)S–, –NHC(O)N(H)–, –N=N– or –S–S–.

6. The compound according to any one of claims 1 to 5, wherein M 1 It is –S–S–.

7. The compound according to any one of claims 1 to 6, wherein M 2 A cleavable linker.

8. The compound according to any one of claims 1 to 6, wherein M 2 For the products containing –C(O)O–, –C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –N=N–, –S–, or –S–S– linkers.

9. The compound according to any one of claims 1 to 8, wherein M 2 is –C(O)O–, –C(O)N(H)–, –C(O)S–, –OC(O)O–, –OC(O)N(H)–, –OC(O)S–, –NHC(O)N(H)–, –N=N– or –S–S–.

10. The compound according to any one of claims 1 to 9, wherein M 2 It is –S–S–.

11. The compound according to any one of claims 1 to 10, wherein E 1 is –C(O)–.

12. The compound according to any one of claims 1 to 10, wherein E 1 It is –C(O)O–.

13. The compound according to any one of claims 1 to 12, wherein E 2 is –C(O)–.

14. The compound according to any one of claims 1 to 12, wherein E 2 It is –C(O)O–.

15. according to the compound described in any one of claims 1-14, wherein U 1 It is –O–.

16. according to the compound described in any one of claims 1-14, wherein U 1 N(R 1b )–.

17. according to the compound described in any one of claims 1-14, wherein U 1 is –N(H)–.

18. according to the compound described in any one of claims 1-17, wherein U 2 It is –O–.

19. according to the compound described in any one of claims 1-17, wherein U 2 N(R 1b )–.

20. The compound according to any one of claims 1-17 and 19, wherein U 2 is –N(H)–.

21. The compound according to claim 1 or 2, which has the structure of formula (Ib): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

22. The compound of claim 1 or 2, which has the structure of formula (Ic): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

23. The compound of claim 1 having the structure of formula (II): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 、R 2 、R 5 and R 6 are each independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a , –C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR 1a C(O)NR 1b R 1c ,–NR 1a C(O)SR 1d ,–NR 1a C(NR 1d )NR 1b R 1c ,–NR 1a C(S)R 1d ,–NR 1a C(S)OR 1d ,–NR 1a C(S)NR 1b R 1c ,–NR 1a S(O)R 1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heteroaryl or heterocyclyl group; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a heteroaryl or heterocyclyl group; R 3 and R 4 are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or heterocyclic group; A is –O– or –N(R 1a )–; L 1 and L 2 Each independently is C 1-6 Alkylene or C 1-6 heteroalkylene; L 3 and L 4 Each independently is C 1-10 Alkylene, C 1-10 Heteroalkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene; X and Z are each independently a chemical bond, -C(O)O-, -C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –S– or –S–S–; and Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NR b R c ,–C(S)R a ,–C(S)OR a , –C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b R c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, 1, 2, 3 or 4) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halogen, nitro, imino and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e , –C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h ,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group. The compound according to claim 1 , wherein A is —O—.

25. The compound of claim 1 or 23, wherein A is -N(R 1b )–.

26. The compound of claim 1, 23 or 25, wherein A is -N(H)-.

27. The compound according to claim 1, which has the structure of formula (III): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 and R 2 are each independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a , –C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR 1a C(O)NR 1b R 1c ,–NR 1a C(O)SR 1d ,–NR 1a C(NR 1d )NR 1b R 1c ,–NR 1a C(S)R 1d ,–NR 1a C(S)OR 1d ,–NR 1a C(S)NR 1b R 1c ,–NR 1a S(O)R 1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heteroaryl or heterocyclyl group; R 3 and R 4 are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or heterocyclic group; L 1 and L 2 Each independently is C 1-6 Alkylene or C 1-6 heteroalkylene; L 3 and L 4 Each independently is C 1-10 Alkylene, C 1-10 Heteroalkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene; M 1 is a linker; U 1 For –O– or –N(R 1b )-;as well as Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NR b R c ,–C(S)R a ,–C(S)OR a , –C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b R c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halogen, nitro, imino and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e , –C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h ,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group.

28. The compound according to claim 27, wherein M 1 A cleavable linker.

29. The compound according to claim 27, wherein M 1 For the products containing –C(O)O–, –C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –N=N–, –S–, or –S–S– linkers.

30. The compound according to claim 27 or 29, wherein M 1 is –C(O)O–, –C(O)N(H)–, –C(O)S–, –OC(O)O–, –OC(O)N(H)–, –OC(O)S–, –NHC(O)N(H)–, –N=N– or –S–S–.

31. according to the compound described in any one of claims 27-30, wherein M 1 It is –S–S–.

32. according to the compound described in any one of claim 27-31, wherein U 1 It is –O–.

33. according to the compound described in any one of claim 27-31, wherein U 1 N(R 1b )–.

34. according to the compound described in any one of claim 27-31 and 33, wherein U 1 is –N(H)–.

35. The compound according to claim 1 or 27, which has the structure of formula (IIIb): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

36. The compound according to claim 1 or 27, which has the structure of formula (IIIc): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

37. The compound according to claim 1, which has the structure of formula (IV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 、R 2 and R 7 are each independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a , –C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR 1a C(O)NR 1b R 1c ,–NR 1a C(O)SR 1d ,–NR 1a C(NR 1d )NR 1b R 1c ,–NR 1a C(S)R 1d ,–NR 1a C(S)OR 1d ,–NR 1a C(S)NR 1b R 1c ,–NR 1a S(O)R 1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heteroaryl or heterocyclyl group; R 3 and R 4 are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or heterocyclic group; A is a chemical bond, –O– or –N(R 1a )–; L 1 Independently C 1-6 Alkylene or C 1-6 heteroalkylene; and Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NR b R c ,–C(S)R a ,–C(S)OR a , –C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b R c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halogen, nitro, imino and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e , –C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h ,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group. The compound according to claim 37 , wherein A is —O—.

39. The compound of claim 37, wherein A is -N(R 1b )–.

40. The compound of claim 37 or 39, wherein A is -N(H)-.

41. The compound according to claim 1, having the structure of Formula (V): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a , –C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR 1a C(O)NR 1b R 1c 、–NR 1a C(O)SR 1d 、–NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a C(S)R 1d 、–NR 1a C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR 1a S(O)R 1d 、–NR 1a S(O)2R 1d 、–NR 1a S(O)NR 1b R 1c 、–NR 1a S(O)2NR 1b R 1c 、–S(O)R 1a 、–S(O)2R 1a 、–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 3 and R 4 are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or heterocyclic group; L 1 and L 2 Each independently is C 1-6 Alkylene or C 1-6 heteroalkylene; L 3 and L 4 Each independently is C 1-10 Alkylene, C 1-10 Heteroalkylene, C 2-10 Alkenylene or C 2-10 Alkynylene; and Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NR b R c ,–C(S)R a ,–C(S)OR a , –C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b R c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halogen, nitro, imino and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e , –C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h ,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group.

42. A compound according to any one of claims 1 to 41, wherein L 1 C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more Q substituents.

43. A compound according to any one of claims 1 to 42, wherein L 1 For–(CR 2a R 2b ) a –, where each R 2a and R 2b are independently (i) hydrogen; or (ii) C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents Q; or R 2a and R 2b Together with the C atoms to which they are attached, they form C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted with one or more substituents Q; a is an integer of 1, 2, 3, 4, 5 or 6.

44. according to the compound described in any one of claims 1-43, wherein L 1 for –(CH2) a –, a is an integer 1, 2, 3, 4, 5 or 6.

45. A compound according to any one of claims 1-36 and 41-44, wherein L 2 C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more Q substituents.

46. ​​A compound according to any one of claims 1-36 and 41-45, wherein L 2 For–(CR 2a R 2b ) b –, where each R 2a and R 2b are independently (i) hydrogen; or (ii) C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents Q; or R 2a and R 2b Together with the C atoms to which they are attached, they form C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted with one or more substituents Q; b is an integer of 1, 2, 3, 4, 5 or 6.

47. A compound according to any one of claims 1-36 and 41-46, wherein L 2 for –(CH2) b –, b is an integer 1, 2, 3, 4, 5, or 6.

48. A compound according to any one of claims 1-36 and 41-47, wherein L 3 C 1-10 Alkylene, the C 1-10 The alkylene group is optionally substituted with one or more Q substituents.

49. A compound according to any one of claims 1-36 and 41-48, wherein L 3 For–(CR 2a R 2b ) c –or–CR 2a R 2b (CR 2a R 2b ) c –, where each R 2a and R 2b are independently (i) hydrogen; or (ii) C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents Q; or R 2a and R 2b Together with the C atoms to which they are attached, they form C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted with one or more substituents Q; each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

50. A compound according to any one of claims 1-36 and 41-49, wherein L 3 for –(CH2) c –, each c is independently an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

51. The compound according to any one of claims 1-36 and 41-50, wherein L 4 C 1-10 Alkylene, the C 1-10 The alkylene group is optionally substituted with one or more Q substituents.

52. A compound according to any one of claims 1-36 and 41-51, wherein L 4 For–(CR 2a R 2b ) d –or–CR 2a R 2b (CR 2a R 2b ) d –, where each R 2a and R 2b are independently (i) hydrogen; or (ii) C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents Q; or R 2a and R 2b Together with the C atoms to which they are attached, they form C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted with one or more substituents Q; each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

53. A compound according to any one of claims 1-36 and 41-52, wherein L 4 for –(CH2) d –, each d is independently an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

54. The compound according to claim 1 or 2, having the structure of formula (If): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

55. The compound according to claim 1 or 2, which has the structure of formula (Ig): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

56. The compound according to claim 1 or 23, which has the structure of formula (IIc): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

57. The compound according to claim 1 or 23, which has the structure of Formula (IId): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

58. The compound according to claim 1 or 27, which has the structure of formula (IIId): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

59. The compound according to claim 1 or 27, which has the structure of formula (IIIe): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

60. The compound according to claim 1 or 37, which has the structure of formula (IVc): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a is an integer of 1, 2, 3, 4, 5 or 6.

61. The compound according to claim 1 or 37, which has the structure of formula (IVd): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a is an integer of 1, 2, 3, 4, 5 or 6.

62. The compound according to claim 1 or 41, having the structure of Formula (Va): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein a and b are each independently an integer of 1, 2, 3, 4, 5 or 6; and c and d are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

63. A compound according to any one of claims 1-62, wherein R 1 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c , –C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a .

64. according to the compound described in any one of claims 1-63, wherein R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more Q substituents.

65. A compound according to any one of claims 1-64, wherein R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl or 2-dimethylaminoethyl.

66. A compound according to any one of claims 1, 23-40, 42-53, 56-61 and 63-65, wherein R 2 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c , –C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a .

67. A compound according to any one of claims 1, 23-40, 42-53, 56-61 and 63-66, wherein R 2 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more Q substituents.

68. A compound according to any one of claims 1, 23-40, 42-53, 56-61 and 63-67, wherein R 2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl or 2-dimethylaminoethyl.

69. A compound according to any one of claims 1-68, wherein R 3 C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 3-10 Cycloalkyl or C 6-14 Aryl, each of which is optionally substituted with one or more substituents Q.

70. A compound according to any one of claims 1-69, wherein R 3 C 1-25 Alkyl, the C 1-25 The alkyl group is optionally substituted with one or more Q substituents.

71. A compound according to any one of claims 1-70, wherein R 3 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, hept-1-yl, oct-1-yl, oct-3-yl, 3,7-dimethyloct-1-yl, 8-methoxycarbonyloct-1-yl, 8-trifluoromethoxycarbonyloct-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, dec-1-yl, undec-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridec-1-yl, pentadec-1-yl, pentadec-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, dec-2-yl or heneicosane-1-yl.

72. A compound according to any one of claims 1-69, wherein R 3 C 1-25 Alkenyl, the C 1-25 The alkenyl group is optionally substituted with one or more Q substituents.

73. A compound according to any one of claims 1-69 and 72, wherein R 3 (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-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-heneicosene-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadec-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

74. A compound according to any one of claims 1-69, wherein R 3 C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted with one or more Q substituents.

75. A compound according to any one of claims 1-69 and 74, wherein R 3 It is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

76. A compound according to any one of claims 1-69, wherein R 3 C 6-14 Aryl, the C 6-14 The aryl group is optionally substituted with one or more Q substituents.

77. A compound according to any one of claims 1-69 and 76, wherein R 3 is 3-pentylphenyl, 4-pentylphenyl or 3,4-dipentylphenyl.

78. A compound according to any one of claims 1-77, wherein R 4 C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 3-10 Cycloalkyl or C 6-14 Aryl, each of which is optionally substituted with one or more substituents Q.

79. A compound according to any one of claims 1-78, wherein R 4 C 1-25 Alkyl, the C 1-25 The alkyl group is optionally substituted with one or more Q substituents.

80. A compound according to any one of claims 1-79, wherein R 4 is propan-1-yl, pentan-1-yl, 2-isopropyl-5-methylhexan-1-yl, hept-1-yl, oct-1-yl, oct-3-yl, 3,7-dimethyloct-1-yl, 8-methoxycarbonyloct-1-yl, 8-trifluoromethoxycarbonyloct-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, dec-1-yl, undec-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridec-1-yl, pentadec-1-yl, pentadec-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, dec-2-yl or heneicosane-1-yl.

81. A compound according to any one of claims 1-78, wherein R 4 C 1-25 Alkenyl, the C 1-25 The alkenyl group is optionally substituted with one or more Q substituents.

82. A compound according to any one of claims 1 to 78 and 81, wherein R4 is (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoronon-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl , (Z)-3-undecen-1-yl, (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-hexadecen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadec-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl or (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl.

83. A compound according to any one of claims 1-78, wherein R 4 C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted with one or more Q substituents.

84. according to the compound described in any one of claim 1-78 and 83, wherein R 4 It is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

85. A compound according to any one of claims 1-78, wherein R 4 C 6-14 Aryl, the C 6-14 The aryl group is optionally substituted with one or more Q substituents.

86. A compound according to any one of claims 1-78 and 85, wherein R 4 is 3-pentylphenyl, 4-pentylphenyl or 3,4-dipentylphenyl.

87. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-86, wherein R 5 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c , –C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a .

88. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-87, wherein R 5 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more Q substituents.

89. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-88, wherein R 5 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl or 2-dimethylaminoethyl.

90. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-89, wherein R 6 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c , –C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a .

91. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-90, wherein R 6 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more Q substituents.

92. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-91, wherein R 6 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl or 2-dimethylaminoethyl.

93. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-92, wherein R 7 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c , –C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a .

94. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-93, wherein R 7 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more Q substituents.

95. A compound according to any one of claims 1, 23-26, 42-53, 56, 57 and 63-94, wherein R 7 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl or 2-dimethylaminoethyl.

96. A compound according to any one of claims 43-95, wherein a is an integer of 1, 2, 3 or 4.

97. A compound according to any one of claims 43-96, wherein a is the integer 2.

98. The compound of any one of claims 42-44, 46-59, and 62-97, wherein b is an integer of 1, 2, 3, or 4.

99. The compound of any one of claims 42-44, 46-59, and 62-98, wherein b is an integer of 1 or 2.

100. The compound of claim 1, wherein the compound has the structure: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein each e, f, and v is independently an integer of 0, 1, 2, 3, 4, or 5; each g and h is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; each i and j is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; each k, m, q, and r is independently an integer of 0, 1, 2, 3, 4, or 5; and each n is independently an integer of 1, 2, 3, 4, 5, or 6.

101. The compound of any one of claims 42-47, 49-59, and 62-100, wherein c is an integer of 1, 2, 3, or 4.

102. The compound of any one of claims 42-47, 49-59, and 62-101, wherein c is an integer of 2.

103. The compound of any one of claims 42-50, 52-59, and 62-102, wherein d is an integer of 1, 2, 3, or 4.

104. The compound of any one of claims 42-50, 52-59, and 62-103, wherein d is an integer of 2.

105. The compound of any one of claims 100-104, wherein X is a chemical bond, -C(O)O-, -C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –S–, or –S–S–.

106. The compound of any one of claims 100-105, wherein X is a chemical bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-.

107. The compound of any one of claims 100-106, wherein Z is a chemical bond, -C(O)O-, -C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–, –S–, or –S–S–.

108. The compound of any one of claims 100-107, wherein Z is a chemical bond, -C(O)O-, -C(O)N(H)-, -C(O)S-, -OC(O)O-, -OC(O)N(H)-, -OC(O)S-, or -S-S-.

109. A compound which is: Bis(2-(pentyldisulfanyl)ethyl)((methylazadiyl)bis(ethane-2,1-diyl))dicarbamate 1; N,N'-((methylazadiyl)bis(ethane-2,1-diyl))bis(2,2-dimethyl-4-(pentyldisulfanyl)butanamide) 2; 4-(3,3-bis(2-(dimethylamino)ethyl)ureido)heptane-1,7-diyl dihexanoate 3; 10-(3-(hexanoyloxy)propyl)-2-methyl-9-oxo-5,6-dithia-2,8,10-triazatridec-13-ylhexanoate 4; 2-((Butoxy(pentyloxy)phosphoryl)amino)-N,N,N-trimethylethane-1-ammonium 5; 2-((Butoxy(pentyloxy)phosphoryl)oxy)-N,N,N-trimethylethane-1-ammonium 6; or Dipentyl((((methylazadiyl)bis(ethane-2,1-diyl))bis(dimethylammoniumdiyl))-bis(ethane-2,1-diyl))bis(phosphonate) 7; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

110. The compound according to claim 1, having the structure: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

111. The compound according to claim 1, wherein R 3 for: wherein each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

112. The compound according to claim 1, wherein R 4 for: wherein each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

113. The compound according to claim 1, wherein R 3 and R 4 Have the same structure.

114. The compound according to claim 1, wherein R 3 It is the tail of the branch chain.

115. The compound according to claim 1, wherein R 4 It is the tail of the branch chain.

116. The compound according to claim 1, wherein R 3 Select from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112, or T-0113.

117. The compound according to claim 1, wherein R 4 Select from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112, or T-0113.

118. The compound according to claim 1, wherein R 3 The number of carbon atoms in the alkyl group is 5-30.

119. The compound according to claim 1, wherein R 4 The number of carbon atoms in the alkyl group is 5-30.

120. The compound of claim 1, wherein R 3 The number of carbon atoms in is selected from: 12, 14, 15, 16, 17, 18, 20, 21, 24, 25 or 28.

121. The compound of claim 1, wherein R 4 The number of carbon atoms in is selected from: 12, 14, 15, 16, 17, 18, 20, 21, 24, 25 or 28.

122. The compound of claim 1, wherein the compound is selected from Group 1.

123. The compound of claim 1, wherein the compound is selected from Group 2.

124. The compound of claim 1, wherein the compound is selected from Group 3.

125. A lipid nanoparticle comprising a compound of any one of claims 1-124, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

126. A pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) mRNA; (ii) a compound of any one of claims 1-124, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol; wherein, Administration of the mRNA to the subject results in higher expression relative to administration of the circular RNA to the subject.

127. A pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) circular RNA; (ii) a compound of any one of claims 1-124, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol; wherein, Administration of the circular RNA to the subject results in higher expression relative to administration of the mRNA to the subject.

128. The pharmaceutical composition of claim 126 or 127, further comprising a conjugated lipid.

129. The pharmaceutical composition of claim 128, wherein the conjugated lipid comprises a polyethylene glycol conjugated lipid.

130. The pharmaceutical composition of any one of claims 126-129, wherein the pharmaceutical composition preferentially distributes to a target organ in a subject in need thereof.

131. The pharmaceutical composition of claim 130, wherein the target organ is an eye, heart, lung, kidney, liver, or spleen of a subject.

132. The pharmaceutical composition of any one of claims 126-131, wherein the pharmaceutical composition is preferentially distributed into liver cells.

133. The pharmaceutical composition of claim 132, wherein the liver cells are hepatocytes.

134. The pharmaceutical composition of any one of claims 126-131, wherein the pharmaceutical composition is preferentially distributed into spleen cells.

135. The pharmaceutical composition of claim 134, wherein the spleen cells are splenocytes.

136. The pharmaceutical composition of any one of claims 126-135, wherein the nucleic acid encodes a biologically active protein or enzyme.

137. The pharmaceutical composition of claim 136, wherein the biologically active protein or enzyme is produced from liver cells or secreted systemically.

138. The pharmaceutical composition of claim 137, wherein the biologically active protein or enzyme is produced in cells of the lungs, heart, eyes, or central nervous system or is excreted systemically.

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