Lipid compound, lipid nanoparticle and pharmaceutical composition

Abstract

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

Description

This application is a divisional application of the Chinese patent application with application number 202380068010.6, application date November 2, 2023, and invention name “Lipid compounds, lipid nanoparticles and pharmaceutical compositions”. 1. Cross-application of related applications

[0001] This application claims priority to international applications PCT / CN2022 / 129490 filed on November 3, 2022, PCT / CN203 / 083169 filed on March 22, 2023, and PCT / CN2023 / 102918 filed on June 27, 2023, the disclosures of each of which are incorporated herein by reference in their entirety. 2. Related sequence list

[0002] This application incorporates by reference the sequence listing submitted with this application, which is an XML file entitled "TFG00919PCT Sequence Listing.XML", created on November 2, 2023, and is 75,000 bytes in size. 3. Technical field

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

[0004] Lipid nanoparticles (LNPs) are promising delivery vehicles for a variety of therapeutic agents, including small molecule drugs, proteins, and nucleic acids. See, Akinc et al., Nat. Nanotechnol. 2019, 14, 1084-87; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. Two FDA-approved COVID-19 mRNA vaccines (mRNA-1273 and BNT162b) use lipid nanoparticles for antigen mRNA delivery. See, Polack et al., N. Engl. J. Med. 2020, 383, 2603-15; Baden et al., N. Engl. J. Med. 2021, 384, 403-16. However, 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. To achieve therapeutic effects, for example, highly charged nucleic acids must reach their intracellular targets. See, Torres-Canegas et al., Pharmaceutics 2021, 13, 428; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. Therefore, lipid compounds for the efficient delivery of therapeutic agents are needed. 5. Application Overview

[0005] The present application provides a compound of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 and R 2 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)NR1b 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 Each independently is C 1-40 Alkyl, C 1-40 Heteroalkyl, C 2-40 Alkenyl, C 2-40 Heteroalkenyl, C 2-40 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or 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 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene; A is –O– or –N(R 1a )–; E is –UC(O)N(R 1a )–, where U is –O– or –N(R 1b )–; 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, 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, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is optionally further substituted 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)Ra 、–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) C1-6 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, 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)Re 、–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) Rf and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group.

[0006] The present application also provides a compound of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 and R 2 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)NR1b 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 Each independently is C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl, C 6-14Aryl, 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; A is –O– or –N(R 1a )–; E is –UC(O)N(R 1a )–, where U is –O– or –N(R 1b )–; 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, and 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 7-15Aralkyl, heteroaryl and heterocyclyl, each of which is optionally further 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 aC(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, 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)NRf R g 、–C(O)SR e 、–C(NR e )NR f R g 、–C(S)R e 、–C(S)OR e 、–C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g 、–NR f R g 、–NR e C(O)R h 、–NR e C(O)OR f 、–NR e C(O)NR f R g 、–NR e C(O)SR f 、–NR e C(NR h )NR f R g 、–NR e C(S)R h 、–NR e C(S)OR f 、–NR e C(S)NR f R g 、–NR e S(O)R h 、–NR eS(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and, –S(O)2NR f R g ; 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 heterocyclic; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclic group.

[0007] In addition, the present application 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] Further, the present application 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, wherein the lipid nanoparticles comprise: (i) a nucleic acid, and (ii) a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof. 6. Exemplary Implementation

[0010] Compounds having the structure of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: 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)R1a 、–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 Each independently is C 1-40 Alkyl, C 1-40 Heteroalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or 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 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene, C 2-20 Heteroalkenylene or C 2-20 Alkynylidene; A is –O– or –N(R 1a )–; E is –UC(O)N(R 1a )–, where U is –O– or –N(R 1b )–; 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, 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, 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 7-15Aralkyl, heteroaryl and heterocyclyl, each of which is optionally further 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 aC(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, 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)NRf R g 、–C(O)SR e 、–C(NR e )NR f R g 、–C(S)R e 、–C(S)OR e 、–C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g 、–NR f R g 、–NR e C(O)R h 、–NR e C(O)OR f 、–NR e C(O)NR f R g 、–NR e C(O)SR f 、–NR e C(NR h )NR f R g 、–NR e C(S)R h 、–NR e C(S)OR f 、–NR e C(S)NR f R g 、–NR e S(O)R h 、–NR eS(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e ,–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; 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.

[0011] In the compound of paragraph

[0010] , R 1 and R 2 are each independently: (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR1b 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 R1c ,–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 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; 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; A is –O– or –N(R 1a )–; E is –UC(O)N(R 1a )–, where U is –O– or –N(R 1b )–; 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 2-6Alkynyl, 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, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is optionally further substituted 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 bR 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, one, two, three or four substituents Q a or (iii) R b and Rc 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.

[0012] In the compound of paragraph

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

[0013] In the compounds of paragraph

[0010] or

[0012] , L 1 For–(CR2a R 2b ) a –, each R 2a and R 2b are independently: (i) hydrogen; or (ii) C 1-6 alkyl, which 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, which is optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5 or 6.

[0014] In the compounds of any one of paragraphs

[0010] to

[0013] , L 1 for –(CH2) a –.

[0015] In the compounds of any of paragraphs

[0010] to

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

[0016] In the compounds of any one of paragraphs

[0010] to

[0015] , 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, which 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, which is optionally substituted with one or more substituents Q; and b is an integer of 1, 2, 3, 4, 5 or 6.

[0017] In the compounds of any one of paragraphs

[0010] to

[0016] , L 2 for –(CH2) b –.

[0018] In the compounds of any one of paragraphs

[0010] to

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

[0019] In the compounds of any one of paragraphs

[0010] to

[0018] , L 3 For–(CR 2a R 2b ) c–, where each R 2a and R 2b are independently: (i) hydrogen; or (ii) C 1-6 alkyl, which 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, which is 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 the compounds of any one of paragraphs

[0010] to

[0019] , L 3 for –(CH2) c –.

[0021] In the compounds of any of paragraphs

[0010] to

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

[0022] In the compounds of any one of paragraphs

[0010] to

[0021] , L 4 For–(CR 2a R 2b ) d –, where each R 2a and R 2b are independently: (i) hydrogen; or (ii) C 1-6 alkyl, which 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, which is 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 compounds of any one of paragraphs

[0010] to

[0022] , L 4 for –(CH2) d –.

[0024] The compound of any one of paragraphs

[0010] to

[0023] has the structure of formula (II): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein 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.

[0025] In the compound of any one of paragraphs

[0010] to

[0024] , E is -OC(O)N(R 1a )–.

[0026] In the compound of any of paragraphs

[0010] to

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

[0027] In the compound of any of paragraphs

[0010] to

[0024] , E is -NR 1a C(O)N(R 1b )–.

[0028] In the compounds of any of paragraphs

[0010] to

[0024] and

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

[0029] The compound of paragraph

[0024] has the structure of formula (III): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein U is -O- or -N(R 1a )–.

[0030] In the compound of any of paragraphs

[0010] to

[0029] , A is -O-.

[0031] In the compound of any one of paragraphs

[0010] to

[0029] , A is -N(R 1a )–.

[0032] In the compounds of any of paragraphs

[0010] to

[0029] and

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

[0033] In the compound of any of paragraphs

[0024] to

[0032] , U is -O-.

[0034] In the compound of any one of paragraphs

[0024] to

[0032] , U is -N(R 1a)–.

[0035] In the compounds of any of paragraphs

[0024] to

[0032] and

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

[0036] The compound of paragraph

[0024] or

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

[0037] The compound of paragraph

[0024] or

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

[0038] The compound of paragraph

[0024] or

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

[0039] The compound of paragraph

[0024] or

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

[0040] In the compounds of any of paragraphs

[0013] to

[0039] , a is an integer of 2.

[0041] In the compounds of any of paragraphs

[0016] to

[0040] , b is an integer of 2.

[0042] In the compound of any one of paragraphs

[0010] to

[0041] , R 1are: (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a ,–C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a ,–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR1a C(O)NR 1b R 1c ,–NR 1a C(O)SR 1d ,–NR 1a C(NR 1d )NR 1b R 1c ,–NR 1a C(S)R 1d ,–NR 1a C(S)OR 1d ,–NR 1a C(S)NR 1b R 1c ,–NR 1a S(O)R 1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c .

[0043] In the compound of any one of paragraphs

[0010] to

[0042] , R 1 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c,–C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a .

[0044] In the compound of any one of paragraphs

[0010] to

[0043] , R 1 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 )ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxy-propyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methyl) oxy-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, dimethyl aminocarbonyl, amidino, methylamino-thiocarbonyl, dimethylaminothiocarbonyl, (E)-N'-cyano-N,N-dimethylamidino, (Z)-N'-cyano-N,N-dimethylamidino, (E)-N'-methoxy-N,N-dimethylamidino, (Z)-N'-methoxy-N,N-dimethylamidino, (E)-N'-methylsulfonyl-N,N-dimethylamidino, (Z)-N'-methylsulfonyl-N,N-dimethylamidino, hydroxyl, methoxy, or methylsulfonyl.

[0045] In the compound of any one of paragraphs

[0010] to

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

[0046] In the compounds of any of paragraphs

[0010] to

[0043] and

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

[0047] In the compound of any one of paragraphs

[0010] to

[0046] , R 2 are: (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a ,–C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a ,–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R1c 、–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 .

[0048] In the compound of any one of paragraphs

[0010] to

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

[0049] In the compound of any one of paragraphs

[0010] to

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

[0050] In the compound of any one of paragraphs

[0010] to

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

[0051] In the compound of any one of paragraphs

[0010] to

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

[0052] In the compounds of any of paragraphs

[0010] to

[0041] and

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

[0053] In the compounds of any of paragraphs

[0010] to

[0041] ,

[0051] and

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

[0054] In the compounds of any of paragraphs

[0010] to

[0041] , and

[0051] to

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

[0055] In the compounds of any of paragraphs

[0010] to

[0041] , and

[0051] to

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

[0056] In the compounds of any of paragraphs

[0010] to

[0041] ,

[0051] and

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

[0057] In the compounds of any of paragraphs

[0010] to

[0041] ,

[0051] ,

[0052] and

[0056] , R 1 and R2 Together with the N atom to which they are attached they 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 compounds of any of paragraphs

[0010] to

[0041] ,

[0051] ,

[0052] ,

[0056] and

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

[0059] In the compounds of any of paragraphs

[0010] to

[0041] and

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

[0060] In the compounds of any of paragraphs

[0010] to

[0041] ,

[0051] and

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

[0061] In the compounds of any of paragraphs

[0010] to

[0041] ,

[0051] ,

[0059] and

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

[0062] In the compounds of any of paragraphs

[0010] to

[0041] ,

[0051] and

[0059] to

[0061] , R 1 and R 2 Together with the N atom to which they are attached, they form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-oxazolidinon-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.

[0063] In the compound of any one of paragraphs

[0010] to

[0062] , R3 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.

[0064] In the compound of any one of paragraphs

[0010] to

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

[0065] In the compound of any one of paragraphs

[0010] to

[0064] , R 3 It is propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxycarbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane-1-yl, tridecane-1-yl, pentadecane-1-yl, pentadecane-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decane-2-yl, or heneicosane-1-yl.

[0066] In the compound of any one of paragraphs

[0010] to

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

[0067] In the compounds of any of paragraphs

[0010] to

[0063] and

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

[0068] In the compound of any one of paragraphs

[0010] to

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

[0069] In the compounds of any of paragraphs

[0010] to

[0063] and

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

[0070] In the compound of any one of paragraphs

[0010] to

[0063] , R 3 C 6-14 Aryl, which is optionally substituted with one or more Q substituents.

[0071] In the compounds of any of paragraphs

[0010] to

[0063] and

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

[0072] In the compound of any one of paragraphs

[0010] to

[0071] , 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.

[0073] In the compound of any one of paragraphs

[0010] to

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

[0074] In the compound of any one of paragraphs

[0010] to

[0073] , R 4 It is propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxycarbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane-1-yl, tridecane-1-yl, pentadecane-1-yl, pentadecane-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decane-2-yl, or heneicosane-1-yl.

[0075] In the compound of any one of paragraphs

[0010] to

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

[0076] In the compounds of any of paragraphs

[0010] to

[0072] and

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

[0077] In the compound of any one of paragraphs

[0010] to

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

[0078] In the compounds of any of paragraphs

[0010] to

[0072] and

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

[0079] In the compound of any one of paragraphs

[0010] to

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

[0080] In the compounds of any of paragraphs

[0010] to

[0072] and

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

[0081] In the compounds of any of paragraphs

[0019] to

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

[0082] In the compounds of any of paragraphs

[0022] to

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

[0083] In the compound of any one of paragraphs

[0010] to

[0083] , 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–.

[0084] In the compound of any of paragraphs

[0010] to

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

[0085] In the compound of any one of paragraphs

[0010] to

[0085] , 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–.

[0086] In the compound of any of 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 -S-S-.

[0087] The compound of paragraph

[0010] has the following structure: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0088] The compounds are 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyl-dihexanoate 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyl-dihexanoate 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)-carbamoyl)oxy)heptane-1,7-diyl-dihexanoate 3; 4-( 3-(2-((2-(dimethylamino)ethyl)amino)ethyl)-ureido)heptane-1,7-diyl-dihexanoate 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.

[0089] The compound has the following structure: or a tautomer thereof, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0090] The lipid nanoparticle comprises a compound of any one of paragraphs

[0010] to

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

[0091] The pharmaceutical composition comprises a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a nucleic acid; (ii) a compound of any one of paragraphs

[0010] to

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

[0092] The pharmaceutical composition of paragraph

[0092] further comprises a conjugated lipid.

[0093] In the pharmaceutical composition of paragraph

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

[0094] In the pharmaceutical composition of any of paragraphs

[0092] to

[0094] , the nucleic acid is mRNA.

[0095] In the pharmaceutical composition of any of paragraphs

[0092] to

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

[0096] In the pharmaceutical composition of any of paragraphs

[0092] to

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

[0097] In the pharmaceutical composition of paragraph

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

[0098] In the pharmaceutical composition of any of paragraphs

[0092] to

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

[0099] In the pharmaceutical composition of paragraph

[0099] , the liver cells are hepatocytes.

[0100] In the pharmaceutical composition of any of paragraphs

[0092] to

[0096] , the pharmaceutical composition preferentially partitions to spleen cells.

[0101] In the pharmaceutical composition of paragraph

[00101] , wherein the spleen cells are splenocytes.

[0102] In the pharmaceutical composition of any of paragraphs

[0092] to

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

[0103] In the pharmaceutical composition of paragraph

[00103] , the biologically active protein or enzyme is produced in or systemically secreted from liver cells.

[0104] In the pharmaceutical composition of paragraph

[00103] , the biologically active protein or enzyme is produced in or systemically secreted from cells of the lungs, heart or eyes, or the central nervous system. 7. Description of the Figures

[0105] Figure 1 Figure 24 shows the in vitro evaluation of luciferase expression of the circular RNA encoding luciferase. This experiment adopts human embryonic kidney 293T cells (HEK 293T cells), non-small cell lung cancer cell line (A549), human hepatocarcinoma cell line (HepG2) and mouse myoblast cell line (c2c12). The figure is processed by the mean value of the corresponding expression of calculating LNP. The relative value of the expression of LNP is divided by the mean value of the expression of reference 1, to obtain the consistency of data.

[0106] See further Figure 1 , Figure 2 In vitro expression of cationic liposomes with different tail types is shown.

[0107] Figure 3 Figure 2 shows the in vivo expression of cationic liposomes of different tail types. The circular RNA encoding luciferase encapsulated by LNP was systemically administered to female BALB / cJ mice of 6-8 weeks of age by tail vein injection or intramuscular injection. 2 mice / group were injected with a predetermined dose by tail vein injection. 1 mouse / group was injected with a predetermined dose by intramuscular injection into the left and right legs. At 6 hours and 24 hours, mice were placed on an imaging platform. Bioluminescence imaging was performed with an IVIS spectrum, and data were obtained. The figure was processed by calculating the mean value of the corresponding expression of LNP.

[0108] See further Figure 3 , Figure 4 Expression with five cationic liposomes is shown. 8. Detailed Description of the Invention 8.1 Definitions

[0109] To facilitate understanding of the disclosure described herein, a number of terms are defined below.

[0110] 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.

[0111] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., with reference to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0112] The terms "treat," "treating," and "treatment" are intended to include alleviating or eliminating a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0113] The terms "prevent," "preventing," and "prevention" are intended to include a method of delaying and / or excluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; preventing a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of developing a disorder, disease, or condition.

[0114] The terms "alleviate" and "alleviating" refer to relieving or alleviating one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms may also refer to reducing an adverse effect associated with an active ingredient. Sometimes, the beneficial effects a subject experiences from a preventive or therapeutic drug do not cure the disorder, disease, or condition.

[0115] The term "contacting" or "contact" refers to the bringing together of a therapeutic agent and a biomolecule (such as a protein, enzyme, RNA or DNA), cell or tissue so that the contact produces a physiological and / or chemical effect. Contact can be performed in vitro, ex vivo or in vivo. In one embodiment, the therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, the therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, contacting the therapeutic agent with the biomolecule, cell or tissue comprises administering the therapeutic agent to a subject having the biomolecule, cell or tissue to be contacted.

[0116] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound that, upon administration, is sufficient to prevent the development of, 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 an amount of a compound that is sufficient to elicit the biological or medical response of a biomolecule (such as a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0117] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with tissues or organs of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 23rd ed.; AdejareEd.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources,2007;PharmaceuticalPreformulation and Formulation,1st ed.;Gibson Ed.;CRC Press,2015.

[0118] The term "about" or "approximately" refers to the acceptable error for a particular value as determined by one of ordinary skill in the art, which depends to some extent 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.

[0119] As used herein, the terms "a / an" in this specification may refer to one or more. The terms "a / an" used in the claims, when used with the term "comprising", may refer to one or more.

[0120] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group, wherein the alkyl group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6Alkyl refers to a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, an alkyl group is a group having 1 to 20 carbon atoms. 1-20 ), 1-15 (C 1-15 ), 1-10 (C 1-10 ) or 1-6 (C 1-6 ) carbon atoms, or a straight-chain saturated monovalent hydrocarbon group having 3-20 (C 3-20 ), 3-15 (C 3-15 ), 3-10 (C 3-10 ) or 3-6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branched C 3-6 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 isomeric forms, such as n-propyl and isopropyl), butyl (including all isomeric forms, such as n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including all isomeric forms, such as n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, such as n-hexyl, isohexyl, and sec-hexyl).

[0121] The terms "alkylene" and "alkanediyl" are used interchangeably herein to refer to a straight or branched chain saturated divalent hydrocarbon radical, wherein the alkanediyl radical is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkanediyl refers to a straight chain saturated divalent hydrocarbon group of 1-6 carbon atoms, or a branched chain saturated divalent hydrocarbon group of 3-6 carbon atoms. In some embodiments, the alkanediyl group is a saturated divalent hydrocarbon group having 1-30 carbon atoms. 1-30 ), 1-20 (C 1-20 ), 1-15 (C 1-15 ), 1-10 (C 1-1 0) or 1-6 (C 1-6 ) carbon atoms, or a straight-chain saturated divalent hydrocarbon group having 3-30 (C 3-30 ), 3-20 (C 3-20 ), 3-15 (C 3-1 5) 3-10 (C 3-10 ) or 3-6(C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branched C 3-6Alkanediyl is also known as "lower alkanediyl". Examples of alkanediyl include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms such as ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms such as propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), butanediyl (including all isomeric forms such as butane-1,1-diyl, butane-1,2-diyl and butane-1,3-diyl), and methyldiyl. 1,5-diyl), and hexane-1,1-diyl (including all isomeric forms, for example, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, –C(O)CH2–, –C(O)(CH2)2–, –C(O)(CH2)3–, –C(O)(CH2)4–, –C(O)(CH2)5–, –C(O)(CH2)6–, –C(O)(CH2)7–, –C(O)(CH2)8–, –C(O)(CH2)9–, –C(O)(CH2) 10 –, –C(O)CH2C(O)–, –C(O)(CH2)2C(O)–, –C(O)(CH2)3C(O)–, –C(O)(CH2)4C(O)–, or –C(O)(CH2)5C(O)–.

[0122] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon group containing one or more heteroatoms in its backbone, each heteroatom independently selected from O, S, and N. The heteroalkyl group is optionally substituted with one or more substituents Q as described herein. For example, C1-6 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 1-20 (C 1-20 )、1-15(C 1-15 )、1-10(C 1-10 ), or 1-6(C 1-6 ) carbon atoms, or a straight-chain saturated monovalent hydrocarbon group having 3-20 (C 3-20 )、3-15(C 3-15 )、3-10(C 3-10 ), or 3-6(C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and straight chain C 3-6Heteroalkyl is also referred to as "lower heteroalkyl." Examples of heteroalkyl include, but are not limited to, -OCH, -OCHCH, -CHOCH, -NHCH, -ONHCH, -NHOCH, -SCH, -CHNHCHCH, and -NHCHCHCH. Examples of substituted heteroalkyl include, but are not limited to, -CHNHC(O)CH and -NHC(O)CHCH.

[0123] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein and refer to a straight or branched saturated divalent hydrocarbon group containing one or more heteroatoms in its backbone, each independently selected from O, S, and N. The heteroalkylene group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms, or a branched chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In some embodiments, the heteroalkylene is a saturated divalent hydrocarbon group having 1 to 20 carbon atoms. 1-20 )、1-15(C 1-15 )、1-10(C 1-10 ) or 1-6(C 1-6 ) carbon atoms, or a straight-chain saturated divalent hydrocarbon group having 3-20 (C 3-20 )、3-15(C 3-15 )、3-10(C 3-10 ) or 3-6(C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branched C 3-6 Heteroalkylene also refers to “lower heteroalkylene”. Examples of heteroalkylene include, but are not limited to, –CH2O–, –(CH2)2O–, –(CH2)3O–, –(CH2)4O–, –(CH2)5O–, –(CH2)6O–, –(CH2)7O–, –(CH2)8O–, –(CH2)9O–, –(CH2) 10O–, –CH2OCH2–, –CH2CH2O–, –(CH2CH2O)2–, –(CH2CH2O)3–, –(CH2CH2O)4–, –(CH2CH2O)5–, –CH2NH–, –CH2NHCH2–, –CH2CH2NH–, –CH2S–, –CH2SCH2–, and –CH2CH2S–. Examples of substituted heteroalkylene include, but are not limited to, –C(O)CH2O–, –C(O)(CH2)2O–, –C(O)(CH2)3O–, –C(O)(CH2)4O–, –C(O)(CH2)5O–, –C(O)(CH2)6O–, –C(O)(CH2)7O–, –C(O)(CH2)8O–, –C(O)(CH2)9O–, –C(O)(CH2) 10 O–, –C(O)CH2OCH2CH2O–, –C(O)CH2O(CH2CH2O)2–, –C(O)CH2O(CH2CH2O)3–, –C(O)CH2O(CH2CH2O)4, –C(O)CH2O(CH2CH2O)5–, –CH2NHC(O)CH2–, or –CH2CH2C(O)NH–.

[0124] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing one or more, in one embodiment, one, two, three or four, and in another embodiment, one carbon-carbon double bond. The alkenyl group is 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 "cis" or "trans" configurations or mixtures thereof, or, alternatively, groups having "Z" or "E" configurations or mixtures thereof. For example, C 2-6 Alkenyl refers to a straight chain unsaturated monovalent hydrocarbon group having 2-6 carbon atoms, or a branched unsaturated monovalent hydrocarbon group having 3-6 carbon atoms. In some embodiments, the alkenyl is a group having 2-20 (C 2-20 )、2-15(C 2-15 )、2-10(C 2-10 ) or 2-6(C 2-6 ) carbon atoms, or a linear monovalent hydrocarbon group having 3-20 (C 3-20 )、3-15(C 3-15 )、3-10(C 3-10 ) or 3-6(C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms such as propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms such as buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0125] The terms "alkenylene" and "alkenediyl" are used interchangeably herein and refer to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, one, two, three or four, and in another embodiment, one carbon-carbon double bond. The alkenediyl radical is optionally substituted with one or more substituents Q as described herein. The term "alkenediyl" includes radicals or mixtures thereof having "cis" or "trans" configurations, or radicals or mixtures thereof having "Z" or "E" configurations, as known to those of ordinary skill in the art. For example, C 2-6 Alkenediyl refers to a straight-chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms, or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In some embodiments, the alkenediyl is 2 to 30 (C 2-30 )、2-20(C 2-20 )、2-15(C 2-15 )、2-10(C 2-10 ) or 2-6(C 2-6 ) carbon atoms, or 3-30 (C 3-30 )、3-20(C 3-20 )、3-15(C 3-15 )、3-10(C 3-10 ) or 3-6(C 3-6 ) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethylenediyl (including all isomeric forms, for example, ethylene-1,1-diyl and ethylene-1,2-diyl), propylenediyl (including all isomeric forms, for example, 1-propylene-1,1-diyl, 1-propylene-1,2-diyl and 1-propylene-1,3-diyl), butenediyl (including all isomeric forms, for example, 1-butene-1,1-diyl, 1-butene-1,2-diyl and 1-butene- 1-hexene-1,4-diyl), pentenediyl (including all isomeric forms, for example, 1-pentene-1,1-diyl, 1-pentene-1,2-diyl and 1-pentene-1,5-diyl) and hexenediyl (including all isomeric forms, for example, 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).

[0126] The term "heteroalkenyl" refers to a straight or branched monovalent hydrocarbon radical containing one or more, in one embodiment, one, two, three or four, in another embodiment, one carbon-carbon double bond, and containing one or more heteroatoms in the hydrocarbon chain, each of which is independently selected from the group consisting of O, S and N. The heteroalkenyl radical is optionally substituted with one or more substituents Q as described herein. The term "heteroalkenyl" includes radicals having "cis" or "trans" configurations or mixtures thereof, or radicals having "Z" or "E" configurations or mixtures thereof, as known to those of ordinary skill in the art. For example, C 2-6 Heteroalkenyl refers to a straight-chain unsaturated monovalent hydrocarbon group of 2-6 carbon atoms, or a branched unsaturated monovalent hydrocarbon group of 3-6 carbon atoms. In some embodiments, the heteroalkenyl is 2-20 (C 2-20 )、2-15(C 2-15 )、2-10(C 2-10 ) or 2-6(C 2-6 ) carbon atoms, or 3-20 (C 3-20 )、3-15(C 3-15 )、3-10(C 3-10 ) or 3-6(C 3-6 ) carbon atoms.

[0127] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing one or more, in one embodiment, one, two, three or four, in another embodiment, one carbon-carbon triple bond. Alkynyl groups do not contain carbon-carbon double bonds. The alkynyl group is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a straight chain unsaturated monovalent hydrocarbon group of 2-6 carbon atoms, or a branched unsaturated monovalent hydrocarbon group of 4-6 carbon atoms. In some embodiments, the alkynyl group is 2-20 (C 2-20 )、2-15(C 2-15 )、2-10(C 2-10 ) or 2-6(C 2-6 ) carbon atoms, or 4-20 (C 4-20 )、4-15(C 4-15 )、4-10(C 4-10 ) or 4-6(C 4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (including all isomeric forms, for example, 1-propynyl (—C≡CCH3) and propargyl (—CH2C≡CH)), butynyl (including all isomeric forms, for example, 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, for example, 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, for example, 1-hexyn-1-yl and 2-hexyn-1-yl).

[0128] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, one, two, three or four, and in another embodiment, one carbon-carbon triple bond. Alkynediyl does not contain a carbon-carbon double bond. The alkynediyl radical is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a straight chain unsaturated divalent hydrocarbon group of 2-6 carbon atoms, or a branched unsaturated divalent hydrocarbon group of 4-6 carbon atoms. In some embodiments, the alkynediyl is 2-30 (C 2-30 )、2-20(C 2-20 )、2-15(C 2-15 )、2-10(C 2-10 ), or 2-6(C 2-6 ) carbon atoms, or 4-30 (C 4-30 )、4-20(C 4-20 )、4-15(C 4-15 )、4-10(C 4-10 ), or 4-6(C 4-6 ) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, for example, 1-propyn-1,3-diyl and 1-propyn-3,3-diyl), butynediyl (including all isomeric forms, for example, 1-butyn-1,3-diyl, 1-butyn-1,4-diyl and 2-butyn-1,1-diyl), pentynediyl (including all isomeric forms, for example, 1-pentyn-1,3-diyl, 1-pentyn-1,4-diyl and 2-pentyn-1,1-diyl), and hexynediyl (including all isomeric forms, for example, 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl and 2-hexyn-1,1-diyl).

[0129] The term "cycloalkyl" is a cyclic monovalent hydrocarbon group that is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl group is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In some embodiments, the cycloalkyl group has 3-20 (C 3-20 )、3-15(C 3-15 )、3-10(C 3-10 ) or 3-7(C 3-7 ) carbon atoms. In one embodiment, the cycloalkyl group is monocyclic. In another embodiment, the cycloalkyl group is bicyclic. In yet another embodiment, the cycloalkyl group is tricyclic. In yet another embodiment, the cycloalkyl group is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0130] 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 group has 6-20 (C 6-20 )、6-15(C 6-15 ) or 6-10(C 6-10 ) 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 yet another embodiment, the aryl is tricyclic. In yet another embodiment, the aryl is polycyclic. In some embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0131] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In some embodiments, the aralkyl group has 7-30 (C 7-30 )、7-20(C 7-20 ) or 7-16(C 7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0132] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group comprising at least one aromatic ring, wherein at least one aromatic ring comprises one or more heteroatoms in the ring, the heteroatoms being independently selected from O, S, and N. For heteroaryl groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not bound to the rest of the molecule through its 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 5-20, 5-15, or 5-10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), yl), imidazopyridinyl (including all isomeric forms, such as imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, such as imidazo[2,1-b]thiazolyl and imidazobi[4,5-d]thiazolyl), indazolyl, indolinazinyl, indolyl, isobenzofuranyl, isobenzothiophenyl (i.e., benzo[c]thiophenyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, 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 isomeric forms, such as pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3, In another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, benzophenanthridinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthanene. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0133] 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 is a heteroatom, each independently selected from: O, S and N; and the remaining ring atoms are carbon atoms. For heterocyclyl groups containing heteroaromatic rings and non-aromatic heterocycles, the heterocyclyl group is not bound to the rest of the molecule through the heteroaromatic ring. In some embodiments, the heterocyclyl or heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7 or 5-6 ring atoms. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may be fused or bridged, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or completely saturated or aromatic. The heterocyclyl group may be attached to the main structure at any heteroatom or carbon atom, which results in a stable compound. Examples of heterocyclic groups include, but are not limited to, azepanyl, benzodioxanyl, benzodioxolanyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzoisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothiophenyl, dihydroisobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl , dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl and isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiazolidinyl, dihydrochromanyl (thiochromanyl), tetrahydroquinolinyl and 1,3,5-trithianyl. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0134] The terms "halogen," "halogenated," or "halo" refer to fluoro, chloro, bromo, and / or iodo.

[0135] The term "optionally substituted" refers to a group or substituent, such as alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl, which may be substituted by one or more, in one embodiment, one, two, three or four substituents Q, each of which is independently selected from, for example, (a) deuterium (-D), cyano (-CN), halogen, imino (=NH), nitro (-NO2) and oxo (=O); (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is optionally further substituted 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 bR c ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(NR d )NR b R c ,–NR a C(S)R d ,–NR a C(S)OR d ,–NR a C(S)NR b R c ,–NR a S(O)R d ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR b R c 、=NOR a ,–SR a ,–S(O)R a ,–S(O)2R a ,–S(O)NR b R c and –S(O)2NR b R c , 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, one, two, three or four substituents Q a or (iii) R b and R cTogether 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 Substitution. As used herein, all groups that can be substituted are "optionally substituted."

[0136] In one embodiment, each Q a are independently selected from: (a) deuterium, cyano, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)–C(O)R e 、–C(O)OR e ,–C(O)NR f R g ,–C(O)SR e ,–C(NR e )NR f R g ,–C(S)R e ,–C(S)OR e ,–C(S)NR f R g 、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f R g 、–OC(O)SR e 、–OC(NR e )NR f R g 、–OC(S)R e 、–OC(S)OR e ,–OC(S)NR f R g 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f R g ,–NR e C(O)R h,–NR e C(O)OR f ,–NR e C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=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.

[0137] In some embodiments, "optically active" and "enantiomeric activity" refer to a collection of molecules having an enantiomeric excess of not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In some embodiments, the optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In some embodiments, the optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In some embodiments, the optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture.

[0138] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center. The prefixes (+) and (-) are used to denote the compound's optical rotation, which is the direction in which the optically active compound rotates the plane of polarized light. The prefix (-) indicates that the compound is levorotatory, meaning that the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, meaning that the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of optical rotation (+) and (-) are unrelated to the absolute configuration, R or S, of the compound.

[0139] The term "isotopically enriched" refers to a compound that contains an unnatural proportion of isotopes on one or more atoms comprising the compound. In some embodiments, an isotopically enriched compound contains an unnatural proportion of one or more isotopes, including but not limited to: hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 (31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I). In some embodiments, the isotopically enriched compound is in a stable form, i.e., non-radioactive. In some embodiments, the isotopically enriched compound contains an unnatural proportion of one or more isotopes, including but not limited to: hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br) and iodine-127( 127 I). In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotopically enriched compound contains an unnatural proportion of one or more isotopes, including but not limited to: tritium ( 3 H), carbon-11 ( 11 C), carbon-14 (14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35( 35 S), chlorine-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and iodine-131( 131 I) It should be understood that in the compounds of the present application, according to the judgment of those skilled in the art, any hydrogen, for example, can be 2 H, or any carbon such as 13 C, or any nitrogen such as 15 N, or any oxygen such as 18 O.

[0140] The terms "nucleic acid," "polynucleotide," and "oligonucleotide" are used interchangeably herein to refer to polymers or oligomers of nucleotides of any length. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides (e.g., methylated, hydroxymethylated, or glycosylated), non-natural nucleotides, non-nucleotide building blocks that exhibit similar structures and / or functions to natural nucleotides (i.e., "nucleotide analogs"), and / or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. The composition of nucleic acids or polynucleotides can be heterogeneous or homogeneous, can be isolated from natural sources, or can be artificially or synthetically produced. In addition, nucleic acids can be DNA or RNA, or mixtures thereof, and can exist permanently or transiently in single-stranded 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, for example, Braasch and Corey, Biochemistry 2002, 4, 4503-10; and US 5,034,506), locked nucleic acids (LNAs; see, for example, Wahlestedt et al., Proc. Natl. Acad. Sci. USA 2000, 97, 5633-8), cyclohexenyl nucleic acids (see, for example, Wang, Am. Chem. Soc. 2000, 122, 8595-602), and / or ribozymes.

[0141] As used herein, "substantially free" with respect to a particular ingredient means that none of the particular ingredient is intentionally formulated into the composition and / or is present only as a contaminant or in trace amounts. Thus, the total amount of the particular ingredient due to any unintentional contamination of the composition is well below 0.1%, preferably below 0.05%, and more preferably below 0.01%. Most preferred are compositions in which the amount of the particular ingredient cannot be detected by standard analytical methods.

[0142] The terms "substantially pure" and "substantially homogeneous" refer to a substance that is sufficiently homogeneous to be free of readily detectable impurities as determined by standard analytical methods used by one of ordinary skill in the art, including but not limited to thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic and biological activity. In some embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less common isotope, the molecule is an impurity relative to the isotopically enriched compound if other isotopes are contained at that particular position. Thus, for a deuterated compound where a particular position is designated as deuterium, a compound containing protium at the same position is an impurity.

[0143] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (e.g., a compound of the present application) and one or more solvent molecules, which are present 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, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0144] For divalent groups described herein, the orientation 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 orientation is specified.

[0145] The phrase "enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variation thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof" has the same meaning as the phrases: "(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variation of a compound mentioned herein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of a compound mentioned herein; or (iii) a pharmaceutically acceptable salt, solvate, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or a hydrate of an isotopic variation of a compound mentioned herein." 8.2 Lipid compounds

[0146] In one embodiment, the present application provides a compound of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 and R 2 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)R1a 、–C(S)OR 1a 、–C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c 、–NR 1b R 1c 、–NR 1a C(O)R 1d 、–NR 1a C(O)OR 1d 、–NR 1a C(O)NR 1b R 1c 、–NR 1a C(O)SR 1d 、–NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a C(S)R 1d 、–NR 1a C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR 1a S(O)R 1d 、–NR 1a S(O)2R 1d 、–NR 1a S(O)NR 1b R 1c 、–NR 1a S(O)2NR 1b R 1c 、–S(O)R 1a,–S(O)2R 1a ,–S(O)NR 1b R 1c 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 Each independently is C 1-40 Alkyl, C 1-40 Heteroalkyl, C 2-40 Alkenyl, C 2-40 Heteroalkenyl, C 2-40 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-30 Aralkyl, heteroaryl or 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 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene; A is –O– or –N(R 1a )–; E is –UC(O)N(R 1a )–, where U is –O– or –N(R 1b )–; 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 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; wherein each 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, halogen, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is optionally further substituted 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, one, two, three or four substituents Q a or (iii) R b and R cTogether 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 ,–NRe C(O)NR f R g ,–NR e C(O)SR f ,–NR e C(NR h )NR f R g ,–NR e C(S)R h ,–NR e C(S)OR f ,–NR e C(S)NR f R g ,–NR e S(O)R h ,–NR e S(O)2R h ,–NR e S(O)NR f R g ,–NR e S(O)2NR f R g 、=NOR e ,–SR e ,–S(O)R e 、–S(O)2R e ,–S(O)NR f R g and –S(O)2NR f R g ; 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.

[0147] In some embodiments, in Formula (I), L 1 C 1-6 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), 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, which 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, which is optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5 or 6. In some embodiments, in Formula (I), L 1 for –(CH2) a –, and a is an integer of 1, 2, 3, 4, 5 or 6. In some embodiments, in Formula (I), L 1 for –(CH2) a –, and a is an integer of 2, 3 or 4. In some embodiments, in Formula (I), L 1 It is –(CH2)2–.

[0148] In some embodiments, in Formula (I), L 2 C 1-6 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L 2 For–(CR 2a R 2b ) b –, where b is an integer 1, 2, 3, 4, 5, or 6; and each R 2a and R 2b As defined herein. In some embodiments, in Formula (I), L 2 for –(CH2) b –, and b is an integer of 1, 2, 3, 4, 5 or 6. In some embodiments, in Formula (I), L 2 for –(CH2) b –, and b is an integer of 2, 3 or 4. In some embodiments, in Formula (I), L 2 It is –(CH2)2–.

[0149] In some embodiments, in Formula (I), L 3 C 1-10 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L 3 For–(CR 2a R 2b ) c –, where c is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2bAs defined herein. In some embodiments, in Formula (I), L 3 for –(CH2) c –, and c is an integer of 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, in Formula (I), L 3 In some embodiments, in formula (I), L 3 It is –(CH2)3–.

[0150] In some embodiments, in Formula (I), L 4 C 1-10 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), L 4 For–(CR 2a R 2b ) d –, where d is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b As defined herein. In some embodiments, in Formula (I), L 4 for –(CH2) d –, and d is an integer of 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, in Formula (I), L 4 In some embodiments, in formula (I), L 4 It is –(CH2)3–.

[0151] In yet another embodiment, provided herein is a compound of formula (II): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein R 1 、R 2 、R 3 、R 4 , A, E, X, Z, a, b, c and d are each as defined herein.

[0152] In some embodiments, in Formula (I) or Formula (II), E is -OC(O)N(R 1a )–, where R 1a As defined herein. In some embodiments, in Formula (I) or Formula (II), E is -OC(O)N(H)-. In some embodiments, in Formula (I) or Formula (II), E is -N(R 1a )C(O)N(R1b )–, where R 1a and R 1b Each is as defined herein. In some embodiments, in Formula (I) or Formula (II), E is -N(H)C(O)N(H)-.

[0153] In yet another embodiment, provided herein is a compound of formula (III): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 1 、R 2 、R 3 、R 4 , A, U, X, Z, a, b, c and d are each as defined herein.

[0154] In some embodiments, in any one of formulae (I) to (III), A is —O—. In some embodiments, in any one of formulae (I) to (III), A is —N(R 1a )–, where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (III), A is -N(H)-.

[0155] In some embodiments, in any one of formulae (I) to (III), U is —O—. In some embodiments, in any one of formulae (I) to (III), U is —N(R 1a )–, where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (III), U is -N(H)-.

[0156] In yet another embodiment, provided herein is a compound of formula (IV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein R 1 、R 2 、R 3 、R 4 , X, Z, a, b, c and d are each as defined herein.

[0157] In yet another embodiment, provided herein is a compound of Formula (V): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein R 1 、R 2 、R 3 、R 4 , X, Z, a, b, c and d are each as defined herein.

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

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

[0160] In some embodiments, in any one of Formulas (I) to (VII), R 1 are: (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 7-15aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a ,–C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a ,–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R 1d ,–NR 1a C(O)OR 1d ,–NR 1a C(O)NR 1b R 1c ,–NR 1a C(O)SR 1d ,–NR 1a C(NR 1d )NR 1b R1c ,–NR 1a C(S)R 1d ,–NR 1a C(S)OR 1d ,–NR 1a C(S)NR 1b R 1c ,–NR 1a S(O)R 1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; where each R 1a 、R 1b 、R 1c and R 1d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)NR 1b R 1c 、–OR 1a or –S(O)2R 1a , where each R1a 、R 1b and R 1c As defined herein.

[0161] In some embodiments, in any one of Formulas (I) to (VII), R 1 C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 1 C 1-6 Alkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein.

[0162] In some embodiments, in any one of Formulas (I) to (VII), R 1 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethyl-amino, acetamido, methylurea, dimethylurea, methylthiourea, 3,3-dimethylthiourea, guanidinyl, methoxyimino, mercapto or methylsulfonamido.

[0163] In some embodiments, in any one of Formulas (I) to (VII), R 1 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxy, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methyl-thioureido, 3,3-dimethylthioureido, guanidinyl, methoxyimino, mercapto or methylsulfonamido.

[0164] In some embodiments, in any one of Formulas (I) to (VII), R 1 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 1-Hydroxybutyl, ...

[0165] In some embodiments, in any one of Formulas (I) to (VII), R 1 C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 1 C 1-6 Alkenyl, optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–ORa ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 It is 1-(dimethylamino)-2-nitrovinyl.

[0166] In some embodiments, in any one of Formulas (I) to (VII), R 1 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 C 3-10 Cycloalkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein.

[0167] In some embodiments, in any one of Formulas (I) to (VII), R 1 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 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 one of formulas (I) to (VII), R 1is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl.

[0168] In some embodiments, in any one of Formulas (I) to (VII), R 1 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 C 6-14 Aryl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 It is 4-dimethyl-aminophenyl.

[0169] In some embodiments, in any one of Formulas (I) to (VII), R 1 C 7-15 Aralkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 C 7-15 Aralkyl, optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 is 4-methoxy-benzyl.

[0170] In some embodiments, in any one of Formulas (I) to (VII), R 1 is a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 1 is heteroaryl, which is optionally substituted by one, two or three substituents Q, each Q being independently: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NRd )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein.

[0171] In some embodiments, in any one of Formulas (I) to (VII), R 1 is a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1 is a monocyclic heteroaryl group, which is optionally substituted by one, two or three substituents Q, each Q being independently: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 is a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 1is 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) to (VII), R 1 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.

[0172] In some embodiments, in any one of Formulas (I) to (VII), R 1 –C(O)R 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 is –C(O)–C 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 1 is –C(O)–C 1-6 Alkyl, wherein the alkyl is optionally substituted with -OR a Replace, and R a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl or isopropionyl. In some embodiments, in any one of formulas (I) to (VII), R 1 -C(O)OR 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 –C(O)OC 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 –C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 for –C(NR 1a )NR 1b R 1c , where R 1a 、R1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 –C(NCN)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 For –C(NOR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 –C(NS(O2)R 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 –C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 In some embodiments, in any one of formulas (I) to (VII), R 1 for –OR 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1In some embodiments, in any one of formulas (I) to (VII), R 1 is –S(O)2R 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 1 It is a methylsulfonyl group.

[0173] In some embodiments, in any one of Formulas (I) to (VII), R 1 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 )ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxy-propyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methyl) oxy-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, dimethyl In some embodiments, in any one of formulas (I) to (VII), R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0174] In some embodiments, in any one of Formulas (I) to (VII), R 2 are: (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(O)SR 1a ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR 1a )NR 1b R 1c ,–C(NS(O2)R 1a )NR 1b R 1c ,–C(S)R 1a ,–C(S)OR 1a ,–C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a ,–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c ,–NR 1b R 1c ,–NR 1a C(O)R1d ,–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 ; where each R 1a 、R 1b 、R 1c and R 1d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R 1c ,–C(NR 1a )NR 1b R 1c ,–C(NCN)NR 1b R 1c 、–C(NOR1a )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 , where each R 1a 、R 1b and R 1c As defined herein.

[0175] In some embodiments, in any one of Formulas (I) to (VII), R 2 C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 2 C 1-6 Alkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein.

[0176] In some embodiments, in any one of Formulas (I) to (VII), R2 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethyl-amino, acetamido, methylurea, dimethylurea, methylthiourea, 3,3-dimethylthiourea, guanidinyl, methoxyimino, mercapto, or methylsulfonamido.

[0177] In some embodiments, in any one of Formulas (I) to (VII), R 2 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxy, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethylureido, 3-methyl-thioureido, 3,3-dimethylthioureido, guanidinyl, methoxyimino, mercapto, or methylsulfonamido.

[0178] In some embodiments, in any one of Formulas (I) to (VII), R 2 The 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 1-Hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0179] In some embodiments, in any one of Formulas (I) to (VII), R 2 C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 2 C 1-6Alkenyl, optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 It is 1-(dimethylamino)-2-nitrovinyl.

[0180] In some embodiments, in any one of Formulas (I) to (VII), R 2 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 2 C 3-10 Cycloalkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NRb R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein.

[0181] In some embodiments, in any one of Formulas (I) to (VII), R 2 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 2 For monocyclic C 3-10 Cycloalkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a or –NR a S(O)2R d , where each R a 、Rb 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 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 one of formulas (I) to (VII), R 2 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl.

[0182] In some embodiments, in any one of Formulas (I) to (VII), R 2 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 2 C 6-14 Aryl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 It is 4-dimethyl-aminophenyl.

[0183] In some embodiments, in any one of Formulas (I) to (VII), R 2 C 7-15 Aralkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 2 C 7-15 Aralkyl, optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 is 4-methoxy-benzyl.

[0184] In some embodiments, in any one of Formulas (I) to (VII), R 2 is a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 2 is heteroaryl, which is optionally substituted by one, two or three substituents Q, each Q being independently: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein.

[0185] In some embodiments, in any one of Formulas (I) to (VII), R 2 is a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 2 is a monocyclic heteroaryl group, which is optionally substituted by one, two or three substituents Q, each Q being independently: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c ,–SR a or –NR a S(O)2R d , where each Ra 、R b 、R c and R d As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 is a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 2 is 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) to (VII), R 2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.

[0186] In some embodiments, in any one of Formulas (I) to (VII), R 2 –C(O)R 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 is –C(O)–C 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 2 is –C(O)–C 1-6 Alkyl, wherein the alkyl is optionally substituted with -OR a Replace, and R a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl or isopropionyl. In some embodiments, in any one of formulas (I) to (VII), R 2 -C(O)OR 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 –C(O)OC 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 –C(O)NR 1b R 1c , where R 1b and R 1cEach is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 for –C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 –C(NCN)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 For –C(NOR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 –C(NS(O2)R 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 –C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, in any one of Formulas (I) to (VII), R2 In some embodiments, in any one of formulas (I) to (VII), R 2 for –OR 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 In some embodiments, in any one of formulas (I) to (VII), R 2 is –S(O)2R 1a , where R 1a As defined herein. In some embodiments, in any one of Formulas (I) to (VII), R 2 It is a methylsulfonyl group.

[0187] In some embodiments, in any one of Formulas (I) to (VII), R 2Methyl, (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 )ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl, 2-guanidinoethyl, 2-(methylsulfonamido)ethyl, isopropyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxy-propyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methylpropyl, 2-hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methyl) oxy-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, dimethyl In some embodiments, in any one of formulas (I) to (VII), R 2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.

[0188] In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a heteroaryl or heterocyclyl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2Together with the N atom to which they are attached, they form a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 5-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 6-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form 1,2,3-triazol-1-yl, pyridin-1-ium, or pyrimidin-1-yl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the nitrogen atom to which they are attached, they form 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-ium, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

[0189] In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a bicyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 5,5-, 5,6-, or 6,6-fused heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2Together with the N atom to which they are attached, they form a 5,5-fused heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 5,6-fused heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 6,6-fused heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a purin-9-yl group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the nitrogen atom to which they are attached, they form 6-aminopurin-9-yl or 2-amino-6-oxo-1,9-dihydropurin-9-yl.

[0190] In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a monocyclic heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 3-membered heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 4-membered heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2Together with the N atom to which they are attached, they form a 5-membered heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they form a 6-membered heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached they form a 7-membered heterocyclic group which is optionally substituted by one or more substituents Q.

[0191] In some embodiments, in any one of Formulas (I) to (VII), R 1 and R 2 Together with the N atom to which they are attached, they 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 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 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 group.

[0192] In some embodiments, in any one of Formulas (I) to (VII), the moiety The amino groups are dimethylamino, (2-cyanoethyl)(methyl)amino, (cyclopropylmethyl)(methyl)amino, (cyclobutyl-methyl)(methyl)amino, (cyclopentylmethyl)(methyl)amino, (cyclohexylmethyl)(methyl)amino, (cycloheptylmethyl)(methyl)amino, (pyridin-2-ylmethyl)(methyl)amino, (pyridin-3-ylmethyl)-(methyl)amino, (pyridin-4-ylmethyl)(methyl)amino, (dimethylaminomethyl)(methyl)amino, (ethyl)(methyl)amino, (2-hydroxyethyl)(methyl)amino, (2-acetamidoethyl)(methyl)amino, (2-guanidinoethyl)(methyl)amino, (2-methylsulfonamidoethyl)(methyl)amino, (2-(3-methyl)amino)- ureido)-ethyl)(methyl)amino, (2-(3,3-dimethylureido)ethyl)(methyl)amino, (2-(3-methylthioureido)-ethyl)(methyl)amino, (2-(3,3-dimethylthioureido)ethyl)(methyl)amino, diethylamino, (1,3-dihydroxypropan-2-yl)amino, (isopropyl)(methyl)amino, (R)-(2-hydroxy-propyl)(methyl)amino, (S)-(2-hydroxypropyl)(methyl)amino, (3-hydroxypropyl)(methyl)amino, (1,3-dihydroxypropan-2-yl)(methyl)amino, (ethyl)(isopropyl)amino, diisopropylamino, (4-hydroxybutyl)(methyl)amino, (R)-(2-hydroxybutyl)(methyl )amino, (S)-(2-hydroxybutyl)-(methyl)amino, (5-hydroxypentyl)-(methyl)amino, (4-(2-hydroxyethoxy)butyl)(methyl)amino, 4-(methoxyimino)butylamino, (4-(methoxyimino)butyl)(methyl)amino, (5-hydroxy-5-carboxypentyl)(methyl)amino, (6-hydroxy-hexyl)(methyl)amino, 1-(methylamino)-2-nitrovinylamino, (cyclopropyl)(methyl)amino, (cyclobutyl)(methyl)amino, (cyclopentyl)(methyl)amino, (cyclohexyl)(methyl)amino, (cycloheptyl)-(methyl)amino, (2-hydroxycycloheptyl)(methyl)amino, 2-dimethylamino-3,4-dioxo-1 -cyclobutenyl, (4-dimethylaminophenyl)amino, (4-methoxybenzyl)(methyl)amino, imidazol-2-ylamino, thiazol-2-ylamino, (pyridin-2-yl)(methyl)amino, (pyridin-3-yl)(methyl)amino, methoxyformamido, methylaminoformamido, dimethylaminoformamido, methylaminothioformamido, dimethylaminothioformamido, acetamido, N-(methyl)acetamido, N-(2-hydroxy)acetamido, N-(2-methoxy)acetamido, N-(2-benzyloxy)acetamido, propionamido, isobutyramide, guanidine, 2-cyano-3,3-dimethylguanidine, 2-methoxy-3,3-dimethylguanidine, 2-methylsulfonyl-3,3-dimethyl-guanidino, N-(methyl)hydroxyamino, N-(methoxy)acetamido, N-(methoxy)methoxyformamido, methylsulfonamido, or N-(methoxy)(methylsulfonamido).

[0193] In some embodiments, in any one of Formulas (I) to (VII), the moiety 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-yl, 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-methylaziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrimidin-1-yl pyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3,5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(4-methoxybenzyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or 1,3-dioxoisoindolin-2-yl.

[0194] In some embodiments, in any one of Formulas (I) to (VII), the moiety Has the following structure: 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 1a As defined herein; in one embodiment, each R 1a Independently C 1-6 alkyl, which is optionally substituted with one or more substituents Q; and in another embodiment, each R 1a It is a methyl group.

[0195] In some embodiments, in any one of Formulas (I) to (VII), R 3 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 arylalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 C1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl or C 6-14 Aryl, each of which is optionally substituted with one or more substituents Q.

[0196] In some embodiments, in any one of Formulas (I) to (VII), R 3 C 1-30 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 C 1-25 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 C 1-20 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 3 It is propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxycarbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane-1-yl, tridecane-1-yl, pentadecane-1-yl, pentadecane-7-yl, heptadecan-1-yl, hept-decane-9-yl, nonadecan-1-yl, decane-2-yl, or heneicosane-1-yl.

[0197] In some embodiments, in any one of Formulas (I) to (VII), R 3 C 1-30 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 C 1-25alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 C 1-20 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 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) to (VII), R 3 are: (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-penta-decen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-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.

[0198] In some embodiments, in any one of Formulas (I) to (VII), R 3 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 3 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 3 is cyclohexyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 3 It is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

[0199] In some embodiments, in any one of Formulas (I) to (VII), R 3 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 3 is phenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 3 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0200] In some embodiments, in any one of Formulas (I) to (VII), R 3 Propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxycarbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane -1-yl, tridec-1-yl, pentadec-1-yl, pentadec-7-yl, heptadec-1-yl, heptadec-9-yl, nonadecan-1-yl, decane-2-yl, heneicosane-1-yl, 2-(dodec-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-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. 1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexyl-cyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0201] In some embodiments, in any one of Formulas (I) to (VII), R 3 for:

[0202] In some embodiments, in any one of Formulas (I) to (VII), 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.

[0203] In some embodiments, in any one of Formulas (I) to (VII), R 3 for: 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.

[0204] In some embodiments, in any one of Formulas (I) to (VII), R 3 for:

[0205] In some embodiments, in any one of Formulas (I) to (VII), R 4 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 arylalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-10 Cycloalkyl or C 6-14 Aryl, each of which is optionally substituted with one or more substituents Q.

[0206] In some embodiments, in any one of Formulas (I) to (VII), R 4 C 1-30alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 C 1-25 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 C 1-20 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 4 It is propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxycarbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane-1-yl, tridecane-1-yl, pentadecane-1-yl, pentadecane-7-yl, heptadecan-1-yl, hept-decane-9-yl, nonadecan-1-yl, decane-2-yl, or heneicosane-1-yl.

[0207] In some embodiments, in any one of Formulas (I) to (VII), R 4 C 1-30 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 C 1-25 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 C 1-20 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4is 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) to (VII), R 4 are: (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-penta-decen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-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.

[0208] In some embodiments, in any one of Formulas (I) to (VII), R 4 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 4 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 4 is cyclohexyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulae (I) to (VII), R 4 It is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.

[0209] In some embodiments, in any one of Formulas (I) to (VII), R 4 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of Formulas (I) to (VII), R 4is phenyl, which is optionally substituted with one or more substituents Q. In some embodiments, in any one of formulas (I) to (VII), R 4 is 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0210] In some embodiments, in any one of Formulas (I) to (VII), R 4 Propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxycarbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane -1-yl, tridec-1-yl, pentadec-1-yl, pentadec-7-yl, heptadec-1-yl, heptadec-9-yl, nonadecan-1-yl, decane-2-yl, heneicosane-1-yl, 2-(dodec-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-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. 1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-octadeca-9,12-dien-1-yl, (5Z,8Z,11Z)-heptadeca-5,8,11-trien-1-yl, (8Z,11Z,14Z)-heptadeca-8,11,14-trien-1-yl, 4-pentylcyclohexyl, 4-cyclohexyl-cyclohexyl, 3-pentylphenyl, 4-pentylphenyl, or 3,4-dipentylphenyl.

[0211] In some embodiments, in any one of Formulas (I) to (VII), R 4 for:

[0212] In some embodiments, in any one of Formulas (I) to (VII), 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.

[0213] In some embodiments, in any one of Formulas (I) to (VII), R 4 for: 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.

[0214] In some embodiments, in any one of Formulas (I) to (VII), R 4 for:

[0215] In one embodiment, provided herein is a compound of Formula A1: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein g and h are each independently an integer 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.

[0216] In another embodiment, provided herein is a compound of Formula A2: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0217] In yet another embodiment, provided herein is a compound of Formula A3: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0218] In yet another embodiment, provided herein is a compound of Formula A4: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein i and j are each independently an integer 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.

[0219] In yet another embodiment, provided herein is a compound of Formula A5: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0220] In yet another embodiment, provided herein is a compound of Formula A6: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0221] In one embodiment, provided herein is a compound of Formula A7: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0222] In another embodiment, provided herein is a compound of Formula A8: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0223] In yet another embodiment, provided herein is a compound of Formula A9: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0224] In yet another embodiment, provided herein is a compound of Formula A10: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0225] In yet another embodiment, provided herein is a compound of Formula A11: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0226] In yet another embodiment, provided herein is a compound of Formula A12: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0227] In one embodiment, provided herein is a compound of formula A13: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0228] In another embodiment, provided herein is a compound of formula A14: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0229] In yet another embodiment, provided herein is a compound of Formula A15: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0230] In yet another embodiment, provided herein is a compound of formula A16: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0231] In yet another embodiment, provided herein is a compound of formula A17: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0232] In yet another embodiment, provided herein is a compound of Formula A18: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0233] In one embodiment, provided herein is a compound of formula A19: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0234] In another embodiment, provided herein is a compound of formula A20: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0235] In yet another embodiment, provided herein is a compound of Formula A21: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0236] In yet another embodiment, provided herein is a compound of Formula A22: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0237] In yet another embodiment, provided herein is a compound of Formula A23: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0238] In yet another embodiment, provided herein is a compound of formula A24: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0239] In one embodiment, provided herein is a compound of formula A25: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0240] In another embodiment, provided herein is a compound of formula A26: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0241] In yet another embodiment, provided herein is a compound of Formula A27: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0242] In yet another embodiment, provided herein is a compound of formula A28: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0243] In yet another embodiment, provided herein is a compound of formula A29: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0244] In yet another embodiment, provided herein is a compound of formula A30: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0245] In one embodiment, provided herein is a compound of formula A31: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0246] In another embodiment, provided herein is a compound of formula A32: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0247] In yet another embodiment, provided herein is a compound of formula A33: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0248] In yet another embodiment, provided herein is a compound of formula A34: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j, k and m are each as defined herein.

[0249] In yet another embodiment, provided herein is a compound of formula A35: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0250] In yet another embodiment, provided herein is a compound of formula A36: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0251] In one embodiment, provided herein is a compound of formula A37: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0252] In another embodiment, provided herein is a compound of formula A38: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0253] In yet another embodiment, provided herein is a compound of formula A39: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0254] In yet another embodiment, provided herein is a compound of formula A40: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0255] In yet another embodiment, provided herein is a compound of Formula A41: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0256] In yet another embodiment, provided herein is a compound of Formula A42: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0257] In one embodiment, provided herein is a compound of formula A43: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0258] In another embodiment, provided herein is a compound of formula A44: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0259] In yet another embodiment, provided herein is a compound of Formula A45: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0260] In yet another embodiment, provided herein is a compound of formula A46: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j and n are each as defined herein.

[0261] In yet another embodiment, provided herein is a compound of Formula A47: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0262] In yet another embodiment, provided herein is a compound of Formula A48: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0263] In one embodiment, provided herein is a compound of formula A49: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0264] In another embodiment, provided herein is a compound of formula A50: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0265] In yet another embodiment, provided herein is a compound of Formula A51: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0266] In yet another embodiment, provided herein is a compound of formula A52: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0267] In yet another embodiment, provided herein is a compound of formula A53: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0268] In yet another embodiment, provided herein is a compound of formula A54: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0269] In one embodiment, provided herein is a compound of Formula Bl: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0270] In another embodiment, provided herein is a compound of Formula B2: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0271] In yet another embodiment, provided herein is a compound of Formula B3: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0272] In yet another embodiment, provided herein is a compound of Formula B4: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, i and j are each as defined herein.

[0273] In yet another embodiment, provided herein is a compound of Formula B5: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0274] In yet another embodiment, provided herein is a compound of Formula B6: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0275] In one embodiment, provided herein is a compound of Formula B7: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0276] In another embodiment, provided herein is a compound of Formula B8: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0277] In yet another embodiment, provided herein is a compound of Formula B9: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0278] In yet another embodiment, provided herein is a compound of Formula B10: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0279] In yet another embodiment, provided herein is a compound of Formula B11: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0280] In yet another embodiment, provided herein is a compound of Formula B12: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0281] In one embodiment, provided herein is a compound of Formula B13: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0282] In another embodiment, provided herein is a compound of Formula B14: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0283] In yet another embodiment, provided herein is a compound of Formula B15: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0284] In yet another embodiment, provided herein is a compound of Formula B16: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0285] In yet another embodiment, provided herein is a compound of Formula B17: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0286] In yet another embodiment, provided herein is a compound of Formula B18: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0287] In one embodiment, provided herein is a compound of formula B19: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0288] In another embodiment, provided herein is a compound of formula B20: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0289] In yet another embodiment, provided herein is a compound of Formula B21: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0290] In yet another embodiment, provided herein is a compound of Formula B22: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0291] In yet another embodiment, provided herein is a compound of Formula B23: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0292] In yet another embodiment, provided herein is a compound of Formula B24: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0293] In one embodiment, provided herein is a compound of formula B25: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0294] In another embodiment, provided herein is a compound of Formula B26: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0295] In yet another embodiment, provided herein is a compound of Formula B27: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0296] In yet another embodiment, provided herein is a compound of Formula B28: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0297] In yet another embodiment, provided herein is a compound of Formula B29: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0298] In yet another embodiment, provided herein is a compound of formula B30: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0299] In one embodiment, provided herein is a compound of Formula B31: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0300] In another embodiment, provided herein is a compound of Formula B32: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0301] In yet another embodiment, provided herein is a compound of Formula B33: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0302] In yet another embodiment, provided herein is a compound of Formula B34: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j, k and m are each as defined herein.

[0303] In yet another embodiment, provided herein is a compound of Formula B35: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0304] In yet another embodiment, provided herein is a compound of Formula B36: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0305] In one embodiment, provided herein is a compound of formula B37: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0306] In another embodiment, provided herein is a compound of Formula B38: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0307] In yet another embodiment, provided herein is a compound of Formula B39: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0308] In yet another embodiment, provided herein is a compound of Formula B40: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0309] In yet another embodiment, provided herein is a compound of Formula B41: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0310] In yet another embodiment, provided herein is a compound of Formula B42: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0311] In one embodiment, provided herein is a compound of formula B43: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0312] In another embodiment, provided herein is a compound of Formula B44: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0313] In yet another embodiment, provided herein is a compound of Formula B45: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0314] In yet another embodiment, provided herein is a compound of Formula B46: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j and n are each as defined herein.

[0315] In yet another embodiment, provided herein is a compound of Formula B47: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0316] In yet another embodiment, provided herein is a compound of Formula B48: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0317] In one embodiment, provided herein is a compound of formula B49: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0318] In another embodiment, provided herein is a compound of formula B50: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0319] In yet another embodiment, provided herein is a compound of Formula B51: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0320] In yet another embodiment, provided herein is a compound of Formula B52: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0321] In yet another embodiment, provided herein is a compound of Formula B53: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0322] In yet another embodiment, provided herein is a compound of Formula B54: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0323] In one embodiment, provided herein is a compound of Formula C1: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0324] In another embodiment, provided herein is a compound of Formula C2: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0325] In yet another embodiment, provided herein is a compound of Formula C3: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0326] In yet another embodiment, provided herein is a compound of formula C4: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, i and j are each as defined herein.

[0327] In yet another embodiment, provided herein is a compound of Formula C5: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0328] In yet another embodiment, provided herein is a compound of formula C6: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0329] In one embodiment, provided herein is a compound of formula C7: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0330] In another embodiment, provided herein is a compound of Formula C8: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0331] In yet another embodiment, provided herein is a compound of formula C9: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0332] In yet another embodiment, provided herein is a compound of formula C10: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0333] In yet another embodiment, provided herein is a compound of formula C11: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0334] In yet another embodiment, provided herein is a compound of formula C12: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0335] In one embodiment, provided herein is a compound of formula C13: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0336] In another embodiment, provided herein is a compound of formula C14: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0337] In yet another embodiment, provided herein is a compound of formula C15: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0338] In yet another embodiment, provided herein is a compound of formula C16: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0339] In yet another embodiment, provided herein is a compound of formula C17: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0340] In yet another embodiment, provided herein is a compound of formula C18: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0341] In one embodiment, provided herein is a compound of formula C19: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0342] In another embodiment, provided herein is a compound of formula C20: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0343] In yet another embodiment, provided herein is a compound of Formula C21: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0344] In yet another embodiment, provided herein is a compound of Formula C22: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0345] In yet another embodiment, provided herein is a compound of Formula C23: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0346] In yet another embodiment, provided herein is a compound of Formula C24: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0347] In one embodiment, provided herein is a compound of formula C25: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0348] In another embodiment, provided herein is a compound of Formula C26: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0349] In yet another embodiment, provided herein is a compound of Formula C27: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0350] In yet another embodiment, provided herein is a compound of Formula C28: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0351] In yet another embodiment, provided herein is a compound of Formula C29: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0352] In yet another embodiment, provided herein is a compound of formula C30: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0353] In one embodiment, provided herein is a compound of Formula C31: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0354] In another embodiment, provided herein is a compound of Formula C32: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0355] In yet another embodiment, provided herein is a compound of Formula C33: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0356] In yet another embodiment, provided herein is a compound of Formula C34: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j, k and m are each as defined herein.

[0357] In yet another embodiment, provided herein is a compound of Formula C35: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0358] In yet another embodiment, provided herein is a compound of Formula C36: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0359] In one embodiment, provided herein is a compound of formula C37: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0360] In another embodiment, provided herein is a compound of Formula C38: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0361] In yet another embodiment, provided herein is a compound of Formula C39: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0362] In yet another embodiment, provided herein is a compound of formula C40: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0363] In yet another embodiment, provided herein is a compound of Formula C41: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0364] In yet another embodiment, provided herein is a compound of Formula C42: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0365] In one embodiment, provided herein is a compound of formula C43: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0366] In another embodiment, provided herein is a compound of Formula C44: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0367] In yet another embodiment, provided herein is a compound of Formula C45: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0368] In yet another embodiment, provided herein is a compound of Formula C46: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j and n are each as defined herein.

[0369] In yet another embodiment, provided herein is a compound of Formula C47: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0370] In yet another embodiment, provided herein is a compound of Formula C48: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0371] In one embodiment, provided herein is a compound of formula C49: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0372] In another embodiment, provided herein is a compound of Formula C50: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0373] In yet another embodiment, provided herein is a compound of Formula C51: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0374] In yet another embodiment, provided herein is a compound of Formula C52: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0375] In yet another embodiment, provided herein is a compound of Formula C53: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0376] In yet another embodiment, provided herein is a compound of Formula C54: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0377] In one embodiment, provided herein is a compound of formula D1: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0378] In another embodiment, provided herein is a compound of formula D2: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0379] In yet another embodiment, provided herein is a compound of formula D3: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e and f are each as defined herein.

[0380] In yet another embodiment, provided herein is a compound of formula D4: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, i and j are each as defined herein.

[0381] In yet another embodiment, provided herein is a compound of formula D5: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0382] In yet another embodiment, provided herein is a compound of formula D6: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, e, f, g and h are each as defined herein.

[0383] In one embodiment, provided herein is a compound of formula D7: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0384] In another embodiment, provided herein is a compound of formula D8: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0385] In yet another embodiment, provided herein is a compound of formula D9: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0386] In yet another embodiment, provided herein is a compound of formula D10: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0387] In yet another embodiment, provided herein is a compound of formula D11: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0388] In yet another embodiment, provided herein is a compound of formula D12: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0389] In one embodiment, provided herein is a compound of formula D13: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0390] In another embodiment, provided herein is a compound of formula D14: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0391] In yet another embodiment, provided herein is a compound of formula D15: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0392] In yet another embodiment, provided herein is a compound of formula D16: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0393] In yet another embodiment, provided herein is a compound of formula D17: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0394] In yet another embodiment, provided herein is a compound of formula D18: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0395] In one embodiment, provided herein is a compound of formula D19: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0396] In another embodiment, provided herein is a compound of formula D20: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0397] In yet another embodiment, provided herein is a compound of formula D21: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0398] In yet another embodiment, provided herein is a compound of formula D22: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0399] In yet another embodiment, provided herein is a compound of formula D23: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0400] In yet another embodiment, provided herein is a compound of formula D24: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0401] In one embodiment, provided herein is a compound of formula D25: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0402] In another embodiment, provided herein is a compound of formula D26: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0403] In yet another embodiment, provided herein is a compound of formula D27: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0404] In yet another embodiment, provided herein is a compound of formula D28: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0405] In yet another embodiment, provided herein is a compound of formula D29: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0406] In yet another embodiment, provided herein is a compound of formula D30: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0407] In one embodiment, provided herein is a compound of formula D31: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0408] In another embodiment, provided herein is a compound of formula D32: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0409] In yet another embodiment, provided herein is a compound of formula D33: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, k and m are each as defined herein.

[0410] In yet another embodiment, provided herein is a compound of formula D34: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j, k and m are each as defined herein.

[0411] In yet another embodiment, provided herein is a compound of formula D35: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0412] In yet another embodiment, provided herein is a compound of formula D36: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h, k and m are each as defined herein.

[0413] In one embodiment, provided herein is a compound of formula D37: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0414] In another embodiment, provided herein is a compound of formula D38: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0415] In yet another embodiment, provided herein is a compound of formula D39: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0416] In yet another embodiment, provided herein is a compound of formula D40: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0417] In yet another embodiment, provided herein is a compound of formula D41: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0418] In yet another embodiment, provided herein is a compound of formula D42: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0419] In one embodiment, provided herein is a compound of formula D43: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0420] In another embodiment, provided herein is a compound of formula D44: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0421] In yet another embodiment, provided herein is a compound of formula D45: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d and n are each as defined herein.

[0422] In yet another embodiment, provided herein is a compound of formula D46: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i, j and n are each as defined herein.

[0423] In yet another embodiment, provided herein is a compound of formula D47: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0424] In yet another embodiment, provided herein is a compound of formula D48: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g, h and n are each as defined herein.

[0425] In one embodiment, provided herein is a compound of formula D49: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0426] In another embodiment, provided herein is a compound of formula D50: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0427] In yet another embodiment, provided herein is a compound of formula D51: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c and d are each as defined herein.

[0428] In yet another embodiment, provided herein is a compound of formula D52: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, i and j are each as defined herein.

[0429] In yet another embodiment, provided herein is a compound of formula D53: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0430] In yet another embodiment, provided herein is a compound of formula D54: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein X, Z, c, d, g and h are each as defined herein.

[0431] In any of Formulae (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, X is a chemical bond, —C(O)O—, —C(O)N(R 1a )–, –C(O)S–, –O–, –OC(O)O–, –OC(O)N(R 1a )–、–OC(O)S–、–N(R 1a )–、–NR 1a C(O)N(R 1b )–、–NR 1a C(O)N(R 1b )-, -S-, or -S-S-; in another embodiment, X is a chemical bond; in yet another embodiment, X is -C(O)O-; in yet another embodiment, X is -C(O)N(R 1a )-; in yet another embodiment, X is -C(O)N(H)-; in yet another embodiment, X is -C(O)S-; in yet another embodiment, X is -O-; in yet another embodiment, X is -OC(O)O-; in yet another embodiment, X is -OC(O)N(R 1a )—; in yet another embodiment, X is —OC(O)N(H)—; in yet another embodiment, X is —OC(O)S—; in yet another embodiment, X is —N(R 1a )—; in yet another embodiment, X is —N(H)—; in yet another embodiment, X is —NR 1a C(O)N(R 1b)-; in yet another embodiment, X is -NHC(O)N(H)-; in yet another embodiment, X is -S-; in yet another embodiment, X is -S-S-; and in yet another embodiment, X is a 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-; wherein each R 1a and R 1b As defined herein.

[0432] In any of Formulae (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, 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 )–、–NR 1a C(O)N(R 1b )-, -S-, or -S-S-; in another embodiment, Z is a chemical bond; in yet another embodiment, Z is -C(O)O-; in yet another embodiment, Z is -C(O)N(R 1a )-; in yet another embodiment, Z is -C(O)N(H)-; in yet another embodiment, Z is -C(O)S-; in yet another embodiment, Z is -O-; in yet another embodiment, Z is -OC(O)O-; in yet another embodiment, Z is -OC(O)N(R 1a )-; in yet another embodiment, Z is -OC(O)N(H)-; in yet another embodiment, Z is -OC(O)S-; in yet another embodiment, Z is -N(R 1a )—; in yet another embodiment, Z is —N(H)—; in yet another embodiment, Z is —NR 1a C(O)N(R 1b )–; in yet another embodiment, Z is –NHC(O)N(H)–; in yet another embodiment, Z is –S–; in yet another embodiment, Z is –S–S–; and in yet another embodiment, Z is a 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–; wherein each R 1a and R 1b As defined herein.

[0433] In some embodiments, in any one of Formulas (II) to (VII), a is an integer of 1. In some embodiments, in any one of Formulas (II) to (VII), a is an integer of 2. In some embodiments, in any one of Formulas (II) to (VII), a is an integer of 3. In some embodiments, in any one of Formulas (II) to (VII), a is an integer of 4. In some embodiments, in any one of Formulas (II) to (VII), a is an integer of 5.

[0434] In some embodiments, in any one of Formulas (II) to (VII), b is an integer of 1. In some embodiments, in any one of Formulas (II) to (VII), b is an integer of 2. In some embodiments, in any one of Formulas (II) to (VII), b is an integer of 3. In some embodiments, in any one of Formulas (II) to (VII), b is an integer of 4. In some embodiments, in any one of Formulas (II) to (VII), b is an integer of 5.

[0435] In any of Formulas (II) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, in one embodiment, c is the integer 1; in another embodiment, c is the integer 2; in yet another embodiment, c is the integer 3; in yet another embodiment, c is the integer 4; in yet another embodiment, c is the integer 5; in yet another embodiment, c is the integer 6; in yet another embodiment, c is the integer 7; in yet another embodiment, c is the integer 8; and in yet another embodiment, c is the integer 2, 3, 4, 5, or 6.

[0436] In any of Formulas (II) 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 an integer of 2, 3, 4, 5, or 6.

[0437] In any of Formulas A1 to A6, B1 to B6, C1 to C6, and D1 to D6, in one embodiment, e is the integer 1; in another embodiment, e is the integer 2; in yet another embodiment, e is the integer 3; in yet another embodiment, e is the integer 4; and in yet another embodiment, e is the integer 5.

[0438] In any of Formulas A1 to A6, B1 to B6, C1 to C6, and D1 to D6, in one embodiment, f is the integer 1; in another embodiment, f is the integer 2; in yet another embodiment, f is the integer 3; in yet another embodiment, f is the integer 4; and in yet another embodiment, f is the integer 5.

[0439] In formula A1, A5 to A7, A11 to A13, A17 to A19, A23 to A25, A29 to A31, A35 to A37, A41 to A43, A47 to A49, A53, A54, B1, B5 to B7, B11 to B13, B17 to B19, B23 to B25, B29 to B31, B35 to B37, B41 to B43, B47 to B49, B53, B54, C1, C5 to C7, C11 to C13, C17 to C19, C23 to C25, C29 to C31, C35 to C In any of C37, C41 to C43, C47 to C49, C53, C54, D1, D5 to D7, D11 to D13, D17 to D19, D23 to D25, D29 to D31, D35 to D37, D41 to D43, D47 to D49, D53, and D54, in one embodiment, g is an integer 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in another embodiment, g is an integer 1; in yet another embodiment, g is an integer In yet another embodiment, g is an integer 2; in yet another embodiment, g is an integer 3; in yet another embodiment, g is an integer 4; in yet another embodiment, g is an integer 5; in yet another embodiment, g is an integer 6; in yet another embodiment, g is an integer 7; in yet another embodiment, g is an integer 8; in yet another embodiment, g is an integer 9; in yet another embodiment, g is an integer 10; in yet another embodiment, g is an integer 11; in yet another embodiment, g is an integer 12; in yet another embodiment, g is an integer 13; in yet another embodiment, g In yet another embodiment, g is an integer of 14; in yet another embodiment, g is an integer of 15; in yet another embodiment, g is an integer of 16; in yet another embodiment, g is an integer of 17; in yet another embodiment, g is an integer of 18; in yet another embodiment, g is an integer of 19; in yet another embodiment, g is an integer of 20; in yet another embodiment, g is an integer of 21; in yet another embodiment, g is an integer of 22; in yet another embodiment, g is an integer of 23; in yet another embodiment, g is an integer of 24; and in yet another embodiment, g is an integer of 25.

[0440] In formula A1, A5 to A7, A11 to A13, A17 to A19, A23 to A25, A29 to A31, A35 to A37, A41 to A43, A47 to A49, A53, A54, B1, B5 to B7, B11 to B13, B17 to B19, B23 to B25, B29 to B31, B35 to B37, B41 to B43, B47 to B49, B53, B54, C1, C5 to C7, C11 to C13, C17 to C19, C23 to C25, C29 to C31, C35 to C In any of C37, C41 to C43, C47 to C49, C53, C54, D1, D5 to D7, D11 to D13, D17 to D19, D23 to D25, D29 to D31, D35 to D37, D41 to D43, D47 to D49, D53, and D54, in one embodiment, h is an integer 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in another embodiment, h is an integer 1; in yet another embodiment, h is an integer In yet another embodiment, h is the integer 2; in yet another embodiment, h is the integer 3; in yet another embodiment, h is the integer 4; in yet another embodiment, h is the integer 5; in yet another embodiment, h is the integer 6; in yet another embodiment, h is the integer 7; in yet another embodiment, h is the integer 8; in yet another embodiment, h is the integer 9; in yet another embodiment, h is the integer 10; in yet another embodiment, h is the integer 11; in yet another embodiment, h is the integer 12; in yet another embodiment, h is the integer 13; in yet another embodiment, h 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.

[0441] In any 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. In one embodiment, i is the integer 3; in yet another embodiment, i is the integer 4; in yet another embodiment, i is the integer 5; in yet another embodiment, i is the integer 6; in yet another embodiment, i is the integer 7; in yet another embodiment, i is the integer 8; in yet another embodiment, i is the integer 9; in yet another embodiment, i is the integer 10; in yet another embodiment, i is the integer 11; in yet another embodiment, i is the integer 12; in yet another embodiment, i is the integer 13; in yet another embodiment, i is the integer 14; and in yet another embodiment, i is the integer 15.

[0442] In any 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. In one embodiment, j is the integer 3; in yet another embodiment, j is the integer 4; in yet another embodiment, j is the integer 5; in yet another embodiment, j is the integer 6; in yet another embodiment, j is the integer 7; in yet another embodiment, j is the integer 8; in yet another embodiment, j is the integer 9; in yet another embodiment, j is the integer 10; in yet another embodiment, j is the integer 11; in yet another embodiment, j is the integer 12; in yet another embodiment, j is the integer 13; in yet another embodiment, j is the integer 14; and in yet another embodiment, j is the integer 15.

[0443] In any of Formulas A31 to A36, B31 to B36, C31 to C36, and D31 to D36, in one embodiment, k is the integer 1; in another embodiment, k is the integer 2; in yet another embodiment, k is the integer 3; in yet another embodiment, k is the integer 4; and in yet another embodiment, k is the integer 5.

[0444] In any 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.

[0445] In any of Formulas A43 to A48, B43 to B48, C43 to C48, and D43 to D48, in one embodiment, n is the integer 1; in another embodiment, n is the integer 2; in yet another embodiment, n is the integer 3; in yet another embodiment, n is the integer 4; in yet another embodiment, n is the integer 5; and in yet another embodiment, n is the integer 6.

[0446] In the formulae described herein, including formulae (I) to (VII), A1 to A54, B1 to B54, C1 to C54, and D1 to D54, the group R 1 、R 2 、R 3 、R 4 , A, E, L 1 , L 2 , L 3 , L 4 , U, X, Z, a, b, c and d are further defined in the embodiments described herein. 1 、R 2 、R 3 、R 4 , A, E, L 1 , L 2 , L 3 , L 4 , U, X, Z, a, b, c, d, e, f, g, h, i, j, k, m, n, p, s and t groups in these chemical formulae described herein, all combinations of these embodiments of the present application are within the scope of the present disclosure.

[0447] In another embodiment, the present application provides a compound of formula E-1-0001 to E-1-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0448] In another embodiment, the present application provides a compound of formula E-2-0001 to E-2-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0449] In another embodiment, the present application provides a compound of formula E-3-0001 to E-3-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0450] In another embodiment, the present application provides a compound of formula E-4-0001 to E-4-0150, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0451] In some embodiments, R 1 In some embodiments, R 1 C 1-6 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 C 1-6 Alkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a , or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxy-ethoxy, dimethylamino, acetamido, methylurea, dimethylurea, methylthiourea, 3,3-dimethylthiourea, guanidinyl, methoxy-imino, thiol, or methylsulfonamido. In some embodiments, R 1 R is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxy-carbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methyl-ureido, 3,3-dimethylureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidinyl, methoxy-imino, sulfhydryl, or methylsulfonamido. In some embodiments, R 1methyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2-(3-methylureido)ethyl, 2-(3,3-dimethylureido)ethyl, 2-(3-methylthioureido)ethyl, 2-(3,3-dimethylthioureido)ethyl 1-Hydroxybutyl, ...

[0452] In some embodiments, R 1 C 1-6 Heteroalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 In some embodiments, R 1 C 2-6 Alkynyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 1 In some embodiments, R 1 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 In some embodiments, R 1 C 7-15 Aralkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R1 In some embodiments, R 1 is heteroaryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is imidazolyl, thiazolyl or pyridinyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl. In some embodiments, R 1 is a heterocyclyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 is a monocyclic heterocyclyl group, which is optionally substituted by one or more substituents Q.

[0453] In some embodiments, R 1 –C(O)R 1a , where R 1a As defined herein. In some embodiments, R 1 is –C(O)–C 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 1 is –C(O)–C 1-6 Alkyl, wherein the alkyl is optionally substituted with -OR a Replace, and R a As defined herein. In some embodiments, R 1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl or isopropionyl. 1 -C(O)OR 1a , where R 1a As defined herein. In some embodiments, R 1 –C(O)OC 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 1 In some embodiments, R 1 –C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1In some embodiments, R 1 –C(O)SR 1a , where R 1a As defined herein. In some embodiments, R 1 for –C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 In some embodiments, R 1 –C(NCN)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 In some embodiments, R 1 For –C(NOR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 In some embodiments, R 1 –C(NS(O2)R 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 In some embodiments, R 1 –C(S)R 1a , where R 1a As defined herein. In some embodiments, R 1 for –C(S)OR 1a , where R 1a As defined herein. In some embodiments, R 1 –C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1In some embodiments, R 1 for –OR 1a , where R 1a As defined herein. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 for–OC(O)R 1a , where R 1a As defined herein. In some embodiments, R 1 -OC(O)OR 1a , where R 1a As defined herein. In some embodiments, R 1 -OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 -OC(O)SR 1a , where R 1a As defined herein. In some embodiments, R 1 For –OC(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 -OC(S)R 1a , where R 1a As defined herein. In some embodiments, R 1 for –OC(S)OR 1a , where R 1a As defined herein. In some embodiments, R 1 -OC(S)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 for–OS(O)R 1a , where R 1a As defined herein. In some embodiments, R 1 -OS(O)2R 1a , where R 1a As defined herein. In some embodiments, R 1 for –OS(O)NR 1b R1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 for –NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 for –NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 for –NR 1a C(O)SR 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a C(S)R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a C(S)OR 1d , where R1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 for –NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 1 for –NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 for –NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 1 -S(O)R 1a , where R 1a As defined herein. In some embodiments, R 1 is –S(O)2R 1a , where R 1a As defined herein. In some embodiments, R 1 In some embodiments, R 1 –S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 1 –S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein.

[0454] In some embodiments, R 2 In some embodiments, R 2 C 1-6 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 C 1-6 Alkyl, which is optionally substituted with one, two or three substituents Q, each Q independently being: (i) cyano, halogen or nitro; (ii) C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more substituents Q a substituted; or (iii) –C(O)OR a ,–C(O)NR b R c ,–C(O)SR a 、–OR a ,–NR b R c ,–NR a C(O)NR b R c ,–NR a C(NR d )NR b R c ,–NR a C(S)NR b R c 、=NOR a ,–SR a , or –NR a S(O)2R d , where each R a 、R b 、R c and R d As defined herein. In some embodiments, R 2 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxy-ethoxy, dimethylamino, acetamido, methylurea, dimethylurea, methylthiourea, 3,3-dimethylthiourea, guanidinyl, methoxy-imino, thiol, or methylsulfonamido. In some embodiments, R 2R is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents Q, each Q independently being: cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3,3-dimethyl-ureido, 3-methylthioureido, 3,3-dimethylthioureido, guanidinyl, methoxyimino, thiol, or methylsulfonamido. In some embodiments, R 2 The 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 1-Hydroxybutyl, (R)-2-hydroxybutyl, (S)-2-hydroxybutyl, 4-hydroxybutyl, 4-(2-hydroxyethoxy)butyl, (E)-4-(methoxyimino)butyl, 5-hydroxypentyl, or 6-hydroxyhexyl.

[0455] In some embodiments, R 2 C 1-6 Heteroalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 In some embodiments, R 2 C 2-6 Alkynyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 For monocyclic C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each of which is optionally substituted with one, two, or three substituents Q. In some embodiments, R 2In some embodiments, R 2 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 In some embodiments, R 2 C 7-15 Aralkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 In some embodiments, R 2 is heteroaryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 is a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 is a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 2 is imidazolyl, thiazolyl or pyridinyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl. In some embodiments, R 2 is a heterocyclyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 2 is a monocyclic heterocyclyl group, which is optionally substituted by one or more substituents Q.

[0456] In some embodiments, R 2 –C(O)R 1a , where R 1a As defined herein. In some embodiments, R 2 is –C(O)–C 1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 2 is –C(O)–C 1-6 Alkyl, wherein the alkyl is optionally substituted with -OR a Replace, and R a As defined herein. In some embodiments, R 2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl or isopropionyl. 2 -C(O)OR 1a , where R 1a As defined herein. In some embodiments, R 2 –C(O)OC1-6 wherein said alkyl is optionally substituted with one or more substituents Q. In some embodiments, R 2 In some embodiments, R 2 –C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 In some embodiments, R 2 –C(O)SR 1a , where R 1a As defined herein. In some embodiments, R 2 for –C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 In some embodiments, R 2 –C(NCN)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 In some embodiments, R 2 For –C(NOR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 In some embodiments, R 2 –C(NS(O2)R 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 In some embodiments, R 2 –C(S)R 1a , where R 1a As defined herein. In some embodiments, R2 for –C(S)OR 1a , where R 1a As defined herein. In some embodiments, R 2 –C(S)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 In some embodiments, R 2 for –OR 1a , where R 1a As defined herein. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 for–OC(O)R 1a , where R 1a As defined herein. In some embodiments, R 2 -OC(O)OR 1a , where R 1a As defined herein. In some embodiments, R 2 -OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 -OC(O)SR 1a , where R 1a As defined herein. In some embodiments, R 2 For –OC(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 -OC(S)R 1a , where R 1a As defined herein. In some embodiments, R 2 for –OC(S)OR 1a , where R 1a As defined herein. In some embodiments, R 2 -OC(S)NR 1b R 1c , where R 1b and R 1cEach is as defined herein. In some embodiments, R 2 for–OS(O)R 1a , where R 1a As defined herein. In some embodiments, R 2 for–OS(O)2R 1a , where R 1a As defined herein. In some embodiments, R 2 for –OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 for –NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 for –NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 for –NR 1a C(O)SR 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R1c and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a C(S)R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a C(S)OR 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 for –NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined herein. In some embodiments, R 2 for –NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 for –NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In some embodiments, R 2 -S(O)R 1a , where R 1a As defined herein. In some embodiments, R 2 is –S(O)2R 1a , where R 1a As defined herein. In some embodiments, R 2 In some embodiments, R2 –S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In some embodiments, R 2 –S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein.

[0457] In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 5-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 6-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form 1,2,3-triazol-1-yl, pyridin-1-ium, or pyrimidin-1-yl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form 1,2,3-triazol-1-yl, 4-tert-butoxymethyl-1,2,3-triazol-1-yl, 4-dimethylaminopyridin-1-ium, 2,4-dioxo-3,4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.

[0458] In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a bicyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2Together with the N atom to which they are attached, they 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, R 1 and R 2 Together with the N atom to which they are attached, they form a 5,5-fused heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 5,6-fused heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 6,6-fused heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a purin-9-yl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form 6-aminopurin-9-yl or 2-amino-6-oxo-1,9-dihydropurin-9-yl.

[0459] In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a monocyclic heterocyclyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they 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, R 1 and R 2 Together with the N atom to which they are attached, they form a 3-membered heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 4-membered heterocyclyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 5-membered heterocyclyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2Together with the N atom to which they are attached, they form a 6-membered heterocyclyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they form a 7-membered heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, R 1 and R 2 Together with the N atom to which they are attached, they 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, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 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 group.

[0460] In some embodiments, R 3 C 1-30 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 1-25 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 1-20 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 R is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 3It is propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxy-carbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane-1-yl, tridecane-1-yl, pentadecane-1-yl, pentadecane-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decane-2-yl, or heneicosane-1-yl.

[0461] In some embodiments, R 3 C 1-30 Heteroalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 In some embodiments, R 3 C 1-30 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 1-25 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 1-20 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 R is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosene, docosenyl, tricosene, tetracosene, or pentacosene, each of which is optionally substituted with one or more substituents Q. In some embodiments, R 3are: (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoro-non-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoro-non-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, ( (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-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.

[0462] In some embodiments, R 3 C 2-30 Alkynyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 For monocyclic C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 is cyclohexyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 In some embodiments, R 3 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 is phenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 is 3-pentyl-phenyl, 4-pentylphenyl or 3,4-dipentylphenyl. In some embodiments, R 3 C 7-30 Aralkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 is heteroaryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 3 is a heterocyclic group, which is optionally substituted by one or more substituents Q.

[0463] In some embodiments, R 4 C 1-30Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 1-25 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 1-20 Alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 R is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, or pentacosyl, each optionally substituted with one or more substituents Q. In some embodiments, R 4 It is propan-1-yl, pentane-1-yl, 2-isopropyl-5-methylhexane-1-yl, heptane-1-yl, octane-1-yl, octane-3-yl, 3,7-dimethyloctane-1-yl, 8-methoxycarbonyloctane-1-yl, 8-trifluoromethoxy-carbonyloctane-1-yl, nonane-1-yl, 8-methylnonane-1-yl, 2-methoxynonane-1-yl, decane-1-yl, undecane-1-yl, dodecane-1-yl, 2-hydroxydodecane-1-yl, tridecane-1-yl, pentadecane-1-yl, pentadecane-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decane-2-yl, or heneicosane-1-yl.

[0464] In some embodiments, R 4 C 1-30 Heteroalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 In some embodiments, R 4 C 1-30 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 1-25 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 1-20 alkenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 R is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosene, docosenyl, tricosene, tetracosene, or pentacosene, each optionally substituted with one or more substituents Q. In some embodiments, R4 are: (Z)-2-hexen-1-yl, (Z)-2-nonen-1-yl, (Z)-2-undecen-1-yl, (Z)-2-tridecen-1-yl, (Z)-3-octen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoro-non-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, (E)-3-methyloct-6-en-1-yl, (Z)-3-nonen-1-yl, (Z)-4,4-difluoro-non-3-en-1-yl, (Z)-5,5-difluoronon-3-en-1-yl, (Z)-3-decen-2-yl, (Z)-3-undecen-1-yl, ( (Z)-8-pentadecen-1-yl, (Z)-8-heptadecen-1-yl, (Z)-8-nonadecen-1-yl, (Z)-8-heneicosen-1-yl, (8Z,11Z)-heptadeca-8,11-dien-1-yl, (9Z,12Z)-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.

[0465] In some embodiments, R 4 C 2-30 Alkynyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 For a single ring C 3-10 Cycloalkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 is cyclohexyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 In some embodiments, R 4 C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 is phenyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 is 3-pentyl-phenyl, 4-pentylphenyl or 3,4-dipentylphenyl. In some embodiments, R 4 C 7-30 Aralkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 is heteroaryl, which is optionally substituted with one or more substituents Q. In some embodiments, R 4 is a heterocyclic group, which is optionally substituted by one or more substituents Q.

[0466] In some embodiments, A is -O-. In some embodiments, A is -N(R 1a )–, where R 1a As defined herein. In some embodiments, A is -N(H)-.

[0467] In some embodiments, E is -UC(O)N(R 1a )–, where R 1a and U are each as defined herein. In some embodiments, E is -OC(O)N(R 1a )–, where R 1a As defined herein. In some embodiments, E is -OC(O)N(H)-. In some embodiments, E is -N(R 1b )C(O)N(R 1a )–, where R 1a and R 1b Each is as defined herein. In some embodiments, E is -N(H)C(O)N(H)-.

[0468] In some embodiments, L 1 C 1-6 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 1 For–(CR 2a R 2b ) a –, where each R 2a 、R 2b and a are as defined herein. In some embodiments, L 1 for –(CH2) a -, wherein a is as defined herein. In some embodiments, L 1 is -(CH2)-. In some embodiments, L 1 is -(CH2)2-. In some embodiments, L 1 is -(CH2)3-. In some embodiments, L 1 is -(CH2)4-. In some embodiments, L 1 is -(CH2)5-. In some embodiments, L 1 It is –(CH2)6–.

[0469] In some embodiments, L 2 C 1-6 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 2 For–(CR 2a R 2b ) b –, where each R 2a、R 2b and b are as defined herein. In some embodiments, L 2 for –(CH2) b -, wherein b is as defined herein. In some embodiments, L 2 is -(CH2)-. In some embodiments, L 2 is -(CH2)2-. In some embodiments, L 2 is -(CH2)3-. In some embodiments, L 2 is -(CH2)4-. In some embodiments, L 2 is -(CH2)5-. In some embodiments, L 2 It is –(CH2)6–.

[0470] In some embodiments, L 3 C 1-10 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 3 For–(CR 2a R 2b ) c –, where each R 2a 、R 2b and c are as defined herein. In some embodiments, L 3 for –(CH2) c –, and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, L 3 is -(CH2)2-. In some embodiments, L 3 is -(CH2)3-. In some embodiments, L 3 is -(CH2)4-. In some embodiments, L 3 is -(CH2)5-. In some embodiments, L 3 is -(CH2)6-. In some embodiments, L 3 C 1-10 Heteroalkylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 3 C 2-10 Alkenylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 3 C 2-10 Alkyneylene, which is optionally substituted with one or more substituents Q.

[0471] In some embodiments, L 4 C 1-10 Alkylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 4 For–(CR2a R 2b ) d –, where each R 2a 、R 2b and d are as defined herein. In some embodiments, L 4 for –(CH2) d –, and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, L 4 is -(CH2)2-. In some embodiments, L 4 is -(CH2)3-. In some embodiments, L 4 is -(CH2)4-. In some embodiments, L 4 is -(CH2)5-. In some embodiments, L 4 is -(CH2)6-. In some embodiments, L 4 C 1-10 Heteroalkylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 4 C 2-10 Alkenylene, which is optionally substituted with one or more substituents Q. In some embodiments, L 4 C 2-10 Alkyneylene, which is optionally substituted with one or more substituents Q.

[0472] In some embodiments, U is -O-. In some embodiments, U is -N(R 1a )–, where R 1a As defined herein. In some embodiments, U is -N(H)-.

[0473] In some embodiments, X is a chemical bond. In some embodiments, X is -C(O)O-. In some embodiments, X is -C(O)N(R 1a )–, where R 1a As defined herein. In some embodiments, X is -C(O)N(H)-. In some embodiments, X is -C(O)S-. In some embodiments, X is -O-. In some embodiments, X is -OC(O)O-. In some embodiments, X is -OC(O)N(R 1a )–, where R 1a As defined herein. In some embodiments, X is -OC(O)N(H)-. In some embodiments, X is -OC(O)S-. In some embodiments, X is -N(R 1a )–, where R 1a As defined herein. In some embodiments, X is -N(H)-. In some embodiments, X is -NR 1aC(O)N(R 1b )–, where R 1a and R 1b Each is as defined herein. In some embodiments, X is -NHC(O)N(H)-. In some embodiments, X is -S-. In some embodiments, X is -S-S-.

[0474] In some embodiments, Z is a chemical bond. In some embodiments, Z is -C(O)O-. In some embodiments, Z is -C(O)N(R 1a )–, where R 1a As defined herein. In some embodiments, Z is -C(O)N(H)-. In some embodiments, Z is -C(O)S-. In some embodiments, Z is -O-. In some embodiments, Z is -OC(O)O-. In some embodiments, Z is -OC(O)N(R 1a )–, where R 1a As defined herein. In some embodiments, Z is -OC(O)N(H)-. In some embodiments, Z is -OC(O)S-. In some embodiments, Z is -N(R 1a )–, where R 1a As defined herein. In some embodiments, Z is -N(H)-. In some embodiments, Z is -NR 1a C(O)N(R 1b )–, where R 1a and R 1b Each is as defined herein. In some embodiments, Z is -NHC(O)N(H)-. In some embodiments, Z is -S-. In some embodiments, Z is -S-S-.

[0475] In some embodiments, a is the integer 1. In some embodiments, a is the integer 2. In some embodiments, a is the integer 3. In some embodiments, a is the integer 4. In some embodiments, a is the integer 5. In some embodiments, a is the integer 6.

[0476] In some embodiments, b is the integer 1. In some embodiments, b is the integer 2. In some embodiments, b is the integer 3. In some embodiments, b is the integer 4. In some embodiments, b is the integer 5. In some embodiments, b is the integer 6.

[0477] In some embodiments, c is an integer of 1. In some embodiments, c is an integer of 2. In some embodiments, c is an integer of 3. In some embodiments, c is an integer of 4. In some embodiments, c is an integer of 5. In some embodiments, c is an integer of 6. In some embodiments, c is an integer of 7. In some embodiments, c is an integer of 8. In some embodiments, c is an integer of 9. In some embodiments, c is an integer of 10.

[0478] In some embodiments, d is an integer of 1. In some embodiments, d is an integer of 2. In some embodiments, d is an integer of 3. In some embodiments, d is an integer of 4. In some embodiments, d is an integer of 5. In some embodiments, d is an integer of 6. In some embodiments, d is an integer of 7. In some embodiments, d is an integer of 8. In some embodiments, d is an integer of 9. In some embodiments, d is an integer of 10.

[0479] In one embodiment, provided herein are the following compounds: 4-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)heptane-1,7-diyl-dihexanoate 1; 4-(3-(2-(2-(dimethylamino)ethoxy)ethyl)ureido)heptane-1,7-diyl-dihexanoate 2; 4-(((2-((2-(dimethylamino)ethyl)amino)ethyl)-carbamoyl)oxy)heptane-1,7-diyl-dihexanoate 3; 4-(3-(2-((2-(dimethylamino)ethyl)amino)ethyl)-ureido)heptane-1,7-diyl-dihexanoate 4; or 7-(((2-(2-(dimethylamino)ethoxy)ethyl)carbamoyl)oxy)tridecane-1,13-diyl-bis(2-hexyldecanoate) 5; or a tautomer thereof, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0480] In some embodiments, the compounds provided herein are isolated or purified. In some embodiments, 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.

[0481] The compound provided herein is intended to include all possible stereoisomers, unless specific stereochemistry is specified. In the case where the compound of the present application contains alkenyl, the compound can exist as a kind of or mixture of geometric cis / trans (or Z / E) isomers. In the case where structural isomers are mutually convertible, the compound can exist as a mixture of single tautomers or tautomers. This can take the form of proton tautomerism in compounds containing, for example, imino, keto or oxime groups; or the so-called valence tautomeric form in compounds containing aromatic moieties. Therefore, a single compound may show more than one type of isomerism.

[0482] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be stereoisomeric mixtures, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Thus, one of ordinary skill in the art will recognize that, for compounds that undergo epimerization in vivo, administration of a compound in its (R) form is equivalent to administration of the compound in its (S) form. Conventional techniques for preparing / isolating individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of enantiomeric mixtures, such as chiral chromatography, recrystallization, resolution, formation of diastereomeric salts, or derivatization into diastereomeric adducts followed by separation.

[0483] When the compounds provided herein contain an acidic or basic moiety, they can also be provided as pharmaceutically acceptable salts. See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0484] Suitable acids for preparing pharmaceutically acceptable salts of the compounds of the present application include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic 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-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-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.

[0485] Suitable bases for preparing pharmaceutically acceptable salts of the compounds of the present application include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, L-arginine, phenethylbenzylamine, benzophenone, choline, dimethylethanolamine, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)ethanol, Ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydroxylamine, 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. 8.3 Lipid Nanoparticles

[0486] In one embodiment, provided herein are lipid nanoparticles 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.

[0487] In another embodiment, provided herein are 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.

[0488] In yet another embodiment, provided herein are 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.

[0489] In another embodiment, provided herein are 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.

[0490] In some embodiments, the lipid nanoparticles of the present application further comprise coupled lipids. In some embodiments, the coupled lipids comprise polyethylene glycol (PEG)-coupled lipids. In some embodiments, the coupled lipids are PEG-coupled lipids.

[0491] Thus, in one embodiment, provided herein are 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.

[0492] In another embodiment, provided herein are 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.

[0493] 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 nucleic acid is a circular RNA. In some embodiments, the nucleic acid is a nucleic acid described in the following documents: US2022 / 0177898 A1; or PCT application No. PCT / CN2022 / 095749 filed on May 27, 2022; or PCT / CN2022 / 095949 filed on May 30, 2022, the disclosures of each of which are incorporated herein by reference in their entirety. In some embodiments, the nucleic acid is siRNA. In some embodiments, the nucleic acid is an antisense oligonucleotide. In some embodiments, the nucleic acid comprises a sequence of any one of SEQ ID NOs: 1-29 and 33-36, or a nucleic acid sequence encoding an amino acid sequence of any one of SEQ ID NOs: 30-32. In some embodiments, the nucleic acid is mRNA. In some embodiments, the nucleic acid is an mRNA having the sequence of SEQ ID NO:36.

[0494] In some embodiments, the phospholipid is dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), 1,2-dielaidylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine (DMPE), dioleoylphosphatidylethanolamine (DOPE), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), palmitoyloleoylphosphatidylethanolamine (POPE), 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE), 1,2-dipalmitoylphosphatidyl-N-methylethanolamine, 1,2-dipalmitoylphosphatidyl-N,N-dimethylethanolamine, dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), palmitoyloleoylphosphatidylcholine (POPC), or a combination thereof.

[0495] In some embodiments, the PEG-coupled lipid is PEG diacylglycerol (DAG), PEG dialkoxypropyl (DAA), PEG-phospholipid, PEG ceramide, or a combination thereof. In some embodiments, the PEG-coupled lipid is 2-(polyethylene glycol)-N,N-ditetradecylacetamide (ALC-0159), 1,2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol (PEG-DMG), PEG-c-DMG, PEG-DSG, PEG-DSPE, or a combination thereof. 8.4 Pharmaceutical Compositions

[0496] In one embodiment, provided herein are pharmaceutical compositions 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; and a pharmaceutically acceptable excipient.

[0497] In another embodiment, provided herein are pharmaceutical compositions comprising lipid nanoparticles, wherein the lipid nanoparticles comprise 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; and a pharmaceutically acceptable excipient.

[0498] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a compound 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.

[0499] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a therapeutic agent, and (ii) a compound 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.

[0500] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a therapeutic agent; (ii) a compound 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.

[0501] In yet another embodiment, provided herein is a pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a nucleic acid, and (ii) a compound 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 there...

Claims

1. A compound of the formula: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. A lipid nanoparticle comprising: a compound of claim 1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. A pharmaceutical composition comprising: a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises: (i) a nucleic acid; (ii) a compound of claim 1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol.

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

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

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

7. The pharmaceutical composition of any one of claims 3 to 6, wherein the nucleic acid is a circular RNA.

8. The pharmaceutical composition of any one of claims 3-7, wherein the pharmaceutical composition is preferentially distributed to a target organ of a subject in need thereof.

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

10. The pharmaceutical composition of any one of claims 3-7, wherein the pharmaceutical composition preferentially partitions into liver cells. The pharmaceutical composition of claim 10 , wherein the liver cells are hepatocytes.

12. The pharmaceutical composition of any one of claims 3-7, wherein the pharmaceutical composition preferentially partitions to spleen cells.

13. The pharmaceutical composition of claim 12, wherein the spleen cells are splenocytes.

14. The pharmaceutical composition of any one of claims 3 to 13, wherein the nucleic acid encodes a biologically active protein or enzyme.

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

16. The pharmaceutical composition of claim 14, wherein the biologically active protein or enzyme is produced in or systemically secreted from cells of the lungs, heart, eyes, or central nervous system.

Images