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  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
  • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/5123—Organic compounds, e.g. fats, sugars
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
  • C07C329/02—Monothiocarbonic acids; Derivatives thereof
  • C07C329/04—Esters of monothiocarbonic acids
  • C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/10—Phosphatides, e.g. lecithin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/22—Amides of acids of phosphorus
  • C07F9/24—Esteramides
  • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
  • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

• lipid compounds Provided herein are lipid compounds, and lipid nanoparticles and pharmaceutical compositions thereof.
• Lipid nanoparticles are a promising delivery vehicle for a variety of therapeutic agents, including small molecule drugs, proteins, and nucleic acids.
• R 1 is (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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c , -OR 1a
• R 3 and R 4 are each independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• E 1 and E 2 are each independently -C (O) -or -C (O) O-;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• M 1 and M 2 are each independently a linker
• U 1 and U 2 are each independently -O-or -N (R 1b ) -;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• R 1 , R 2 , R 5 , and R 6 are each independently (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R 1a , -C (O) OR 1a , -C (O) NR 1b R 1c , -C (O) SR 1a , -C (NR 1a ) NR 1b R 1c , -C (NCN) NR 1b R 1c , -C (NOR 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• A is -O-or -N (R 1a ) -;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• X and Z are each independently a 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 is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c ,
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• M 1 is a linker
• U 1 is -O-or -N (R 1b ) -;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• R 1 , R 2 , and R 7 are each independently (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R 1a , -C (O) OR 1a , -C (O) NR 1b R 1c , -C (O) SR 1a , -C (NR 1a ) NR 1b R 1c , -C (NCN) NR 1b R 1c , -C (NOR 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• A is a bond, -O-, or -N (R 1a ) -;
• L 1 is independently C 1-6 alkylene or C 1-6 heteroalkylene
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a , -C (O) OR a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• R 1 is (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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c , -OR 1a
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• lipid nanoparticle comprising a compound of any one of Formulae (I) to (V) , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• lipid nanoparticle comprising (i) a nucleic acid and (ii) a compound of any one of Formulae (I) to (V) , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• a pharmaceutical composition comprising a lipid nanoparticle that comprises (i) a nucleic acid and (ii) a compound of any one of Formulae (I) to (V) , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• a compound has the structure of Formula (I) , (II) , (III) , (IV) , or (V) :
• each R 1 , R 2 , R 5 , R 6 , and R 7 is 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -
• each R 3 and R 4 is independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• each A is independently -O-or -N (R 1a ) -;
• each E 1 and E 2 is independently -C (O) -or -C (O) O-;
• each L 1 and L 2 is independently C 1-6 alkylene or C 1-6 heteroalkylene;
• each L 3 and L 4 is independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• each M 1 and M 2 is independently a linker
• each U 1 and U 2 is independently -O-or -N (R 1b ) -;
• each X and Z is independently a 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 is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• R 1 is (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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c , -OR 1a
• R 3 and R 4 are each independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• E 1 and E 2 are each independently -C (O) -or -C (O) O-;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• M 1 and M 2 are each independently a linker
• U 1 and U 2 are each independently -O-or -N (R 1b ) -;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• M 1 is a cleavable linker.
• M 1 is -S-S-.
• M 2 is a cleavable linker
• M 2 is -S-S-.
• E 1 is -C (O) -.
• E 1 is -C (O) O-.
• E 2 is -C (O) -.
• E 2 is -C (O) O-.
• U 1 is -O-.
• U 1 is -N (R 1b ) -.
• U 1 is -N (H) -.
• U 2 is -O-.
• U 2 is -N (R 1b ) -.
• U 2 is -N (H) -.
• an enantiomer a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• an enantiomer a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• R 1 , R 2 , R 5 , and R 6 are each independently (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R 1a , -C (O) OR 1a , -C (O) NR 1b R 1c , -C (O) SR 1a , -C (NR 1a ) NR 1b R 1c , -C (NCN) NR 1b R 1c , -C (NOR 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• A is -O-or -N (R 1a ) -;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• X and Z are each independently a 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 is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• A is -O-.
• A is -N (R 1b ) -.
• A is -N (H) -.
• 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c ,
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• M 1 is a linker
• U 1 is -O-or -N (R 1b ) -;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• M 1 is a cleavable linker
• M 1 is -S-S-.
• U 1 is -O-.
• U 1 is -N (R 1b ) -.
• U 1 is -N (H) -.
• an enantiomer a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• an enantiomer a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• R 1 , R 2 , and R 7 are each independently (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R 1a , -C (O) OR 1a , -C (O) NR 1b R 1c , -C (O) SR 1a , -C (NR 1a ) NR 1b R 1c , -C (NCN) NR 1b R 1c , -C (NOR 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• A is a bond, -O-, or -N (R 1a ) -;
• L 1 is independently C 1-6 alkylene or C 1-6 heteroalkylene
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a , -C (O) OR a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• A is -O-.
• A is -N (R 1b ) -.
• A is -N (H) -.
• R 1 is (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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c , -OR 1a
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 1 is - (CR 2a R 2b ) a -, wherein each R 2a and R 2b is independently (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 1 is - (CH 2 ) a -and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 2 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 2 is - (CR 2a R 2b ) b -, wherein each R 2a and R 2b is independently (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and b is an integer of 1, 2, 3, 4, 5, or 6.
• L 2 is - (CH 2 ) b -and b is an integer of 1, 2, 3, 4, 5, or 6.
• L 3 is C 1-10 alkylene, optionally substituted with one or more substituents Q.
• L 3 is - (CR 2a R 2b ) c -or -CR 2a R 2b (CR 2a R 2b ) c -, wherein each R 2a and R 2b is independently (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• L 3 is - (CH 2 ) c -or -C (CH 3 ) 2 (CH 2 ) c -; and each c is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• L 4 is C 1-10 alkylene, optionally substituted with one or more substituents Q.
• L 4 is - (CR 2a R 2b ) d -or -CR 2a R 2b (CR 2a R 2b ) d -, wherein each R 2a and R 2b is independently (i) hydrogen; or (ii) C 1-6 alkyl optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• L 4 is - (CH 2 ) d -or -C (CH 3 ) 2 (CH 2 ) d -; and each d is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• a is an integer of 1, 2, 3, 4, 5, or 6.
• a is an integer of 1, 2, 3, 4, 5, or 6.
• 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.
• R 1 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b R 1c , -OR 1a , or -S (O) 2 R 1a .
• R 1 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 2 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b R 1c , -OR 1a , or -S (O) 2 R 1a .
• R 2 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 3 is C 1-30 alkyl, C 1- 30 heteroalkyl, C 2-30 alkenyl, C 3-10 cycloalkyl, or C 6-14 aryl, each optionally substituted with one or more substituents Q.
• R 3 is C 1-25 alkyl, optionally substituted with one or more substituents Q.
• R 3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or
• R 3 is C 1-25 alkenyl, optionally substituted with one or more substituents Q.
• R 3 is (Z) -2-hexen-1-yl, (Z) -2-nonen-1-yl, (Z) -2-undecen-1-yl, (Z) -2-tridecen-1-yl, (Z) -3-octen-1-yl, (E) -3-methyloct-6-en-1-yl, (Z) -3-nonen-1-yl, (Z) -4, 4-difluoronon-3-en-1-yl, (Z) -5, 5-difluoronon-3-en-1-yl, (Z) -3-decen-2-yl, (Z) -3-undecen-1-yl, (Z) -8-pentadecen-1-yl, (Z) -8-heptadecen-1-yl, (Z) -8-nonadecen-1-yl, (Z) -8-pentadecen-1-yl, (Z) -8-hept
• R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.
• R 3 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 3 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.
• R 4 is C 1-30 alkyl, C 1- 30 heteroalkyl, C 2-30 alkenyl, C 3-10 cycloalkyl, or C 6-14 aryl, each optionally substituted with one or more substituents Q.
• R 4 is C 1-25 alkyl, optionally substituted with one or more substituents Q.
• R 4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridecan-1-yl, pentadecan-1-yl, pentadecan-7-yl, heptadecan-1-yl, heptadecan-9-yl, nonadecan-1-yl, decan-2-yl, or
• R 4 is C 1-25 alkenyl, optionally substituted with one or more substituents Q.
• R 4 is (Z) -2-hexen-1-yl, (Z) -2-nonen-1-yl, (Z) -2-undecen-1-yl, (Z) -2-tridecen-1-yl, (Z) -3-octen-1-yl, (E) -3-methyloct-6-en-1-yl, (Z) -3-nonen-1-yl, (Z) -4, 4-difluoronon-3-en-1-yl, (Z) -5, 5-difluoronon-3-en-1-yl, (Z) -3-decen-2-yl, (Z) -3-undecen-1-yl, (Z) -8-pentadecen-1-yl, (Z) -8-heptadecen-1-yl, (Z) -8-nonadecen-1-yl, (Z)
• R 4 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.
• R 4 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 4 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.
• R 5 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b
• R 5 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 5 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 6 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b
• R 6 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 6 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 7 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b
• R 7 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 7 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• a is an integer of 1, 2, 3, or 4.
• a is an integer of 2.
• b is an integer of 1, 2, 3, or 4.
• b is an integer of 1 or 2.
• each e, f, and v is independently an integer of 0, 1, 2, 3, 4, or 5; each g and h is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; each i and j is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; each k, m, q, and r is independently an integer of 0, 1, 2, 3, 4, or 5; and each n is independently an integer of 1, 2, 3, 4, 5, or 6.
• c is an integer of 1, 2, 3, or 4.
• c is an integer of 2.
• d is an integer of 1, 2, 3, or 4.
• d is an integer of 2.
• X is a 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-.
• 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-.
• Z is a 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-.
• 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-.
• an enantiomer a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
• each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
• R 3 is selected from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112 or T-0113.
• R 4 is selected from: T-0014, T-0020, T-0021, T-0022, T-0023, T-0024, T-0025, T-0092, T-0106, T-0108, T-0109, T-0110, T-0111, T-0112 or T-0113.
• a lipid nanoparticle comprises a compound of any one of paragraphs [0013] to [00136] , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
• a pharmaceutical composition comprises a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) mRNA; (ii) a compound of any one of paragraphs [0013] to [00136] , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol; wherein administration of the mRNA to the subject results in a higher expression relative to administration of a circular RNA to the subject.
• a pharmaceutical composition comprises a lipid nanoparticle and a pharmaceutically acceptable excipient; wherein the lipid nanoparticle comprises (i) circular RNA; (ii) a compound of any one of paragraphs [0013] to [00136] , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (iii) a phospholipid; and (iv) cholesterol; wherein administration of the circular RNA to the subject results in a higher expression relative to administration of a mRNA to the subject.
• the lipid nanoparticle comprises (i) circular RNA; (ii) a compound of any one of paragraphs [0013] to [00136] , or an enantiomer, a mixture of enantiomers, a diaste
• composition of paragraphs [00138] and [00139] further comprises a conjugated lipid.
• the conjugated lipid comprises a polyethylene glycol-conjugated lipid.
• the pharmaceutical composition is preferentially distributed into a targeted organ of a subject in need thereof.
• the targeted organ is an eye, heart, lung, kidney, liver, or spleen of the subject.
• the pharmaceutical composition is preferentially distributed into a liver cell.
• the liver cell is a hepatocyte.
• the pharmaceutical composition is preferentially distributed into a spleen cell.
• spleen cell is a spleenocyte.
• the nucleic acid encodes a bioactive protein or enzyme.
• the bioactive protein or enzyme is produced in or systemically excreted from a liver cell.
• the bioactive protein or enzyme is produced in or systemically excreted from a cell of a lung, heart, or ocular, or central nervous system.
• FIG. 1 shows in vitro evaluation of a luciferase-coding circular RNA for luciferase expression via LNPs containing different tail types of ionizable lipids.
• the human embryonic kidney 293T cells HEK 293T cells
• the figure was processed by calculating the average of the corresponding expression of LNP.
• the F-luc luminescence values of each LNPs were normalized to that of ALC-0315-containing LNP and summarized by tail code and the C atom number of each lipid tails respectively.
• FIG. 2 shows in vitro evaluation of a luciferase-coding circular RNA for luciferase expression via LNPs containing different tail group of ionizable lipids.
• the human embryonic kidney 293T cells HEK 293T cells
• the figure was processed by calculating the average of the corresponding expression of LNP.
• the Fluc luminescence values of each LNPs were normalized to that of ALC-0315-containing LNP and summarized by tail group.
• 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.
• primate e.g., human
• subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
• treat, ” “treating, ” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause (s) of the disorder, disease, or condition itself.
• prevent, ” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
• alleviate and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition.
• the terms can also refer to reducing adverse effects associated with an active ingredient.
• the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
• contacting or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA) , cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo.
• a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule.
• a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell.
• the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
• terapéuticaally effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
• therapeutically effective amount or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA) , cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
• a biological molecule e.g., a protein, enzyme, RNA, or DNA
• pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
• each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
• the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%of a given value or range.
• alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
• C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ) , 1 to 15 (C 1-15 ) , 1 to 10 (C 1-10 ) , or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3-20 ) , 3 to 15 (C 3-15 ) , 3 to 10 (C 3-10 ) , or 3 to 6 (C 3-6 ) carbon atoms.
• linear C 1-6 and branched C 3-6 alkyl groups are also referred as “lower alkyl.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl) , butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl) , pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl) , and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl) .
• alkylene and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally be substituted with one or more substituents Q as described herein.
• C 1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C 1-30 ) , 1 to 20 (C 1-20 ) , 1 to 15 (C 1-15 ) , 1 to 10 (C 1-10 ) , or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C 3-30 ) , 3 to 20 (C 3-20 ) , 3 to 15 (C 3-15 ) , 3 to 10 (C 3-10 ) , or 3 to 6 (C 3-6 ) carbon atoms.
• linear C 1-6 and branched C 3-6 alkanediyl groups are also referred as “lower alkanediyl. ”
• alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1, 1-diyl and ethane-1, 2-diyl) , propanediyl (including all isomeric forms, e.g., propane-1, 1-diyl, propane-1, 2-diyl, and propane-1, 3-diyl) , butanediyl (including all isomeric forms, e.g., butane-1, 1-diyl, butane-1, 2-diyl, butane-1, 3-diyl, and butane-1, 4-diyl) , pentanediyl (including all isomeric forms, e.g.,
• substituted alkanediyl groups include, but are not limited to, -C (O) CH 2 -, -C (O) (CH 2 ) 2 -, -C (O) (CH 2 ) 3 -, -C (O) (CH 2 ) 4 -, -C (O) (CH 2 ) 5 -, -C (O) (CH 2 ) 6 -, -C (O) (CH 2 ) 7 -, -C (O) (CH 2 ) 8 -, -C (O) (CH 2 ) 9 -, -C (O) (CH 2 ) 10 -, -C (O) CH 2 C (O) -, -C (O) (CH 2 ) 2 C (O) -, -C (O) (CH 2 ) 3 C (O) -, -C (O) (CH 2 ) 4 C (O) -, or -C (O) (CH 2 ) 5 C (O)
• heteroalkyl refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N.
• the heteroalkyl is optionally substituted with one or more substituents Q as described herein.
• C 1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ) , 1 to 15 (C 1-15 ) , 1 to 10 (C 1-10 ) , or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3-20 ) , 3 to 15 (C 3-15 ) , 3 to 10 (C 3-10 ) , or 3 to 6 (C 3-6 ) carbon atoms.
• linear C 1-6 and branched C 3-6 heteroalkyl groups are also referred as “lower heteroalkyl.
• heteroalkyl groups include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , -NHCH 3 , -ONHCH 3 , -NHOCH 3 , -SCH 3 , -CH 2 NHCH 2 CH 3 , and -NHCH 2 CH 2 CH 3 .
• substituted heteroalkyl groups include, but are not limited to, -CH 2 NHC (O) CH 3 and -NHC (O) CH 2 CH 3 .
• heteroalkylene and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N.
• the heteroalkylene is optionally substituted with one or more substituents Q as described herein.
• C 1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C 1-20 ) , 1 to 15 (C 1-15 ) , 1 to 10 (C 1-10 ) , or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3-20 ) , 3 to 15 (C 3-15 ) , 3 to 10 (C 3-10 ) , or 3 to 6 (C 3-6 ) carbon atoms.
• linear C 1-6 and branched C 3-6 heteroalkylene groups are also referred as “lower heteroalkylene.
• heteroalkylene groups include, but are not limited to, -CH 2 O-, - (CH 2 ) 2 O-, - (CH 2 ) 3 O-, - (CH 2 ) 4 O-, - (CH 2 ) 5 O-, - (CH 2 ) 6 O-, - (CH 2 ) 7 O-, - (CH 2 ) 8 O-, - (CH 2 ) 9 O-, - (CH 2 ) 10 O-, -CH 2 OCH 2 -, -CH 2 CH 2 O-, - (CH 2 CH 2 O) 2 -, - (CH 2 CH 2 O) 3 -, - (CH 2 CH 2 O) 4 -, - (CH 2 CH 2 O) 5 -, -CH 2 NH-, -CH 2 NHCH 2 -, -CH 2 CH 2 NH-, -CH 2 S-, -CH 2 SCH 2 -, and -CH 2 CH 2 S-.
• substituted heteroalkylene groups include, but are not limited to, -C (O) CH 2 O-, -C (O) (CH 2 ) 2 O-, -C (O) (CH 2 ) 3 O-, -C (O) (CH 2 ) 4 O-, -C (O) (CH 2 ) 5 O-, -C (O) (CH 2 ) 6 O-, -C (O) (CH 2 ) 7 O-, -C (O) (CH 2 ) 8 O-, -C (O) (CH 2 ) 9 O-, -C (O) (CH 2 ) 10 O-, -C (O) CH 2 OCH 2 CH 2 O-, -C (O) CH 2 O (CH 2 CH 2 O) 2 -, -C (O) CH 2 O (CH 2 CH 2 O) 3 -, -C (O) CH 2 O (CH 2 CH 2 O) 4 , -C (O) CH 2 O (CH 2 CH 2 O) 5
• alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond (s) .
• the alkenyl is optionally substituted with one or more substituents Q as described herein.
• alkenyl embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
• C 2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ) , 2 to 15 (C 2-15 ) , 2 to 10 (C 2-10 ) , or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-20 ) , 3 to 15 (C 3-15 ) , 3 to 10 (C 3-10 ) , or 3 to 6 (C 3-6 ) carbon atoms.
• alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl) , and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl) .
• alkenylene and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond (s) .
• the alkenediyl is optionally substituted with one or more substituents Q as described herein.
• alkenediyl embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
• C 2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C 2-30 ) , 2 to 20 (C 2-20 ) , 2 to 15 (C 2-15 ) , 2 to 10 (C 2-10 ) , or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C 3-30 ) , 3 to 20 (C 3-20 ) , 3 to 15 (C 3-15 ) , 3 to 10 (C 3-10 ) , or 3 to 6 (C 3-6 ) carbon atoms.
• alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene-1, 1-diyl and ethene-1, 2-diyl) , propenediyl (including all isomeric forms, e.g., 1-propene-1, 1-diyl, 1-propene-1, 2-diyl, and 1-propene-1, 3-diyl) , butenediyl (including all isomeric forms, e.g., 1-butene-1, 1-diyl, 1-butene-1, 2-diyl, and 1-butene-1, 4-diyl) , pentenediyl (including all isomeric forms, e.g., 1-pentene-1, 1-diyl, 1-pentene-1, 2-diyl, and 1-pentene-1, 5-diyl) , and hexenediyl (including all isomeric
• alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond (s) .
• An alkynyl group does not contain a carbon-carbon double bond.
• the alkynyl is optionally substituted with one or more substituents Q as described herein.
• C 2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms.
• the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ) , 2 to 15 (C 2-15 ) , 2 to 10 (C 2-10 ) , or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C 4-20 ) , 4 to 15 (C 4-15 ) , 4 to 10 (C 4-10 ) , or 4 to 6 (C 4-6 ) carbon atoms.
• alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) , propynyl (including all isomeric forms, e.g., 1-propynyl (-C ⁇ CCH 3 ) and propargyl (-CH 2 C ⁇ CH) ) , butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl) , pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl) , and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl) .
• alkynylene and alkynediyl are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond (s) .
• An alkynylene group does not contain a carbon-carbon double bond.
• the alkynediyl is optionally substituted with one or more substituents Q as described herein.
• C 2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
• the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C 2-30 ) , 2 to 20 (C 2-20 ) , 2 to 15 (C 2-15 ) , 2 to 10 (C 2-10 ) , or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C 4-30 ) , 4 to 20 (C 4-20 ) , 4 to 15 (C 4-15 ) , 4 to 10 (C 4-10 ) , or 4 to 6 (C 4- 6 ) carbon atoms.
• alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1-propyne-1, 3-diyl and 1-propyne-3, 3-diyl) , butynediyl (including all isomeric forms, e.g., 1-butyne-1, 3-diyl, 1-butyne-1, 4-diyl, and 2-butyne-1, 1-diyl) , pentynediyl (including all isomeric forms, e.g., 1-pentyne-1, 3-diyl, 1-pentyne-1, 4-diyl, and 2-pentyne-1, 1-diyl) , and hexynediyl (including all isomeric forms, e.g., 1-hexyne-1, 3-diyl, 1-hexyn
• cycloalkyl refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
• the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group.
• the cycloalkyl has from 3 to 20 (C 3-20 ) , from 3 to 15 (C 3-15 ) , from 3 to 10 (C 3-10 ) , or from 3 to 7 (C 3-7 ) carbon atoms.
• the cycloalkyl is monocyclic.
• the cycloalkyl is bicyclic.
• the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, decalinyl, and adamantyl.
• aryl refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C 6-20 ) , from 6 to 15 (C 6-15 ) , or from 6 to 10 (C 6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
• the aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) .
• the aryl is monocyclic.
• the aryl is bicyclic.
• the aryl is tricyclic.
• the aryl is polycyclic.
• the aryl is optionally substituted with one or more substituents Q as described herein.
• aralkyl or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C 7-30 ) , from 7 to 20 (C 7-20 ) , or from 7 to 16 (C 7-16 ) carbon atoms.
• 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) .
• the aralkyl is optionally substituted with one or more substituents Q as described herein.
• heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring.
• heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring.
• Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
• the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
• the heteroaryl is monocyclic.
• heteroaryl groups examples include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
• the heteroaryl is bicyclic.
• bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo [2, 3-b] pyridinyl, furo [2, 3-c] pyridinyl, furo [3, 2-b] pyridinyl, furo [3, 2-c] pyridinyl, furo [3, 4-b] pyridinyl, and furo [3, 4-c] pyridinyl) , imidazopyridinyl (including all isomeric forms, e.g., imidazo [1, 2-a] pyridinyl, imidazo [4, 5-b] pyridinyl, and imidazo [4, 5-c] pyridinyl
• the heteroaryl is tricyclic.
• tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1, 5-phenanthrolinyl, 1, 6-phenanthrolinyl, 1, 7-phenanthrolinyl, 1, 9-phenanthrolinyl, and 2, 10-phenanthrolinyl) , phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
• the heteroaryl is optionally substituted with one or more substituents Q as described herein.
• heterocyclyl refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
• heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring.
• the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
• the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
• the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
• heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., 1, 4-dihydrobenzo [d] [1, 3] oxazinyl, 3, 4-dihydrobenzo [c] [1, 2] -oxazinyl, and 3, 4-dihydrobenzo [d] [1, 2] oxazinyl) , dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo [c] thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazoly
• halogen refers to fluoro, chloro, bromo, and/or iodo.
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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) e
• optically active and ” enantiomerically active refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
• an optically active compound comprises about 95%or more of one enantiomer and about 5%or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
• an optically active compound comprises about 98%or more of one enantiomer and about 2%or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99%or more of one enantiomer and about 1%or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
• the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center (s) .
• the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
• the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
• the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
• the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the compound, R and S.
• isotopically enriched refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
• an isotopically enriched compound contains unnatural proportions 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-
• an isotopically enriched compound is in a stable form, that is, non-radioactive.
• an isotopically enriched compound contains unnatural proportions 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) .
• an isotopically enriched compound is in an unstable form, that is, radioactive.
• an isotopically enriched compound contains unnatural proportions 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) .
• any hydrogen can be 2 H, as example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, or any oxygen can be 18 O, as example, where feasible according to the judgment of one of ordinary skill in the art.
• nucleic acid refers to a polymer or oligomer of nucleotides of any length.
• the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides (such as methylated, hydroxymethylated, or glycosylated) , non-natural nucleotides, non-nucleotide building blocks that exhibit similar structure and/or function as natural nucleotides (i.e., “nucleotide analogs” ) , and/or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.
• the nucleic acids or polynucleotides can be heterogenous or homogenous in composition, can be isolated from naturally occurring sources, or can be artificially or synthetically produced.
• the nucleic acids may be DNA or RNA, or a mixture thereof, and can exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states.
• Nucleic acid structures also include, for instance, a DNA/RNA helix, peptide nucleic acid (PNA) , morpholino nucleic acid (see, e.g., Braasch and Corey, Biochemistry 2002, 4, 4503-10; and US 5, 034, 506) , locked nucleic acid (LNA; see, e.g., Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5633-8) , cyclohexenyl nucleic acid (see, e.g., Wang, Am. Chem. Soc. 2000, 122, 8595-602) , and/or a ribozyme.
• PNA peptide nucleic acid
• morpholino nucleic acid see, e.g., Braasch and Corey, Biochemistry 2002, 4, 4503-10; and US 5, 034, 506
• LNA locked nucleic acid
• essentially free, in terms of a specified component is used herein to mean that none of the specified component has been purposefully formulated into a composition and/or is present only as a contaminant or in trace amounts.
• the total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.1%, preferably below 0.05%, and more preferably below 0.01%.
• Most preferred is a composition in which no amount of the specified component can be detected with a standard analytical method.
• substantially pure and substantially homogeneous mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC) , gel electrophoresis, high performance liquid chromatography (HPLC) , gas chromatography (GC) , nuclear magnetic resonance (NMR) , and mass spectrometry (MS) ; or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
• TLC thin layer chromatography
• HPLC high performance liquid chromatography
• GC gas chromatography
• NMR nuclear magnetic resonance
• MS mass spectrometry
• 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.
• a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound.
• a deuterated compound that has an atom at a particular position designated as deuterium a compound that contains a protium at the same position is an impurity.
• solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount.
• Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid.
• the solvent is pharmaceutically acceptable.
• the complex or aggregate is in a crystalline form.
• the complex or aggregate is in a noncrystalline form.
• the solvent is water
• the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
• an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof” has the same meaning as the phrase “ (i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a pharmaceutically acceptable
• mRNA refers to messenger RNA.
• cRNA refers to circular RNA.
• R 1 is (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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c , -OR 1a
• R 3 and R 4 are each independently C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• E 1 and E 2 are each independently -C (O) -or -C (O) O-;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• M 1 and M 2 are each independently a linker
• U 1 and U 2 are each independently -O-or -N (R 1b ) -;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• M 1 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by a ⁇ -glycosidase. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by a galactosidase.
• M 1 is a linker cleavable by a ⁇ -galactosidase. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by a ⁇ -glucuronidase. In certain embodiments, in Formula (I) , M 1 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.
• M 1 is -S-S-.
• M 1 is
• M 2 is a cleavable linker. In certain embodiments, in Formula (I) , M 2 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (I) , M 2 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by glutathione. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by an enzyme. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a protease.
• M 2 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a ⁇ -glycosidase. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a galactosidase.
• M 2 is a linker cleavable by a ⁇ -galactosidase. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a ⁇ -glucuronidase. In certain embodiments, in Formula (I) , M 2 is a linker cleavable by a phosphatase. Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.
• M 2 is -S-S-.
• M 2 is
• R 1 , R 3 , R 4 , E 1 , E 2 , L 1 , L 2 , L 3 , L 4 , U 1 , and U 2 are each as defined herein.
• E 1 is -C (O) -. In certain embodiments, in Formula (I) or (Ia) , E 1 is -C (O) O-. In certain embodiments, in Formula (I) or (Ia) , E 2 is -C (O) -. In certain embodiments, in Formula (I) or (Ia) , E 2 is -C (O) O-.
• U 1 in Formula (I) or (Ia) , U 1 is -O-. In certain embodiments, in Formula (I) or (Ia) , U 1 is -N (R 1b ) -, wherein R 1b is as defined herein. In certain embodiments, in Formula (I) or (Ia) , U 1 is -N (H) -. In certain embodiments, in Formula (I) or (Ia) , U 2 is -O-. In certain embodiments, in Formula (I) or (Ia) , U 2 is -N (R 1b ) -, wherein R 1b is as defined herein. In certain embodiments, in Formula (I) or (Ia) , U 2 is -N (H) -.
• R 1 , R 3 , R 4 , L 1 , L 2 , L 3 , and L 4 are each as defined herein.
• R 1 , R 3 , R 4 , L 1 , L 2 , L 3 , and L 4 are each as defined herein.
• L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 1 is - (CR 2a R 2b ) a -, wherein each R 2a and R 2b is independently (i) hydrogen; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q; or R 2a and R 2b together with the C atom to which they are attached form C 3-10 cycloalkyl, optionally substituted with one or more substituents Q; and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 1 is - (CH 2 ) a -and a is an integer of 1, 2, 3, 4, 5, or 6. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L 1 is - (CH 2 ) a -and a is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L 1 is - (CH 2 ) 2 -.
• L 2 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 2 is - (CR 2a R 2b ) b -, wherein b is an integer of 1, 2, 3, 4, 5, or 6;and each R 2a and R 2b is as defined herein.
• L 2 is - (CH 2 ) b -and b is an integer of 1, 2, 3, 4, 5, or 6.
• L 2 is - (CH 2 ) b -and b is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L 2 is - (CH 2 ) 2 -.
• L 3 is C 1-10 alkylene, optionally substituted with one or more substituents Q.
• L 3 is - (CR 2a R 2b ) c -, wherein c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b is as defined herein.
• L 3 is - (CH 2 ) c -and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 3 is - (CR 2a R 2b ) (CR 2a R 2b ) c -, wherein c is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b is as defined herein.
• L 3 is - (C (CH 3 ) 2 ) (CH 2 ) c -and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 3 is - (CH 2 ) 2 -. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L 3 is - (CH 2 ) 3 -.
• L 4 is C 1-10 alkylene, optionally substituted with one or more substituents Q.
• L 4 is - (CR 2a R 2b ) d -, wherein d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b is as defined herein.
• L 4 is - (CH 2 ) d -and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 4 is - (CR 2a R 2b ) (CR 2a R 2b ) d -, wherein d is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R 2a and R 2b is as defined herein.
• L 4 is - (C (CH 3 ) 2 ) (CH 2 ) d -and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 4 is - (CH 2 ) 2 -. In certain embodiments, in any one of Formulae (I) and (Ia) to (Ic) , L 4 is - (CH 2 ) 3 -.
• R 1 , R 3 , R 4 , M 1 , M 2 , a, b, c, and d are each as defined herein.
• R 1 , R 3 , R 4 , M 1 , M 2 , a, b, c, and d are each as defined herein.
• M 1 is a cleavable linker. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by glutathione. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by an enzyme.
• M 1 is a linker cleavable by a protease. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by a glycosidase.
• M 1 is a linker cleavable by a ⁇ -glycosidase. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by a ⁇ -galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by a glucuronidase.
• M 1 is a linker cleavable by a ⁇ -glucuronidase. In certain embodiments, in Formula (Id) or (Ie) , M 1 is a linker cleavable by a phosphatase.
• Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.
• M 1 is -S-S-.
• M 1 is
• M 2 is a cleavable linker. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by glutathione. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by an enzyme.
• M 2 is a linker cleavable by a protease. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by a glycosidase.
• M 2 is a linker cleavable by a ⁇ -glycosidase. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by a galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by a ⁇ -galactosidase. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by a glucuronidase.
• M 2 is a linker cleavable by a ⁇ -glucuronidase. In certain embodiments, in Formula (Id) or (Ie) , M 2 is a linker cleavable by a phosphatase.
• Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; and Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.
• M 2 is -S-S-.
• M 2 is
• R 1 , R 3 , R 4 , a, b, c, and d are each as defined herein.
• R 1 , R 3 , R 4 , a, b, c, and d are each as defined herein.
• R 1 , R 2 , R 5 , and R 6 are each independently (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R 1a , -C (O) OR 1a , -C (O) NR 1b R 1c , -C (O) SR 1a , -C (NR 1a ) NR 1b R 1c , -C (NCN) NR 1b R 1c , -C (NOR 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• A is -O-or -N (R 1a ) -;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• X and Z are each independently a 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 is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• A in Formula (II) , A is -O-. In certain embodiments, in Formula (II) , A is -N (R 1b ) -, wherein R 1b is as defined herein. In certain embodiments, in Formula (II) , A is -N (H) -.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , L 4 , X, and Z are each as defined herein.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , L 4 , X, and Z are each as defined herein:
• L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 1 is - (CR 2a R 2b ) a -, wherein each R 2a , R 2b , and a is as defined herein.
• L 1 is - (CH 2 ) a -and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 1 is - (CH 2 ) a -and a is an integer of 2, 3, or 4. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L 1 is - (CH 2 ) 2 -.
• L 2 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 2 is - (CR 2a R 2b ) b -, wherein each R 2a , R 2b , and b is as defined herein.
• L 2 is - (CH 2 ) b -and b is an integer of 1, 2, 3, 4, 5, or 6.
• L 2 is - (CH 2 ) b -and b is an integer of 2, 3, or 4. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L 2 is - (CH 2 ) 2 -.
• L 3 is C 1-10 alkylene, optionally substituted with one or more substituents Q.
• L 3 is - (CR 2a R 2b ) c -, wherein each R 2a , R 2b , and c is as defined herein.
• L 3 is - (CH 2 ) c -and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 3 is - (CH 2 ) 2 -. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L 3 is - (CH 2 ) 3 -.
• L 4 is C 1-10 alkylene, optionally substituted with one or more substituents Q.
• L 4 is - (CR 2a R 2b ) d -, wherein each R 2a , R 2b , and d is as defined herein.
• L 4 is - (CH 2 ) d -and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 4 is - (CH 2 ) 2 -. In certain embodiments, in Formula (II) , (IIa) , or (IIb) , L 4 is - (CH 2 ) 3 -.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Z, a, b, c, and d are each as defined herein.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Z, a, b, c, and d are each as defined herein.
• 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c ,
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• M 1 is a linker
• U 1 is -O-or -N (R 1b ) -;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• M 1 is a cleavable linker. In certain embodiments, in Formula (III) , M 1 is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, in Formula (III) , M 1 is a cleavable linker comprising a reducible disulfide. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by glutathione. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by an enzyme. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a protease.
• M 1 is a linker cleavable by a lysosomal protease. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by cathepsin B. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a glycosidase. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a ⁇ -glycosidase. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a galactosidase.
• M 1 is a linker cleavable by a ⁇ -galactosidase. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a glucuronidase. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a ⁇ -glucuronidase. In certain embodiments, in Formula (III) , M 1 is a linker cleavable by a phosphatase.
• Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.
• M 1 is -S-S-.
• M 1 is
• R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , U 1 , X, and Z are each as defined herein.
• U 1 in Formula (III) or (IIIa) , U 1 is -O-. In certain embodiments, in Formula (III) or (IIIa) , U 1 is -N (R 1b ) -, wherein R 1b is as defined herein. In certain embodiments, in Formula (III) or (IIIa) , U 1 is -N (H) -.
• R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X, and Z are each as defined herein.
• R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X, and Z are each as defined herein.
• L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 1 is - (CR 2a R 2b ) a -, wherein each R 2a , R 2b , and a is as defined herein.
• L 1 is - (CH 2 ) a -and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 1 is - (CH 2 ) a -and a is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L 1 is - (CH 2 ) 2 -.
• L 2 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 2 is - (CR 2a R 2b ) b -, wherein each R 2a , R 2b , and b is as defined herein.
• L 2 is - (CH 2 ) b -and b is an integer of 1, 2, 3, 4, 5, or 6.
• L 2 is - (CH 2 ) b -and b is an integer of 2, 3, or 4. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L 2 is - (CH 2 ) 2 -.
• L 3 is C 1- 10 alkylene, optionally substituted with one or more substituents Q.
• L 3 is - (CR 2a R 2b ) c -, wherein each R 2a , R 2b , and c is as defined herein.
• L 3 is - (CH 2 ) c -and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 3 is - (CH 2 ) 2 -. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L 3 is - (CH 2 ) 3 -.
• L 4 is C 1- 10 alkylene, optionally substituted with one or more substituents Q.
• L 4 is - (CR 2a R 2b ) d -, wherein each R 2a , R 2b , and d is as defined herein.
• L 4 is - (CH 2 ) d -and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
• L 4 is - (CH 2 ) 2 -. In certain embodiments, in any one of Formulae (III) and (IIIa) to (IIIc) , L 4 is - (CH 2 ) 3 -.
• R 1 , R 2 , R 3 , R 4 , X, Z, a, b, c, and d are each as defined herein.
• R 1 , R 2 , R 3 , R 4 , X, Z, a, b, c, and d are each as defined herein.
• R 1 , R 2 , and R 7 are each independently (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C (O) R 1a , -C (O) OR 1a , -C (O) NR 1b R 1c , -C (O) SR 1a , -C (NR 1a ) NR 1b R 1c , -C (NCN) NR 1b R 1c , -C (NOR 1a ) NR 1b R 1c , -C (NS (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• A is a bond, -O-, or -N (R 1a ) -;
• L 1 is independently C 1-6 alkylene or C 1-6 heteroalkylene
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a , -C (O) OR a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• A in Formula (IV) , is -O-. In certain embodiments, in Formula (IV) , A is -N (R 1b ) -, wherein R 1b is as defined herein. In certain embodiments, in Formula (IV) , A is -N (H) -.
• R 1 , R 2 , R 3 , R 4 , R 7 , and L 1 are each as defined herein.
• R 1 , R 2 , R 3 , R 4 , R 7 , and L 1 are each as defined herein.
• L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 1 is - (CR 2a R 2b ) a -, wherein each R 2a , R 2b , and a is as defined herein.
• L 1 is - (CH 2 ) a -and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 1 is - (CH 2 ) a -and a is an integer of 2, 3, or 4. In certain embodiments, in Formula (IV) , (IVa) , or (IVb) , L 1 is - (CH 2 ) 2 -.
• R 1 , R 2 , R 3 , R 4 , R 7 , and a are each as defined herein.
• R 1 , R 2 , R 3 , R 4 , R 7 , and a are each as defined herein.
• R 1 is (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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) R 1a , -C (S) OR 1a , -C (S) NR 1b R 1c , -OR 1a
• R 3 and R 4 are each independently hydrogen, C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl;
• L 1 and L 2 are each independently C 1-6 alkylene or C 1-6 heteroalkylene
• L 3 and L 4 are each independently C 1-10 alkylene, C 1-10 heteroalkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
• each R 1a , R 1b , R 1c , and R 1d is 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 heterocyclyl;
• each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C (O) R a ,
• each Q a is independently selected from: (a) deuterium, cyano, halo, 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
• L 1 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 1 is - (CR 2a R 2b ) a -, wherein each R 2a , R 2b , and a is as defined herein.
• L 1 is - (CH 2 ) a -and a is an integer of 1, 2, 3, 4, 5, or 6.
• L 1 is - (CH 2 ) a -and a is an integer of 2, 3, or 4.
• L 1 is - (CH 2 ) 2 -.
• L 2 is C 1-6 alkylene, optionally substituted with one or more substituents Q.
• L 2 is - (CR 2a R 2b ) b -, wherein each R 2a , R 2b , and b is as defined herein.
• L 2 is - (CH 2 ) b -and b is an integer of 1, 2, 3, 4, 5, or 6.
• L 2 is - (CH 2 ) b -and b is an integer of 2, 3, or 4.
• L 2 is - (CH 2 ) 2 -.
• L 3 is C 1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V) , L 3 is - (CR 2a R 2b ) c -, wherein each R 2a , R 2b , and c is as defined herein. In certain embodiments, in Formula (V) , L 3 is - (CH 2 ) c -and c is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in Formula (V) , L 3 is - (CH 2 ) 2 -. In certain embodiments, in Formula (V) , L 3 is - (CH 2 ) 3 -.
• L 4 is C 1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V) , L 4 is - (CR 2a R 2b ) d -, wherein each R 2a , R 2b , and d is as defined herein. In certain embodiments, in Formula (V) , L 4 is - (CH 2 ) d -and d is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, in Formula (V) , L 4 is - (CH 2 ) 2 -. In certain embodiments, in Formula (V) , L 4 is - (CH 2 ) 3 -.
• R 1 , R 3 , R 4 , a, b, c, and d are each as defined herein.
• R 1 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c
• R 1 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 1 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; 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 a C (NR b R c , -NR a C (NR a C (NR a C (NR b R c , -NR a C (NR a C (NR a C (NR b R c , -NR a C (NR NR
• R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthioureido, 3, 3-dimethylthioureido, guanidino, me
• R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3, 3-dimethylureido, 3-methylthio-
• R 1 is methyl, cyclopropylmethyl, cyclobutyl-methyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthiour
• R 1 is C 2-6 alkenyl, optionally substituted with one or more substituents Q.
• R 1 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 1 is 1- (dimethylamino) -2-nitrovinyl.
• R 1 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 1 is C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 1 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 1 is monocyclic C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 , and (Va) , R 1 is monocyclic C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloal
• R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q.
• R 1 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl.
• R 1 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 1 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 (O) NR b R c , -NR a C
• R 1 is 4-dimethylamino-phenyl.
• R 1 is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
• R 1 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 (O) NR b R c , -NR
• R 1 is 4-methoxybenzyl.
• R 1 is heteroaryl, optionally substituted with one or more substituents Q.
• R 1 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 a C (NR b R c , -NR a C (NR a C (NR NR b R c , -NR a C (NR NR a C (NR NR b R c , -NR a C (NR NR a C (NR
• R 1 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 1 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 1 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 1 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q.
• R 1 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.
• R 1 is -C (O) R 1a , wherein R 1a is as defined herein.
• R 1 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 1 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein.
• R 1 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxy-acetyl, benzyloxyacetyl, propionyl, or isopropionyl.
• R 1 is -C (O) OR 1a , wherein R 1a is as defined herein.
• R 1 is -C (O) OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 1 is methoxycarbonyl.
• R 1 is -C (O) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 1 is methylaminocarbonyl or dimethylamino-carbonyl.
• R 1 is -C (NR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 1 is carbamimidoyl.
• R 1 is -C (NCN) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 1 is N’-cyano-N, N-dimethylcarbamimidoyl.
• R 1 is -C (NOR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 1 is N’-methoxy-N, N-dimethylcarbamimidoyl.
• R 1 is -C (NS (O 2 ) R 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 1 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl.
• R 1 is -C (S) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 1 is methylaminothiocarbonyl or dimethylaminothiocarbonyl.
• R 1 is -OR 1a , wherein R 1a is as defined herein.
• R 1 is hydroxyl or methoxy.
• R 1 is -S (O) 2 R 1a , wherein R 1a is as defined herein.
• R 1 is methylsulfonyl.
• R 1 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-yl-methyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido
• R 1 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylamino-methyl, or 2-dimethylaminoethyl.
• R 2 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b R 1c
• R 2 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 2 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; 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 (NR d ) NR b R c , -NR 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, hal
• R 2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methyl
• R 2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3, 3-dimethylureido, 3-methylthioureido, 3, 3-dimethylthioureido,
• R 2 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthio- ureido) ethyl, 2- (3, 3-dimethylthioureido) e
• R 2 is C 2-6 alkenyl, optionally substituted with one or more substituents Q.
• R 2 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 ,
• R 2 is 1- (dimethylamino) -2-nitrovinyl.
• R 2 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 2 is C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 2 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 2 is monocyclic C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 2 is cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q.
• R 2 is cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl.
• R 2 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 2 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 , -OR a , -NR b R c , -NR a C (O) NR b R c , -NR a C (NR d ) NR b R c ,
• R 2 is 4-dimethylaminophenyl.
• R 2 is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
• R 2 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 (NR d ) NR b R c
• R 2 is 4-methoxybenzyl.
• R 2 is heteroaryl, optionally substituted with one or more substituents Q.
• R 2 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 (NR d ) NR b R c , -NR NR a C (NR d ) NR b R c , -NR NR a C (NR d ) NR
• R 2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 2 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 (NR d ) NR b R c ,
• R 2 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 2 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q.
• R 2 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.
• R 2 is -C (O) R 1a , wherein R 1a is as defined herein.
• R 2 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 2 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein.
• R 2 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxy-acetyl, benzyloxyacetyl, propionyl, or isopropionyl.
• R 2 is -C (O) OR 1a , wherein R 1a is as defined herein.
• R 2 is -C (O) OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 2 is methoxycarbonyl.
• R 2 is -C (O) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 2 is methylaminocarbonyl or dimethylaminocarbonyl.
• R 2 is -C (NR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 2 is carbamimidoyl.
• R 2 is -C (NCN) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 2 is N’-cyano-N, N-dimethylcarbamimidoyl.
• R 2 is -C (NOR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 2 is N’-methoxy-N, N-dimethylcarbamimidoyl.
• R 2 is -C (NS (O 2 ) R 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 2 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl.
• R 2 is -C (S) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 2 is methylamino-thiocarbonyl or dimethylaminothiocarbonyl. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R 2 is -OR 1a , wherein R 1a is as defined herein.
• R 2 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , R 2 is -S (O) 2 R 1a , wherein R 1a is as defined herein.
• R 2 is methylsulfonyl
• R 2 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethyl-amino) -2-nitrovinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexyl-methyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-yl-methyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylamino-ethyl, 2- (3-methylureido) ethyl, 2- (3, 3-di
• R 2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 1 and R 2 together with the N atom to which they are attached form heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5-membered heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 6-membered heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, pyridin-1-iumyl, or pyrimidin-1-yl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2, 4-dioxo-3, 4-dihydro-pyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.
• R 1 and R 2 together with the N atom to which they are attached form bicyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5, 5-, 5, 6-, or 6, 6-fused heteroaryl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5, 5-fused heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5, 6-fused heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 6, 6-fused heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form purin-9-yl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 6-aminopurin-9-yl or 2-amino-6-oxo-1, 9-dihydro-purin-9-yl.
• R 1 and R 2 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 3-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 4-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 6-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 7-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, imidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, piperazin-1-yl, or isoindolin-2-yl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2, 5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2, 5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3, 5-dioxomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- (4-methoxybenzyl) piperazin-1-yl, 4- (2-hydroxethyl) piperazin
• R 1 and R 2 together with the N atom to which they are attached form heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 5-membered heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 6-membered heteroaryl, optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, pyridin-1-iumyl, or pyrimidin-1-yl, each optionally substituted with one or more substituents Q.
• R 1 and R 2 together with the N atom to which they are attached form 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2, 4-dioxo-3, 4-dihydropyrimidin-1-yl, or 4-amino-2-oxopyrimidin-1-yl.
• the moiety is dimethylamino, (2-cyanoethyl) (methyl) amino, (cyclopropylmethyl) (methyl) amino, (cyclobutylmethyl) (methyl) amino, (cyclopentylmethyl) - (methyl) amino, (cyclohexylmethyl) (methyl) amino, (cycloheptylmethyl) (methyl) amino, (pyridin-2-ylmethyl) (methyl) amino, (pyridin-3-ylmethyl) (methyl) amino, (pyridin-4-ylmethyl) (methyl) -amino, (dimethylaminomethyl) (methyl) amino, (ethyl) (methyl) amino, (2-hydroxyethyl) (methyl) -amino, (2-acetamidoethyl) (methyl
• the moiety is 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2, 4-dioxo-3, 4-dihydropyrimidin-1-yl, 4-amino-2-oxopyrimidin-1-yl, 6-aminopurin-9-yl, 2-amino-6-oxo-1, 9-dihydropurin-9-yl, 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2, 5-dioxopyrrolidin-1-yl, 2-oxoxazolidin-3-yl
• the moiety in any one of Formulae (II) to (IV) , (IIa) to (IId) , (IIIa) to (IIIe) , and (IVa) to (IVd) , the moiety has the structure of: wherein e and f are each independently an integer of 0, 1, 2, 3, 4, or 5; each k and m is independently an integer of 0, 1, 2, 3, 4, or 5; n is an integer of 0, 1, 2, 3, 4, 5, or 6; and each R 1a is as defined herein; in one embodiment, each R 1a is independently C 1-6 alkyl, optionally substituted with one or more substituents Q; and in another embodiment, each R 1a is methyl.
• R 3 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 heterocyclyl, each optionally substituted with one or more substituents Q.
• R 3 is 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 optionally substituted with one or more substituents Q.
• R 3 is C 1-30 alkyl, optionally substituted with one or more substituents Q.
• R 3 is C 1-25 alkyl, optionally substituted with one or more substituents Q.
• R 3 is C 1-20 alkyl, optionally substituted with one or more substituents Q.
• R 3 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octanyl, nonyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, penta-decanyl, hexadecanyl, heptadecanyl, octadecanyl, nonadecanyl, eicosanyl, heneicosanyl, docosanyl, tricosanyl, tetracosanyl, or pentacosanyl, each optionally substituted with one or more substituents Q.
• R 3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methyl-hex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridecan-1-yl, pentadecan
• R 3 is C 1-30 alkenyl, optionally substituted with one or more substituents Q.
• R 3 is C 1-25 alkenyl, optionally substituted with one or more substituents Q.
• R 3 is C 1-20 alkenyl, optionally substituted with one or more substituents Q.
• 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 optionally substituted with one or
• R 3 is (Z) -2-hexen-1-yl, (Z) -2-nonen-1-yl, (Z) -2-undecen-1-yl, (Z) -2-tri-decen-1-yl, (Z) -3-octen-1-yl, (E) -3-methyloct-6-en-1-yl, (Z) -3-nonen-1-yl, (Z) -4, 4-difluoronon-3-en-1-yl, (Z) -5, 5-difluoronon-3-en-1-yl, (Z) -3-decen-2-yl, (Z) -3-undecen-1-yl, (Z)
• R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 3 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 3 is cyclohexyl, optionally substituted with one or more substituents Q.
• R 3 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.
• R 3 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 3 is phenyl, optionally substituted with one or more substituents Q.
• R 3 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.
• R 3 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methylhex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyl-octan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1- yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridecan-1-yl, pent
• R 3 is wherein each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.
• R 3 is
• 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.
• R 4 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 heterocyclyl, each optionally substituted with one or more substituents Q.
• R 4 is 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 optionally substituted with one or more substituents Q.
• R 4 is C 1-30 alkyl, optionally substituted with one or more substituents Q.
• R 4 is C 1-25 alkyl, optionally substituted with one or more substituents Q.
• R 4 is C 1-20 alkyl, optionally substituted with one or more substituents Q.
• R 4 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octanyl, nonyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, penta-decanyl, hexadecanyl, heptadecanyl, octadecanyl, nonadecanyl, eicosanyl, heneicosanyl, docosanyl, tricosanyl, tetracosanyl, or pentacosanyl, each optionally substituted with one or more substituents Q.
• R 4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methyl-hex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridecan-1-yl, pentadecan
• R 4 is C 1-30 alkenyl, optionally substituted with one or more substituents Q.
• R 4 is C 1-25 alkenyl, optionally substituted with one or more substituents Q.
• R 4 is C 1-20 alkenyl, optionally substituted with one or more substituents Q.
• R 4 is butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, or pentacosenyl, each optionally substituted with one or
• R 4 is (Z) -2-hexen-1-yl, (Z) -2-nonen-1-yl, (Z) -2-undecen-1-yl, (Z) -2-tri-decen-1-yl, (Z) -3-octen-1-yl, (E) -3-methyloct-6-en-1-yl, (Z) -3-nonen-1-yl, (Z) -4, 4-difluoronon-3-en-1-yl, (Z) -5, 5-difluoronon-3-en-1-yl, (Z) -3-decen-2-yl, (Z) -3-undecen-1-yl, (Z)
• R 4 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 4 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 4 is cyclohexyl, optionally substituted with one or more substituents Q.
• R 4 is 4-pentylcyclohexyl or 4-cyclohexylcyclohexyl.
• R 4 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 4 is phenyl, optionally substituted with one or more substituents Q.
• R 4 is 3-pentylphenyl, 4-pentylphenyl, or 3, 4-dipentylphenyl.
• R 4 is prop-1-yl, pent-1-yl, 2-isopropyl-5-methyl-hex-1-yl, hept-1-yl, octan-1-yl, octan-3-yl, 3, 7-dimethyloctan-1-yl, 8-methoxycarbonyloctan-1-yl, 8-trifluoromethoxycarbonyloctan-1-yl, non-1-yl, 8-methylnon-1-yl, 2-methoxynon-1-yl, decan-1-yl, undecan-1-yl, dodec-1-yl, 2-hydroxydodec-1-yl, tridecan-1-yl, pentadecan
• R 4 is wherein each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.
• R 4 is 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.
• R 3 is:
• each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
• R 4 is:
• each p is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; wherein each s and t is independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
• R 3 is T-0020.
• R 3 is T-0021.
• R 3 is T-0022.
• R 3 is T-0023.
• R 3 is T-0025.
• R 3 is T-0092.
• R 3 is T-0108.
• R 3 is T-0109.
• R 3 is T-0110.
• R 3 is T-0111.
• R 3 is T-0112.
• R 3 is T-0113.
• R 4 is T-0020.
• R 4 is T-0021.
• R 4 is T-0022.
• R 4 is T-0023.
• R 4 is T-0025.
• R 4 is T-0092.
• R 4 is T-0108.
• R 4 is T-0109.
• R 4 is T-0110.
• R 4 is T-0111.
• R 4 is T-0112.
• R 4 is T-0113.
• the number of carbon atoms in R 3 is an integer of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27 or 28.
• the number of carbon atoms in R 3 is 12.
• the number of carbon atoms in R 3 is 14.
• the number of carbon atoms in R 3 is 15.
• the number of carbon atoms in R 3 is 16.
• the number of carbon atoms in R 3 is 17.
• the number of carbon atoms in R 3 is 18.
• the number of carbon atoms in R 3 is 20.
• the number of carbon atoms in R 3 is 21.
• the number of carbon atoms in R 3 is 24.
• the number of carbon atoms in R 3 is 25.
• the number of carbon atoms in R 3 is 28.
• the number of carbon atoms in R 4 is an integer of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27 or 28.
• the number of carbon atoms in R 4 is 12.
• the number of carbon atoms in R 4 is 14.
• the number of carbon atoms in R 4 is 15.
• the number of carbon atoms in R 4 is 16.
• the number of carbon atoms in R 4 is 17.
• the number of carbon atoms in R 4 is 18.
• the number of carbon atoms in R 4 is 20.
• the number of carbon atoms in R 4 is 21.
• the number of carbon atoms in R 4 is 24.
• the number of carbon atoms in R 4 is 25.
• the number of carbon atoms in R 4 is 28.
• R 3 is branched 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 heterocyclyl.
• R 4 is branched 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 heterocyclyl.
• R 5 is (i) C 1- 6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b R 1c , -OR 1a , or -S (O) 2 R 1a , wherein each R 1a ,
• R 5 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
• R 5 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; 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 ,
• R 5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.
• R 5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3, 3-dimethylureido, 3-methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamid
• R 5 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclo-heptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylamino- methyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3, 3-dimethyl-thioureido) ethyl, 2-guanidinoethyl, 2- (methylsulfonamido) e
• R 5 is C 2-6 alkenyl, optionally substituted with one or more substituents Q.
• R 5 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 5 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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)
• R 5 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 5 is monocyclic C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) -C (O) OR a , -C (O) NR b R c , -C (O) SR a , -OR a , -NR b R c , -NR
• R 5 is cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q.
• R 5 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3, 4-dioxo-1-cyclobutenyl.
• R 5 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 5 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 5 is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
• R 5 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 5 is heteroaryl, optionally substituted with one or more substituents Q.
• R 5 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 NR a C (O) NR b R c , -NR
• R 5 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 5 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 5 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 5 in any one of Formulae (II) and (IIa) to (IId) , R 5 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q.
• R 5 in any one of Formulae (II) and (IIa) to (IId) , R 5 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.
• R 5 is -C (O) R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 5 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein.
• R 5 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl.
• R 5 is -C (O) OR 1a , wherein R 1a is as defined herein.
• R 5 is -C (O) OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 5 is methoxy-carbonyl.
• R 5 in any one of Formulae (II) and (IIa) to (IId) , R 5 is -C (O) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is -C (NR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 5 is carbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is -C (NCN) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is N’-cyano-N, N-dimethylcarbamimidoyl.
• R 5 is -C (NOR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is N’-methoxy-N, N-dimethyl-carbamimidoyl.
• R 5 is -C (NS (O 2 ) R 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 5 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl.
• R 5 in any one of Formulae (II) and (IIa) to (IId) , R 5 is -C (S) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is methylaminothiocarbonyl or dimethylamino-thiocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is -OR 1a , wherein R 1a is as defined herein.
• R 5 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is -S (O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 5 is methylsulfonyl.
• R 5 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3-methylthioureido) e
• R 5 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 6 is (i) C 1- 6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b R 1c , -OR 1a , or -S (O) 2 R 1a , wherein each R 1a ,
• R 6 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; 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 ,
• R 6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethyl-amino, acetamido, methylureido, dimethylureido, methyl-thioureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.
• R 6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3, 3-dimethylureido, 3-methyl-thioureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfona
• R 6 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclo-heptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylamino-methyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3, 3-dimethyl-thioureido) ethyl, 2-guanidinoethyl, 2- (methylsulfonamido) eth
• R 6 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 6 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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)
• R 6 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is monocyclic C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) -C (O) OR a , -C (O) NR b R c , -C (O) SR a , -OR a , -NR b R c , -NR
• R 6 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q.
• R 6 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethylamino-3,4-dioxo-1-cyclobutenyl.
• R 6 is C 6-14 aryl, optionally substituted with one or more substituents Q.
• R 6 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 6 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 6 is heteroaryl, optionally substituted with one or more substituents Q.
• R 6 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 NR a C (O) NR b R c , -NR
• R 6 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 6 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 6 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (O) R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q.
• R 6 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein.
• R 6 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (O) OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (O) OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is methoxy-carbonyl.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (O) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (NR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 6 is carbamimidoyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (NCN) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is N’-cyano-N, N-dimethylcarbamimidoyl.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (NOR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is N’-methoxy-N, N-dimethyl-carbamimidoyl.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (NS (O 2 ) R 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is -C (S) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is methylaminothiocarbonyl or dimethylamino-thiocarbonyl. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is -OR 1a , wherein R 1a is as defined herein.
• R 6 in any one of Formulae (II) and (IIa) to (IId) , R 6 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is -S (O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (II) and (IIa) to (IId) , R 6 is methylsulfonyl.
• R 6 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2- hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2-
• R 6 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• R 5 and R 6 together with the N atom to which they are attached form bicyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 5, 5-, 5, 6-, or 6, 6-fused heteroaryl, each optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 5, 5-fused heteroaryl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 5, 6-fused heteroaryl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 6, 6-fused heteroaryl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form purin-9-yl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 6-aminopurin-9-yl or 2-amino-6-oxo-1, 9-dihydropurin-9-yl.
• R 5 and R 6 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 3-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 4-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 5-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 6-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 7-membered heterocyclyl, optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, imidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, piperazin-1-yl, or isoindolin-2-yl, each optionally substituted with one or more substituents Q.
• R 5 and R 6 together with the N atom to which they are attached form 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2, 5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2, 5-dioxoimidazolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 3, 5-dioxomorpholin-4-yl, piperazin-1-yl, 4- methylpiperazin-1-yl, 4- (4-methoxybenzyl) piperazin-1-yl, 4- (2-hydroxethyl) piperazin-1-yl, or 1, 3-dioxoisoindolin-2-yl.
• the moiety is dimethylamino, (2-cyanoethyl) (methyl) amino, (cyclopropylmethyl) (methyl) amino, (cyclobutylmethyl) (methyl) amino, (cyclopentylmethyl) (methyl) amino, (cyclohexylmethyl) - (methyl) amino, (cycloheptylmethyl) (methyl) amino, (pyridin-2-ylmethyl) (methyl) amino, (pyridin-3-ylmethyl) (methyl) amino, (pyridin-4-ylmethyl) (methyl) amino, (dimethylamino-methyl) (methyl) amino, (ethyl) (methyl) amino, (2-hydroxyethyl) (methyl) amino, (2-acetamido-ethyl) (methyl) amino, (2-guanidinoethyl) (methyl) amino, (2-methylsulfonamidoethyl)
• the moiety is 1, 2, 3-triazol-1-yl, 4-tert-butoxymethyl-1, 2, 3-triazol-1-yl, 4-dimethylaminopyridin-1-iumyl, 2, 4-dioxo-3, 4-dihydropyrimidin-1-yl, 4-amino-2-oxopyrimidin-1-yl, 6-aminopurin-9-yl, 2-amino-6-oxo-1, 9-dihydropurin-9-yl, 2-methylaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2, 5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2, 5-dioxoimidazolidin-1-yl, piperidin-1-yl, a
• the moiety in any one of Formulae (II) and (IIa) to (IId) , has the structure of: wherein e and f are each independently an integer of 0, 1, 2, 3, 4, or 5; each k and m is independently an integer of 0, 1, 2, 3, 4, or 5; n is an integer of 0, 1, 2, 3, 4, 5, or 6; and each R 1a is as defined herein; in one embodiment, each R 1a is independently C 1-6 alkyl, optionally substituted with one or more substituents Q; and in another embodiment, each R 1a is methyl.
• R 7 is (i) C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl, each 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 (O 2 ) R 1a ) NR 1b R 1c , -C (S) NR 1b R 1c , -OR 1a , or -S (O) 2 R 1a , wherein each R 1a , R 1
• R 7 is C 1- 6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q a ; 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 (O) NR b R c , -NR a C (O) NR b R
• R 7 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, hydroxyethoxy, dimethylamino, acetamido, methylureido, dimethylureido, methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.
• R 7 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one, two, or three substituents Q, each of which is independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, methoxycarbonyl, methylthiocarbonyl, hydroxyl, 2-hydroxyethoxy, dimethylamino, acetamido, 3-methylureido, 3, 3-dimethylureido, 3-methylthio-ureido, 3, 3-dimethylthioureido, guanidino, methoxyimino, mercapto, or methylsulfonamido.
• R 7 is methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclo-heptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylamino-methyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3, 3-dimethyl-thioureido) ethyl, 2-guanidinoethyl, 2- (methylsulfonamido) ethyl,
• R 7 is C 2- 6 alkenyl, optionally substituted with one or more substituents Q.
• R 7 is C 1-6 alkenyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 , -OR a , -NR b R c , -NR a C (O) NR b R c , --OR a , -NR b R c
• R 7 is C 3- 10 cycloalkyl, optionally substituted with one or more substituents Q.
• R 7 is C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3- 10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 7 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is monocyclic C 3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of wherein is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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)
• R 7 is cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl, cycloheptyl, or cyclobutenyl, each optionally substituted with one, two, or three substituents Q.
• R 7 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, or 2-dimethyl-amino-3, 4-dioxo-1-cyclobutenyl.
• R 7 is C 6- 14 aryl, optionally substituted with one or more substituents Q.
• R 7 is C 6-14 aryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 NR a C (O) NR b R c , -NR
• R 7 is C 7- 15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is C 7-15 aralkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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
• R 7 is heteroaryl, optionally substituted with one or more substituents Q.
• R 7 is heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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)
• R 7 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) cyano, halo, or nitro; (ii) C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; 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 NR a C (O) NR b R c , -NR
• R 7 is 5-or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
• R 7 is imidazolyl, thiazolyl, or pyridinyl, each optionally substituted with one or more substituents Q.
• R 7 is imidazol-2-yl, thiazol-2-yl, pyridin-2-yl, or pyridin-3-yl.
• R 7 is -C (O) R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (O) -C 1-6 alkyl, wherein the alkyl is optionally substituted with -OR a , and R a is as defined herein.
• R 7 is acetyl, hydroxyacetyl, methoxyacetyl, phenoxyacetyl, benzyloxyacetyl, propionyl, or isopropionyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (O) OR 1a , wherein R 1a is as defined herein.
• R 7 is -C (O) OC 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is methoxycarbonyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (O) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 7 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (NR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is carbamimidoyl.
• R 7 is -C (NCN) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is N’-cyano-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (NOR 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
• R 7 is N’-methoxy-N, N-dimethylcarbamimidoyl. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -C (NS (O 2 ) R 1a ) NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is N’-methylsulfonyl-N, N-dimethylcarbamimidoyl.
• R 7 is -C (S) NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
• R 7 is methyl-aminothiocarbonyl or dimethylaminothiocarbonyl.
• R 7 is -OR 1a , wherein R 1a is as defined herein.
• R 7 is hydroxyl or methoxy. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is -S (O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of Formulae (IV) and (IVa) to (IVd) , R 7 is methylsulfonyl.
• R 7 is methyl, (E) -1- (dimethylamino) -2-nitrovinyl, (Z) -1- (dimethylamino) -2-nitrovinyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, dimethylaminomethyl, ethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-acetamidoethyl, 2-dimethylaminoethyl, 2- (3-methylureido) ethyl, 2- (3, 3-dimethylureido) ethyl, 2- (3-methylthioureido) ethyl, 2- (3, 3-d
• R 7 is methyl, ethyl, isopropyl, 2-hydroxyethyl, dimethylaminomethyl, or 2-dimethylaminoethyl.
• a is an integer of 1, 2, 3, or 4. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 1.
• a is an integer of 2. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , (IVc) , (IVd) , and (Va) , a is an integer of 3.
• a is an integer of 4.
• b is an integer of 1, 2, 3, or 4. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 1. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 2.
• b is an integer of 3. In certain embodiments, in any one of Formulae (Id) to (Ig) , (IIc) , (IId) , (IIId) , (IIIe) , and (Va) , b is an integer of 4.
• g and h are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; and e is as defined herein.
• i and j are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and e is as defined herein.
• i and j are each as defined herein.
• i and j are each as defined herein.
• i and j are each as defined herein.
• i and j are each as defined herein.
• n is as defined herein.
• n is as defined herein.
• i, j, and n are each as defined herein.
• i and j are each as defined herein.
• g and h are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; and e is as defined herein.
• i and j are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and e is as defined herein.
• i and j are each as defined herein.
• i and j are each as defined herein.
• i and j are each as defined herein.
• i and j are each as defined herein.
• n is as defined herein.
• n is as defined herein.
• i, j, and n are each as defined herein.
• i and j are each as defined herein.
• X, Z, c, d, e, f, g, and h are each as defined herein.
• X, Z, c, d, e, and f are each as defined herein.
• X, Z, c, d, e, and f are each as defined herein.
• X, Z, c, d, e, f, i, and j are each as defined herein.
• X, Z, c, d, e, f, g, and h are each as defined herein.
• X, Z, c, d, e, f, g, and h are each as defined herein.
• X, Z, c, d, g, and h are each as defined herein.
• X, Z, c, and d are each as defined herein.
• X, Z, c, and d are each as defined herein.
• X, Z, c, d, i, and j are each as defined herein.
• X, Z, c, d, g, and h are each as defined herein.

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