WO2025054401A2 - Analogues de coiffe et leurs méthodes d'utilisation - Google Patents

Analogues de coiffe et leurs méthodes d'utilisation Download PDF

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WO2025054401A2
WO2025054401A2 PCT/US2024/045502 US2024045502W WO2025054401A2 WO 2025054401 A2 WO2025054401 A2 WO 2025054401A2 US 2024045502 W US2024045502 W US 2024045502W WO 2025054401 A2 WO2025054401 A2 WO 2025054401A2
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substituted
unsubstituted
nhc
och
mixture
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WO2025054401A3 (fr
Inventor
Hengyuan Lang
Chunping Xu
Chanfeng Zhao
Alexandre V. Lebedev
Ilya Vladimirovich ILICHEV
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Trilink Biotechnologies LLC
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Trilink Biotechnologies LLC
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Priority to AU2024337685A priority Critical patent/AU2024337685A1/en
Priority to IL326531A priority patent/IL326531A/en
Priority to CN202480056968.8A priority patent/CN121794279A/zh
Publication of WO2025054401A2 publication Critical patent/WO2025054401A2/fr
Publication of WO2025054401A3 publication Critical patent/WO2025054401A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/30—Nucleotides
    • C12P19/34—Polynucleotides, e.g. nucleic acids, oligoribonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination

Definitions

  • the field of this invention relates to cap analogs and methods of making and using the same. Additionally, the invention relates to using the cap analogs for preparing 5 ’-capped RNAs.
  • mRNAs In vitro transcribed messenger RNAs (mRNAs) have numerous in vivo applications, such as vaccination, where mRNA encoding specific antigen(s) is administered to elicit protective immunity in a patient; cell therapy, where mRNA is transfected into cells ex vivo to alter cell phenotype or function prior to delivery of these altered cells to a patient: or replacement therapy, where mRNA encoding a therapeutic protein is administered to the patient.
  • vaccination where mRNA encoding specific antigen(s) is administered to elicit protective immunity in a patient
  • cell therapy where mRNA is transfected into cells ex vivo to alter cell phenotype or function prior to delivery of these altered cells to a patient: or replacement therapy, where mRNA encoding a therapeutic protein is administered to the patient.
  • a primary structural element of an mRNA molecule that is utilized in in vivo applications includes a Cap structure on the 5 ’-end of the mRNA.
  • Naturally occurring Cap structures include a 7-methylguanosine ( 7m G or m7 G) linked through a 5‘- to 5 ’-triphosphate chain at the 5 ’-end of the mRNA molecule.
  • the Cap must be present for the mRNA to retain template activity for protein synthesis.
  • the chemical structure of the Cap can modulate translation efficiency in a cell. Therefore, effective Cap structures are necessary. Described herein are new Cap structures, which can be used for preparing 5 ’-capped mRNAs.
  • B 1 , B 2 , and B 3 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O. S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary 1, or substituted or unsubstituted heteroaryl;
  • R 7 is hydrogen, halogen, -CCI3. -CBn, -CF3, -Ch, -CHCh. -CH Bn.
  • each R 19 is independently hydrogen, halogen. -CCh, -CBrs. -CF3, -Cl3, -CHCl2, -CHBn.
  • R 11 is hydrogen, halogen, -CCh, -CBr3, -CF3, -Cl3 -CHCl2, -CH Bn. -CHF2, -CHI 2 , - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3.
  • R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A ,and R 19B is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH2, -COOH, -CONH2,
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 101 is hydrogen, oxo. halogen, -CCI3, -CBn. -CF3. -CI3, -CHCh, -CHBrs. -CHF2. -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr 3 , -OCI3, -OCHCl 2 ,-OCHBr 2 , -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -
  • n is an integer from 0 to 3;
  • X is -Cl, -Br, -I or -F; with the proviso that the compound of formula (I) is not: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof
  • B ' is a natural nucleoside base
  • R 4 is independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 5 is independently hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A , substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 6 is hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCh, -CHBn.
  • R 14 is hydrogen, halogen, -CCb, -CBn. -CF3. -CI3. -CHCh, -CHBn.
  • R 14A . and R 14B is independently hydrogen, -CX3, -CHX2, -CH2X.
  • R 6A and R 6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R 14A and R 14B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 1 , R 2 , R 3 , R 7 , R 11 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , n, and Ring A are each as defined herein, including in embodiments.
  • R 8 is independently hydrogen, halogen. -CCI3, -CBrs, -CF3, -Ch. -CHCh, -CHBn, -CHF2, -CHI2, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)R 8A , -NHC(O)OH, -NHOH.
  • -OCH2F. -N3, -SFs substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 9 is independently hydrogen, halogen, -CCI3, -CBr?. -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI 2 , -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 9A .
  • -NR 9A R 9B -COOH, -CONH2, -NO2.
  • R 10 is hydrogen, halogen, -CCk, -CBn. -CF3. -Ch, -CHCh, -CHBr 2 . -CHF2. -CHI 2 , -CH2CL -CH 2 Br, -CH2F, -CH2I, -CN, -OR 10A , -NR 1OA R 1OB , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH.
  • R 8 and R 10 or R 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R 8A , R 8B , R 8 ’ A , R 8 ’ B
  • R 8A and R 8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 8 A and R 8 B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 9A and R 9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 10A and R 10B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R 1 , R 2 , R 3 , R 4 , R 5 .
  • R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 and n, are each as defined herein, including in embodiments.
  • IC enantiomer
  • a mixture of enantiomers a mixture of two or more 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 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are as defined herein, including in embodiments.
  • a compound of formula (ID) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein.
  • R 12 is independently hydrogen, -C(O)R 12A , -C(O)OR 12A , -OR 12A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroary l;
  • R 13 is independently hydrogen, -C(O)R 1 JA , -C(O)OR 13A , -OR 13A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 12 and R 13 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; each R 12A and R 13A is independently hydrogen, -CX3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, X, and n, are each as defined herein, including in embodiments.
  • R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (IF) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 19 , X 1 , X 2 , Y 1 . Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n, are each as defined herein, including in embodiments.
  • R 15 is hydrogen, halogen, -CCh, -CBn. -CF3. -CI3. -CHCh, -CHBn. -CHF2. -CHI2, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 15A , -NR 15A R 15B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr 3 , -OCI3, -OCHCl2, -OCHBr 2 , -OCHI2.
  • R 16 is independently hydrogen, -C(O)R 16A , -C(O)OR 16A .
  • -OR 16A substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R 15A , R 15B , and R ,6A is independently hydrogen.
  • R 15A and R 15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroary l.
  • R 1 , R 2 , R 3 . R 4 . R 5 , R 6 , R 7 , R 11 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, X, and n, are each as defined herein, including in embodiments.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (I J) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof; wherein R 1 . R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 . R 11 , R 15 , R 16 .
  • R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (IK) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, and n are each as defined herein, including in embodiments.
  • a compound of formula (IL) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein R 1 , R 2 , R 1 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • IP formula (IP): (IP); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (IR) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 . R 8 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 . R 19 . X 1 . X 2 . Y 1 . Y 2 , Y 3 , Y 4 , Y 5 , B 3 . and n are each as defined herein, including in embodiments.
  • a compound of formula (IS) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 12 , R lj , R 15 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , X, and n are each as defined herein, including in embodiments.
  • a compound of formula (IT) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • R 17 is hydrogen, halogen, -CCh, -CBn. -CF3. -CI3. -CHCh, -CHBn. -CHF2. -CHI2, - CH2CL -CH 2 Br, -CH2F, -CH2I, -CN, -OR 17A , -NR 17A R 17B , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBr 3 , -OCI3, -OCHCl2, -OCHBr 2 , -OCHI2.
  • R 18 is independently hydrogen, -C(O)R 18A , -C(O)OR 18A .
  • -OR 18A substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R 17A , R 17B , and R 18A , is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2.
  • Ring A, X. and n are each as defined herein, including in embodiments.
  • a compound of formula (IV) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 18 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (IW) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 7 , R 11 , R 14 , R 17 , R 18 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, and n are each as defined herein, including in embodiments.
  • a compound of formula (IX) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 . R 14 , R 17 . R 18 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (IZ) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 11 , R 14 , R 17 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, and n are each as defined herein, including in embodiments.
  • a compound of formula (IAA) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 14 , R 17 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (II) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • B 1 and B 2 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , and Y 4 are each independently O. S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary 1, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • R 7 is independently hydrogen, halogen. -CCI3, -CBrs, -CF3, -Ch. -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCF3, -OCBn, -OCI3, -OCHCI2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI.
  • each R 19 is independently hydrogen, halogen. -CCI3, -CBr?. -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI.
  • R 11 is hydrogen, halogen, -CCI3, -CBn. -CF3. -Ch. -CHCh, -CHBn. -CHF2, -CHI 2 , - CH2CL -CH 2 Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3, -OCBrs, -OCI 3 , -OCHCl2, -OCHBn.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A ,and R 19B is independently' hydrogen, -CX3, -CHX2, -CH 2
  • R 5 is independently hydrogen, -C(O)R 5A . -C(O)OR 5A , -OR 5A . substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary 1; or R 4 and R 5 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 6 is hydrogen, halogen, -CCI3. -CBrs, -CF3, -CI3, -CHCh. -CH Bn. -CHF2, -CHI 2 , - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH.
  • R 14 is hydrogen, halogen, -CCI3, -CBn. -CF3. -CI3, -CHCh, -CHBn, -CHF2, -CHI 2 . - CH2CI. -CH 2 Br, -CH2F, -CH2I, -CN, -OR 14A , -NR 14A R 14B , -COOH. -CONH2.
  • R 14A . and R 14B is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH. -C(O)NH 2 . -CN, -OH, -NH2, -COOH, -CONH2.
  • R 6A and R 6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and R 14A and R 14B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 1 , R 2 , R 3 , R 7 , R 11 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Ring A, and n, are each as defined herein, including in embodiments.
  • a compound of formula (IIB) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • R 8 is independently hydrogen, halogen, -CCI3, -CBn, -CFs, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHSO2H, -NHC(O)R 8A , -NHC(O)OH, -NHOH.
  • R 8 is independently hydrogen, halogen, -CCI3, -CBr. -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CL -CH 2 Br, -CH2F, -CH2I, -CN, -OR 8 A , -NR 8 A R 8 B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)R 8 A .
  • each R 9 is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF 2 , -CHI2, - CH2CI, -CH 2 Br, -CH 2 F, -CH 2
  • R 10 is hydrogen, halogen, -CCls, -CBn, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 10A , -NR 1OA R 1OB , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2.
  • R 8 ’ D , R 9A , R 9D , R 1OA , and R 10D is independently hydrogen.
  • -NHSO2H, -NHC (O)H, -NHC(O)OH. -NHOH, -OCX3.
  • R 8A and R 8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 8 A and R 8 B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 9A and R 9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 5 . R 6 , R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , and n, are each as defined herein, including in embodiments.
  • a compound of formula (IIC) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , and n, are each as defined herein, including in embodiments.
  • Ring A is a substituted or unsubstituted heterocycloalkylene.
  • R 1 is independently hydrogen or substituted or unsubstituted alkyl.
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t- butyl, pentyl, isopentyl, or hexyl. In embodiments, R 1 is independently hydrogen or methyl. In embodiments. R 1 is independently hydrogen.
  • R 2 is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 2 is independently hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t- butyl, pentyl, isopentyl, or hexyl. In embodiments, R 2 is independently hydrogen or methyl. In embodiments. R 2 is independently hydrogen. [0040] In embodiments. R 3 is independently hydrogen or substituted or unsubstituted alkyl.
  • R 3 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopentyl, or hexyl. In embodiments, R 3 is independently hydrogen or methyl. In embodiments, R 3 is independently methyl.
  • R 4 is independently hydrogen. -C(O)R 4A . substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyd.
  • R 4 is independently hydrogen, -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 4 is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl.
  • R 4 is independently hydrogen or methyl.
  • R 5 is independently hydrogen -C(O)R 5A , substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalk l.
  • R 3 is independently hydrogen, -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 5 is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl.
  • R 5 is independently hydrogen or methyl.
  • R 6 is hydrogen, halogen, or -NR 6A R 6B . In embodiments, R 6 is hydrogen. -F, -NHMe, -NH2, or -NMe2. In embodiments, R 6 is hydrogen, -NH2. or -NHMe. In embodiments, R 6 is hydrogen.
  • R 4 is independently hydrogen or methyl; or (ii) R 5 is independently hydrogen or methyl.
  • R 7 is independently hydrogen, halogen, or -OR 7A . In embodiments. R 7 is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R 7 is independently methoxy.
  • R 8 is independently hydrogen, halogen, -OR 8A , or -NHC(O)R 8A .
  • R 8 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t- butoxy.
  • R 8 is independently hydrogen, hydroxy or methoxy.
  • R 8 is independently hydrogen or hydroxy.
  • R 8 is independently hydroxy.
  • R 8A is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 8A is independently hydrogen or methyl. In embodiments, R 8A is independently hydrogen. In embodiments, R 8A is independently methyl.
  • R 8 is independently hydrogen, halogen, -OR 8 A , or -NHC(O)R 8 A .
  • R 8 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t- butoxy.
  • R 8 is independently hydrogen, hydroxy or methoxy.
  • R 8 is independently hydrogen or hydroxy.
  • R 8 is independently hydrogen.
  • R 8 A is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 8 A is independently hydrogen or methyl. In embodiments, R 8 A is independently hydrogen. In embodiments, R 8 A is independently methyl.
  • R 9 is independently hydrogen, halogen, -OR 9A , or -NHC(O)R 9A .
  • R 9 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t- butoxy. In embodiments, R 9 is independently methoxy.
  • R 9A is independently hydrogen or substituted or unsubstituted alkyl.
  • R 8 and R 9 or R 8 and R 9 together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkydene.
  • R 10 is hydrogen
  • R 8 and R 10 orR 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalky lene.
  • R 8 and R 10 or R 8 and R 10 together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).
  • LNA locked nucleic acid
  • R 19 is independently hydrogen.
  • R 7 and R 19 together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).
  • LNA locked nucleic acid
  • R 11 is independently hydrogen, halogen, or -OR 11A . In embodiments, R 11 is independently methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R 11 is independently methoxy.
  • R 12 is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 12 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopentyl, or hexyl. In embodiments, R 12 is independently hydrogen or methyl.
  • R lj is independently hydrogen or substituted or unsubstituted alkyl.
  • R 13 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyd, or hexyl.
  • R 13 is independently hydrogen or methyl.
  • R 14 is hydrogen, halogen, or -NR 14A R 14B .
  • R 14 is hydrogen, -F, -NHMe, -NH2, or -NMe2.
  • R 14 is hydrogen or -NH2.
  • R 14 is -NH2.
  • R 13 is hydrogen, halogen, or -NR 15A R 13B .
  • R 13 is hydrogen, -F, -NHMe, -NH2, or -NMe2.
  • R 13 is hydrogen, -NHMe, or -NH2.
  • R 15 is hydrogen.
  • R 16 is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 16 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, penty l, isopentyl, or hexyl. In embodiments, R 16 is hydrogen.
  • R 17 is hydrogen, halogen, or -NR 17A R 17B .
  • R 17 is hydrogen, -F, -NHMe, -NH2, or -NMe2.
  • R 17 is hydrogen, -NHMe, or -NH2.
  • R 17 is hydrogen.
  • R 18 is hydrogen or substituted or unsubstituted alkyl. In embodiments. R 18 is hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, R 18 is hydrogen.
  • X 1 is -O-, -CH2-, or -CX2-. In embodiments, X 1 is -O-, -CH2-, or - CF2-. In embodiments, X 1 is -O-.
  • X 2 is -O-, -CH2-, -CX2-, -N(R 101 )-, or -BH-. In embodiments. X 2 is -O-. -CH2-, -CF2-. -NH-, or -BH-. In embodiments. X 2 is -O-, -CH2-. or -NH-. In embodiments. X 2 is -O-. In embodiments, X 2 is -CH2- or -NH-.
  • Y 1 , Y 2 , Y 3 , and Y 4 are each independently O or S. In embodiments, Y’, Y 2 , Y 3 , and Y 4 are O.
  • Y 5 is O or S. In embodiments. Y 5 is O.
  • n is 1 or 2. In embodiments, n is 1.
  • B 3 is adenine, guanine, cytosine or uracil. In embodiments, B 3 is guanine.
  • the compound provided herein has the structure: or an enantiomer. a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or on enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, sob. ate. or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hvdrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more 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 mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers. a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hvdrate thereof
  • the compound provided herein has the structure: or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt. In embodiments, the pharmaceutically acceptable salt is a sodium salt.
  • RNA molecule comprising a 5 ’-cap, wherein the 5 ’-cap comprises any one of the compounds described herein, including in embodiments.
  • the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.
  • a pharmaceutical composition comprising any one of the compounds described herein, including in embodiments and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising an RNA molecule comprising a 5'-cap, wherein the 5'-cap comprises any one of the compounds described herein, including in embodiments, and a pharmaceutically acceptable excipient.
  • an initiating capped oligonucleotide primer of formula m7 G 3'OMepppA2’OM e pA2’OMepG is provided herein. In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3' 0M e ppp m6 A20Mep m6 A20MepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3 OMeppp(s)A2’OMepA2’OM e pG.
  • an initiating capped oligonucleotide primer of formula m7 G3’OMepppA2’OMepA2’OM e pU is provided herein.
  • an initiating capped oligonucleotide primer of formula m7 G3’OM e pppA2 OMepG2 OM e pA is provided herein.
  • an initiating capped oligonucleotide primer of formula m7 G3’OM e pppA2’OM e p m6 A2’OM e pU is provided herein.
  • an initiating capped oligonucleotide primer of formula m7 G3’OM e pppA2’OMep(s)A2’OM e pG is provided herein.
  • an initiating capped oligonucleotide primer of formula m7 G3 OMepppA2 OMepU2 OMepC In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3’OMepppA2’OM e pU2’OM e pG. In an aspect, provided herein is an initiating capped oligonucleotide primer of forrnula m7 G3’OM e pppC2’OMepG2’OMepG.
  • an initiating capped oligonucleotide primer of forrnula m7 G3’OMeppp m6 A2’OMepA2’OMepU In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3’OM C ppp m6 A2 OMcpG2 OMcpA. In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3 OMeppp m6 A2 OMep m6 A2 OMepU.
  • an initiating capped oligonucleotide primer of formula m7 G3’OM e ppp m6 A2 OMepU2’OMepA In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3’OM e pppU2’OMepG2’OMepG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3 OMepppU2 OMepU2 OMepG.
  • an initiating capped oligonucleotide primer of formula m7 G3 OMeppp m6 A2’onpA2 OMepG is provided herein. In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3’OM e ppp N6 ‘ 1Pr6 A2’OMepA2’OM e pG. In an aspect, provided herein is an initiating capped oligonucleotide primer of formula m7 G3’OM 6 ppp N6 ' cyclopropyl A2’OMepA2’OMepG.
  • an initiating capped oligonucleotide primer of formula m7 G3 OMeppp N6 ' ethylurea A2-oMepA2 OMepG is provided herein.
  • an initiating capped oligonucleotide primer of formula m7 GpppA2 OM e pG2 OMe is provided herein.
  • RNA molecule comprising any one of the initiating capped oligonucleotide primers, stereoisomer, or a pharmaceutically acceptable salt thereof, as described herein including in embodiments.
  • the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.
  • RNA molecule comprising any one of the initiating capped oligonucleotide primers, stereoisomers, or a pharmaceutically acceptable salt thereof, as described herein, including in embodiments, and a pharmaceutically acceptable excipient.
  • RNA molecules described herein comprising administering to the subject any one of RNA molecules described herein, including in embodiments.
  • RNA transcripts comprising:
  • reaction mixture comprising a compound as described herein, a DNA template, an RNA polymerase, and nucleotide triphosphates (NTPs); and
  • a method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (I) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • B 1 , B 2 , and B 3 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A . -C(O)OR 2A .
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH.
  • each R 19 is independently hydrogen, halogen.
  • -OCH2F. -Ns, -SF 5 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;
  • R 11 is hydrogen, halogen, -CCh, -CB13. -CF3, -Ch, -CHCh, -CHB12. -CHF2, -CHI 2 , - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH.
  • -OCHX2, -OCH2X substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 101 is hydrogen, oxo, halogen, -CCI3, -CBr 3 , -CF3, -CI3, -CHCI2, -CHBr 2 , -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3, -OCBn, -OCI3, -OCHC12,-OCHBr 2 .
  • n is an integer from 0 to 3;
  • X is -Cl. -Br, -I or -F; with the proviso that the compound of formula (I) is not:
  • enantiomer a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; into a mixture comprising a polynucleotide template, an RNA polymerase, and nucleotide triphosphates (NTPs), under conditions conducive to transcription by the RNA polymerase of the polynucleotide template and incubating said mixture for a time sufficient to allow for transcription of said template.
  • NTPs nucleotide triphosphates
  • a method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (II) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable sail, solvate, or hydrate thereof; wherein:
  • B 1 and B 2 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , and Y 4 are each independently O, S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A . -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is independently hydrogen, halogen, -CCI3, -CBn. -CF3, -CI3. -CHCh, -CH Bn. -CHF2, -CHI2. - CH2CI. -CH 2 Br, -CH2F, -CH 2 I, -CN, -OR 7A .
  • -NR 7A R 7B -COOH, -CONH 2 , -NO2, -SH, -SO3H, -SO4H, -SO 2 NH 2 , -NHNH2, -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr 2 , -OCHI 2 , -OCHF2, -OCH2CI, -OCH 2 Br, -OCH2I.
  • each R 19 is independently hydrogen, halogen, -CCI3, -CBrs, -CFs, -CI3, -CHCh, -CHBr 2 , -CHF 2 , -CHI 2 .
  • R 11 is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCI2, -C'HBn.
  • each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A ,and R 19B is independently hydrogen, -CX3, -CHX 2 , -CH2X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 11A and R 11B substituents bonded to the same nitrogen atom may 7 optionally be joined to form a substituted or unsubstituted heterocycloalky 7 ! or substituted or unsubstituted heteroaryl;
  • R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 101 is hydrogen, oxo, halogen, -CCk, -CBr 3 , -CF3, -Ch, -CHCh, -CHBr 2 , -CHF 2 , -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO2NH2, -NHNH2, -ONH 2 , -NHC(O)NHNH 2 .
  • n is an integer from 0 to 3;
  • X is -Cl. -Br, -I or -F; with the proviso that R 11 is not OH; into a mixture comprising a polynucleotide template, an RNA polymerase, and nucleotide triphosphates (NTPs), under conditions conducive to transcription by the RNA polymerase of the polynucleotide template and incubating said mixture for a time sufficient to allow for transcription of said template.
  • NTPs nucleotide triphosphates
  • FIG. 1A-B show hEPO protein production with IFNa pretreatment relative to no IFNa pretreatment, using wildtype uridine triphosphates (FIG. 1A) or N1 -methylpseudouridine triphosphates (FIG. IB) for hEPO mRNA synthesis.
  • FIG. 2 shows LC-MS trace of a fragment cleaved from the 5’ end of the mRNA to determine capping efficiency of A- 12 cap.
  • FIG. 3A-B show total hEPO protein expression after 72 hours in A-549 cells, using wildtype uridine triphosphates (FIG. 3A) or N1 -methylpseudouridine triphosphates (FIG. 3B) for hEPO mRNA synthesis.
  • FIG. 4A-D show total hEPO protein expression after 72 hours in A-549 cells, using wildtype uridine triphosphates for hEPO mRNA synthesis, without IFNa pretreatment (FIG. 4A) or with IFNa pretreatment (FIG. 4B); using N 1 -methylpseudouridine triphosphates for hEPO mRNA synthesis, without IFNa pretreatment (FIG. 4C) or with IFNa pretreatment (FIG. 4D).
  • FIG. 5A-B show RIG-I induction of innate immune response in HEK293-Lucia RIG-I cells (after overnight incubation), using wildtype uridine triphosphates (FIG. 5A) or N 1 - methylpseudouridine triphosphates (FIG. 5B) for hEPO mRNA synthesis.
  • the term "about” means a range of values including the specified value, which a person of ordinary' skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
  • Ranges include the endpoints of the range. For example, “between 0 and 2” includes 0, 1, 2, and (unless the context requires otherwise) fractional values greater than 0 and less than 2.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g.. -CH2O- is equivalent to -OCH2-.
  • alky l by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec- butyl, homologs and isomers of, for example, n-pentyl. n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, croty l, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl. 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alky l moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alky lene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alky l, as exemplified, but not limited by, - CH2CH2CH2CH2-.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) e.g., O, N, S, Si. or P
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety' may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N. S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g.. O, N. S, Si, or P).
  • the term "heteroalkenyl/’ by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
  • the term “heteroalkynyl,” by itself or in combination with another term means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • a heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', - NR'R", -OR 1 , -SR', and/or -SO2R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • cycloalkyl and heterocycloalkyl mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyd are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl. 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3- yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • a “cycloalkydene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic.
  • cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CIEjw . where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one nng system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • a cycloalkyl is a cycloalkenyl.
  • the term “cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system.
  • monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic.
  • monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl.
  • bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CEtyty, where w is 1, 2, or 3).
  • alkylene bridge of between one and three additional carbon atoms
  • bicyclic cycloalkenyls include, but are not limited to, norbomenyl and bicyclo[2.2.2]oct 2 enyl.
  • fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • a heterocycloalkyl is a heterocyclyl.
  • heterocyclyl as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle.
  • the heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, P, and S where the ring is saturated or unsaturated, but not aromatic.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N, P, and S.
  • the 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N, P, and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N, P, and S.
  • the heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle.
  • heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl. isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl. oxazolinyl.
  • oxazolidinyl piperazinyl, piperidinyl. pyranyl, pyrazolinyl. pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.
  • the heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl.
  • the heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
  • Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl.
  • heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
  • Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicychc aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring.
  • multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • multicyclic heterocyclyl groups include, but are not limited to lOH-phenothiazin- 10- yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, lOH-phenoxazin-10-yl, 10,11-dihydro- 5H-dibenzo[b,f
  • halo or halogen. by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl. 4-chlorobutyl, 3-bromopropyl. and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring ary l) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • the term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O. or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • 5.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a
  • 6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl.
  • pyrazolyl pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4- biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl.
  • arylene and heteroarylene independently or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.
  • a fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.
  • Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom.
  • the individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings.
  • Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings).
  • Spirocylic rings maybe substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g.. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alk l group as defined above. R' may have a specified number of carbons (e.g. originate “C1-C4 alkylsulfonyl”).
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula:
  • An alkylaiylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, - CCh, -CBn.
  • alkylarylene is unsubstituted.
  • R, R', R", R'", and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroal ⁇ 1, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alky l, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R'.
  • R", R'", and R"" group when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R includes, but is not limited to, 1 -pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -C hCFs) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF3 and -C hCFs
  • acyl e.g., -C(O)CH3, -C(O)CF3, -C(O)CH 2 OCH 3 , and the like.
  • R', R', and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R groups are independently selected as are each R', R", R'
  • Substituents for rings may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ringforming substituents are attached to adjacent members of the base structure.
  • two ringforming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • tw o ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Tw o of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently - NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S- , -S(O) -, -S(O) 2 -, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adj acent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is -O-.
  • R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroalom or ‘Ting heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a ‘‘substituent group,” as used herein, means a group selected from the following moieties:
  • unsubstituted alkyl e.g.. Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., Ci-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • unsubstituted aryl e.g., C6-C10 aryl. C10 aryl, or
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl
  • heterocycloalkyl e.g.,
  • -OCHBn, -OCHI2, -OCHF2, -Ns unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyd, or C1-C4 alkyd), unsubstituted heteroalky l (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalky l (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl.
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyd, or C1-C4 alkyd
  • unsubstituted heteroalky l
  • aryl e.g., Ce-Cio aryl, C10 ary l, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd
  • cycloalkyl e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyd, or 5 to 6 membered heterocycloalkyl
  • aryl e.g., Ce-Cio aryl, C10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered hetero
  • -NHSO2H -NHC(0)H, -NHC(O)OH, -NHOH, -OCCI3, -OCFs, -OCBr 3 , -OCI3, -OCHCl2, -OCHBn, -OCHI2, -OCHF2, -Ns, unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g...
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalky 1, or 5 to 6 membered heterocycloalkyd
  • unsubstituted ary l e.g., Ce-Cio ary l, C10 ary l, or pheny
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyd, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd
  • cycloalkyl e.g., Cs-Cs cycloalkyl, Cs-Ce cycloalkyl, or Cs-Ce cycloalkyl
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl.
  • aryl e.g., Ce-Cio aryl, C10 aryl, or phenyl
  • heteroaryl e.g.. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • -CN -OH. -NH2. -COOH. -CONH2. -NO2, -SH. -S OsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH 2 ,
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyd
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • unsubstituted and e.g., Cs
  • a “size-limited substituent’' or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Cg-Cio aryl, and each substituted or unsubstituted heteroaryl
  • a “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted w ith at least one sizelimited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyd may be a substituted or unsubstituted C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl
  • each substituted or unsubstituted heteroary l is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted Ce- C10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3- C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted cycloalkyl, substituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkydene, substituted or unsubstituted heteroalky dene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryd, substituted
  • a substituted moiety e.g.. substituted alkyl, substituted heteroalkyl, substituted cycloalky 1, substituted heterocycloalkyl, substituted aryl, substituted heteroaryd, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted ary lene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality 7 of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one lower substituent group wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally' be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted ary lene, and/or substituted heteroarylene
  • the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • “optically active” and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%.
  • the 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 racemate in question.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • each nucleoside base position that contains more than one possible nucleoside base. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
  • 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 present in 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.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable.the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal, such as human (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and when the molecule contains a basic functionality, salts of organic or inorganic acids.
  • the pharmaceutically acceptable salts of the compounds described herein are suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein.
  • These salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and lauryl sulphonate salts, and the like.
  • Salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See S.M. Barge et al., J. Pharm. Sci. (1977) 66, 1; and Remington: The Science and Practice of Pharmacy, 23d Edition. Adejare et al. eds., Academic Press (2020); which are incorporated herein by reference in their entireties
  • cap analog means a structural derivative of an RNA cap.
  • complement refers to specific base pairing between nucleotides or nucleic acids.
  • Complementary nucleotides are, generally. A and T (or A and U), and G and C.
  • Complementarity for example, between a capped oligonucleotide primer and a single stranded DNA template or one strand of dsDNA template, may be “complete” or “total” where all of the nucleotide bases of two nucleic acid strands are matched according to recognized base pairing rules, it may be “partial” in which only some of the nucleotide bases of an initiating capped oligonucleotide primer and a DNA template are matched according to recognized base pairing rules, or it may be “absent” where none of the nucleotide bases of two nucleic acid strands are matched according to recognized base pairing rules.
  • Complementarity 7 can also be “substantial complementarity 7 ” where the nucleotide bases of two nucleic acids are matched according to recognized base pairing rules, but include one or more mismatches (e.g., 1, 2, 3, 4) from total complementarity.
  • a “deoxyribonuclease (DNase)” is an enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA.
  • DNase deoxyribonuclease
  • the term “hybridize” or “specifically hybridize” refers to a process where initiating trinucleotide primer anneals to a DNA template under appropriately stringent conditions during a transcription reaction. Hybridizations to DNA are conducted with an initiating capped oligonucleotide primer which, in certain embodiments, is 3-10 nucleotides in length including the 5 ’-5’ inverted cap structure.
  • Nucleic acid hybridization techniques are well known in the art (e.g., Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Press, Plainview, N.Y.(1989); Ausubel, F.M., et al., Current Protocols in Molecular Biology, John Wiley & Sons, Secaucus, N.J. (1994)).
  • impurities refers to substances which differ from the chemical composition of the target material (e g., mRNA transcripts). Impurities are also referred to as contaminants.
  • Inorganic pyrophosphatase refers to an enzy me that catalyzes the conversion of one ion of pyrophosphate to two phosphate ions, thus inhibiting aggregation and in some instances preventing interaction of pyrophosphate with magnesium ions during T7 transcription reactions.
  • the term “intemucleotide linkage” refers to the bond or bonds that connect two nucleosides of an oligonucleotide or nucleic acid and may be a natural phosphodiester linkage or modified linkage (any linkage that is not a phosphodiester linkage).
  • phosphorothioate linkage refers to a linkage between nucleosides in which the phosphorodiester linkage is modified by replacing one of the oxygen atoms, connected to a phosphorus atom, with a sulfur atom.
  • in vitro' refers to a process that takes place outside a living organism (e.g., a multi-cellular organism, such as a human or a non-human animal), for example, in a test tube, culture dish, or elsewhere outside a living organism.
  • a living organism e.g., a multi-cellular organism, such as a human or a non-human animal
  • in vivo refers to events that occur within a living organism.
  • in vivo assays refer to methods used to detect and/or measure capacity of one or more of the compounds or molecules including the compounds (e.g., mRNA molecules in, for example, a therapeutic dose) to increase or decrease a property relative to a control (e.g., biomarker levels).
  • a control e.g., biomarker levels
  • in vivo assays as described herein can be used to determine a subject's tolerability levels to a given compound or molecule.
  • Exemplary measurements for assessing tolerability include one or more of body weight, organ weight, aspartate aminotransferase (AST) levels, alanine transaminase (ALT) levels, C-reactive protein (CRP) levels, procalcitonin (PCT) levels, interleukin-6 (IL-6) levels, ery throcyte sedimentation rate (ESR), serum amyloid A levels, and serum ferritin levels.
  • AST aspartate aminotransferase
  • ALT alanine transaminase
  • CRP C-reactive protein
  • PCT procalcitonin
  • IL-6 interleukin-6
  • ESR ery throcyte sedimentation rate
  • serum amyloid A levels serum ferritin levels.
  • LNA locked nucleic acid
  • RNA transcript is a transcript transcribed from a DNA template encoding a desired polypeptide.
  • the mRNA transcript may contain coding and non-coding regions.
  • the DNA template can comprise an RNA polymerase promoter sequence, a 5’ UTR sequence, an open reading frame, and a 3’ UTR sequence.
  • the DNA template also comprises a nucleic acid sequence encoding a poly (A) tail.
  • nucleoside refers to a nitrogenous base linked to a 5- carbon sugar (e.g., ribose or deoxyribose).
  • the term includes all nucleosides, including all forms of nucleoside bases and furanoses.
  • naturally nucleoside refers to adenosine, guanosine, cytidine, uridine and thymidine.
  • N2,7,2-()-trimethy (guanosine, N2,2-O-dimethy [guanosine, 1 ,2-O-di methylguanosine, 2-O- methylguanosine, N2,N2.2-0-trimethylguanosine. N2.N2.7-trimethylguanosine. peroxy wybutosme. galactosyl-queuosine, mannosyl-queuosine, queuosine.
  • 5-methylaminomethyluridine 5- carboxymethylnridine, 5-carboxymethylaminometliyluridine, 5 -hydroxy uridme, 5-methyluridine, 5-taurinomethyluridine, 5-carbamoylmetbyluridine, 5-(carboxyhYdroxymethyl)uridine methyl ester, dihydrouridine, 5-methyldihydrouridine, 5-methylaminomethyl-2-thiouridine, 5- (carboxyhydroxyniethyl)uridine, 5-(isopentenylaminomethyl)uridine, 5-(isopenteiiylandnometiiyl)- 2-thiouridme.
  • nucleosides are unnatural nucleosides AU unnatural nucleosides are considered modified.
  • Modified nucleosides (whether natural or unnatural) have, independently, a modified sugar moiety and/or modified nucleobase.
  • Modified nucleotides (whether natural or unnatural) have, independently, a modified sugar moiety, a modified intemucleotide linkage, and/or modified nucleobase
  • nucleoside base refers to a nitrogenous base.
  • a “natural nucleoside base” includes purine and pyrimidine rings. Purine rings include, for example, adenine and guanine. Pyrimidine rings include, for example, cytosine, thymine, and uracil.
  • modified nucleoside base describes natural modified nucleoside bases, including but is not limited to, for example, pseudouracil, 5 -methylcytosine, N6- methyladenine, hypoxanthine, 5-hydroxymethylcytosine, 5-carboxylcytosine, N4-acetylcytosine, N4-methylcytosine, N1 -methyladenine, N2, N2-dimethylguanine and the like. Also, see naturally occurring modified nucleosides above.
  • unnatural nucleoside base refers to all nucleoside bases that are not natural (whether modified or not; see naturally occurring modified nucleosides above) including but is not limited to, for example, N1 -methylpseudouracil, 7-deazaadenine, 2- aminoadenine, 5-methylisocytosine, 5 -fluorouracil, 5 -bromouracil, 5-iodouracil, 2- methylthioadenine, 2-thio-5-methyluracil, 2-amino-6-methylthiopurine and the like. Natural nucleosides are described above.
  • modified sugar means substitution and/or any change from a natural sugar moiety.
  • nucleoside analogs include synthetic nucleosides as described herein.
  • Nucleoside derivatives also include nucleosides having modified base or/and sugar moi eties, with or without protecting groups and include, for example, 2'-deoxy-2’-fluorouridine, 5 -fluorouridine and the like.
  • the compounds and methods provided herein include such base rings and synthetic analogs thereof, as well as unnatural heterocycle-substituted base sugars, and acyclic substituted base sugars.
  • nucleoside derivatives that may be utilized with the present disclosure include, for example, LNA nucleosides, halogen-substituted purines (e.g., 6-fluoropurine), halogen-substituted pyrimidines, N 6 -ethyladenine, N 4 -(alkyl)-cytosines, 5-ethylcytosine. and the like (U.S. Patent No. 6,762,298).
  • the term “nucleoside triphosphate,” “nucleoside 5’ triphosphate” or “NTP” refers to a nucleoside linked to three phosphate groups.
  • NTP adenosine triphosphate
  • UDP uridine triphosphate
  • GTP guanine triphosphate
  • CTP cytosine triphosphate
  • modified NTP refers to a nucleoside 5 ’-triphosphate having a chemical moiety group bound at any position or substituted at any position, including the sugar, base, triphosphate chain, or any combination of these three locations.
  • the chemical moiety' group may be a group of any nature compatible w ith the process of transcription.
  • NTPs examples include inosine triphosphate, dihydrouridine triphosphate, 2’-fluoro-2’- deoxy cytidine triphosphate, pseudouridine triphosphate, N 1 -methylpseudouridine triphosphate, and 5-methyluridine triphosphate, and can be found, for example in “Nucleoside Triphosphates and Their Analogs: Chemistry, Biotechnology and Biological Applications,” Vaghefi, M., ed., Taylor and Francis, Boca Raton (2005).
  • modified oligonucleotide or “modified trinucleotide” includes, for example, an oligonucleotide containing a modified nucleoside, a modified intemucleotide linkage, or having any combination of modified nucleosides and intemucleotide linkages.
  • intemucleotide linkage modifications include, but are not limited to, phosphorothioate, phosphotriester and methylphosphonate derivatives (Stec, W.J., et al., Chem. Int. Ed.
  • oligo dT purification is an affinity chromatography method for purification of mRNA comprising or including a poly-A tail.
  • a “primary’ RNA” or “primary’ RNA transcript” means the RNA molecule that is newly synthesized by an RNA polymerase in vitro and which RNA molecule has a triphosphate on the 5 '-end.
  • RNA transcript refers to incomplete products of an in vitro transcription reaction. Prematurely aborted RNA sequences may be any length that is less than the intended length of the desired transcriptional product.
  • promoter refers to a nucleotide sequence in a DNA template that directs and controls the initiation of transcription of a particular DNA sequence. Promoters are typically immediately adjacent to (or partially overlap with) the DNA sequence to be transcribed. Promoter sequences are typically located directly upstream or at the 5' end of the transcription initiation site. Nucleotide positions in the promoter are designated relative to the transcriptional start site, where transcription of DNA begins (position +1).
  • RNA transcripts are purified by removal of contaminating proteins or other undesired nucleic acid species (e g., double-stranded RNA, DNA, and/or incomplete or aborted RNA transcripts).
  • Purified substances e.g., capped mRNA transcripts
  • RNase inhibitor or “ribonuclease inhibitor” refers to a protein that inhibits RNAse activity for example, during an in vitro transcription reaction.
  • RNA polymerase refers to an enzyme that synthesizes RNA using a DNA template.
  • single subunit phage RNA polymerases derived from T7, T3, SP6, KI -5, K1E, K1F or KI 1 bacteriophages, or variants thereof, are typically used.
  • This family of polymerases has simple, minimal promoter sequences of about 17 nucleotides which require no accessory proteins and have minimal constraints of the initiating nucleotide sequence.
  • ‘self-amplifying RNA,” or “saRNA,” is a linear, single-stranded RNA molecule that encodes the gene of interest.
  • saRNA is a type of mRNA, but also includes non- structural proteins that encode a viral replicase. The viral replicase enables the RNA to selfreplicate once delivered into the cell.
  • the term “specific” when used in reference to an initiating trinucleotide primer sequence and its ability to hybridize to a DNA template is a sequence that has at least 50% sequence identity with a portion of the DNA template when the initiating trinucleotide primer and DNA strand are aligned. Higher levels of sequence identity include at least 66%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, and optionally 100% sequence identity.
  • substantially free refers to a state in which relatively little or no amount of an undesired substance (e.g., prematurely aborted RNA sequences, DNA, and/or double-stranded RNA) is present in a sample.
  • substantially free of impurities means impurities are present at a level less than approximately 5%, 4%, 3%, 2%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%. 0.3%, 0.2%, 0.1% or less (w/w) in a sample.
  • substantially free of double-stranded RNA means double-stranded RNA is present at a level less than approximately 5%, 4%, 3%, 2%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less (w/w) in a sample.
  • tangential flow filtration is a type of filtration wherein the material to be filtered is passed tangentially across a filter rather than through it.
  • TFF tangential flow filtration
  • undesired permeate passes through the filter, while the desired retentate passes along the filter and is collected downstream.
  • the desired material is typically contained in the retentate, which is the opposite of what is encountered when performing traditional membrane or dead-end filtration.
  • RNA transcript As used herein, the term “transcription” refers to enzymatically making or synthesizing RNA that is complementary to a noncoding strand of the DNA template, thereby producing a number of RNA copies of a DNA sequence.
  • the RNA molecule synthesized in a transcription reaction is an “RNA transcript,” “primary transcript,” or “transcript.” Transcription reactions involving the compositions and methods provided herein employ initiating capped oligonucleotide primers described herein. Transcription of a DNA template may be exponential, nonlinear or linear.
  • a DNA template may be a double-stranded linear DNA, a partially double- stranded linear DNA. circular double-stranded DNA. DNA plasmid. PCR amplified product, or a modified nucleic acid template that is compatible with RNA polymerase.
  • the terms “universal base,” “degenerate base,” “universal base analog” and “degenerate base analog” include, for example, a nucleoside analog with an artificial base which is. in certain embodiments, recognizable by RNA polymerase as a substitute for one of the natural NTPs (e.g. ATP, UTP, CTP and GTP) or other specific NTP.
  • Universal bases or degenerate bases are disclosed in Loakes, D., Nucleic Acids Res., 29:2437-2447 (2001); Crey- Desbiolles, C., et. al., Nucleic Acids Res 33:1532-1543 (2005); Kincaid, K., et.
  • the term “unsubstituted” or “unmodified” in the context of the initiating capped oligonucleotide primer and NTPs refers to an initiating capped oligonucleotide primer and NTPs that have not been modified.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the term “subject” or “patient” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • immunosens or “vaccination” describes the process of treating a subject for therapeutic or prophylactic reasons.
  • an amount of the therapeutic agent that when administered to a subject, is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • Therapeutically effective amounts of the therapeutic agents provided herein will vary' depending upon the relative activity of the therapeutic agent, and depending upon the subject and disease condition being treated, the weight and age and sex of the subject, the severity of the disease condition in the subject, the manner of administration, drugs used in combination or coincidental with the specific compound employed and the like, which can readily be determined by one of ordinary skill in the art.
  • a therapeutically effective amount will depend on certain aspects of the subject to be treated and the disorder to be treated and may be ascertained by one skilled in the art using known techniques.
  • adjustments for age as well as the body weight, general health, sex, diet, time of administration, drug interaction, and the severity of the disease may be necessary 7 .
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.
  • dosage form means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
  • a dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline.
  • Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
  • Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alphatocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, poly oxy ethylene9-10 nonyl phenol, sodium deoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g..).
  • buffers e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate
  • pH adjustment agents e.g., hydrochloric acid, sodium or potassium hydro
  • a dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
  • administering refers to the physical introduction of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • exemplary' routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional.
  • the formulation is administered via a non-parenteral route, e.g., orally.
  • non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally. vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • Treating is to be understood broadly and encompasses any beneficial effect, including, e.g., delaying, slowing, or arresting the worsening of symptoms associated with a viral disease or remedying such symptoms, at least in part.
  • the term is intended to include the cure or elimination of the disease, disorder or condition.
  • Those in need of treatment include those who already have the disease or disorder, as well as those who should prevent the disease or disorder.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • the term “therapeutic agent” includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • anti-infectives such as antibiotics and antiviral agents
  • analgesics and analgesic combinations anorexics, antiinflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethy cellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary 7 agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
  • auxiliary 7 agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
  • auxiliary 7 agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
  • auxiliary 7 agents such as lubricants, preservatives, stabilizers
  • a “sub-therapeutic amount” of an agent or therapy is an amount less than the effective amount for that agent or therapy as a single agent, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.
  • Combination therapy or “in combination with” refer to the use of more than one therapeutic agent to treat a particular disorder or condition. By “in combination with,” it is not intended to imply that the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of this disclosure.
  • a therapeutic agent can be administered concurrently with, prior to (e.g., 5 minutes, 15 minutes.
  • the therapeutic agents in a combination therapy can also be administered on an alternating dosing schedule, with or without a resting period (e.g, no therapeutic agent is administered on certain days of the schedule).
  • the administration of a therapeutic agent “in combination with” another therapeutic agent includes, but is not limited to, sequential administration and concomitant administration of the two agents. In general, each therapeutic agent is administered at a dose and/or on a time schedule determined for that particular agent.
  • RNA molecule comprising a 5 : -cap, wherein the 5’- cap includes a trinucleotide cap analog as described herein.
  • Methods of inducing a therapeutic effect in a subject are also described herein, the methods including a step of administering to the subject a trinucleotide cap analog or RNA molecule including the trinucleotide cap analog.
  • a compound of formula (I) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • B 1 , B 2 , and B 3 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene:
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-. -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is hydrogen, halogen, -CCk, -CBn, -CF3, -CI3, -CHCh, -CHBn.
  • each R 19 is independently hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCI2, -CHBn, -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -
  • R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;
  • R 11 is hydrogen, halogen, -CCls, -CBrs, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI 2 , - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2. -SH, -SO3H, -SO4H. -SO2NH2, -NHNH2, -ONH2.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A ,and R 19B is independently hydrogen, -CX3, -CHX 2 , -CH2X
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 101 is hydrogen, oxo, halogen, -CCls, -CBrs, -CF3, -CI3, -CHCh, -CHBr 2 , -CHF 2 , -CHI 2 , - CH 2 C1, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH2. -ONH2, -NHC(O)NHNH 2 .
  • n is an integer from 0 to 3;
  • X is -Cl, -Br, -I or -F; with the proviso that the compound of formula (I) is not:
  • an enantiomer a mixture of enantiomers, a mixture of two or more 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 complex comprising a compound and a DNA template, wherein the compound is of formula (I): or an enantiomer, a mixture of enantiomers. a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • B 1 , B 2 . and B 3 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene;
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A . -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI. -CH 2 Br, -CH2F, -CH 2 I, -CN, -OR 7A .
  • -NR 7A R 7B -COOH, -CONH 2 , -NO2, -SH, -SO3H, -SO4H, -SO 2 NH 2 , -NHNH2, -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr 2 , -OCHI 2 , -OCHF2, -OCH2CI, -OCH 2 Br, -OCH2I.
  • each R 19 is independently hydrogen, halogen, -CCk, -CBrs, -CFs, -Ch, -CHCh, -CHBr 2 , -CHF 2 , -CHI 2 .
  • R 11 is hydrogen, halogen, -CCk, -CBn, -CF3, -Ch, -CHCI2, -CHBn.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkyd ene; each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 101 is hydrogen, oxo, halogen, -CCI3, -CBrs. -CF3, -CI3, -CHCh, -CHBr 2 , -CHF2, -CHI 2 , - CH 2 C1, -CH 2 Br. -CH 2 F. -CH 2 I, -CN, -OH, -NHy -COOH, -CONH 2 , -NOy -SH. -SO3H.
  • n is an integer
  • a complex comprising an initiating capped oligonucleotide primer and a DNA template, wherein the initiating capped oligonucleotide primer comprises a structure of formula (I): or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
  • B 1 , B 2 , and B 3 are each independently a natural, modified, or unnatural nucleoside base
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-;
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se;
  • R 1 is independently hydrogen, -C(O)R 1A .
  • -C(O)OR 1A -OR 1A substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 is independently hydrogen, -C(O)R 2A . -C(O)OR 2A , -OR 2A . substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is hydrogen, halogen, -CCh. -CBrs, -CF3, -CI3, -CHCh. -CHBn, -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3, -OCBr 3 , -OCI3, -OCHCI2, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH 2 Br
  • each R 19 is independently hydrogen, halogen. -CCI3, -CBn, -CF3, -CI3, -CHCh, -CHBn, -CHF2, -CHI2. - CH2CI.
  • -OCH2F -N3, -SFs, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene;
  • R 11 is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCI2, -CHBr2,
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 101 is hydrogen, oxo. halogen, -CCh, -CBn. -CF3. -Ch, -CHCh, -CHB . -CHF2. -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3, -OCBr 3 , -OCI3, -OCHCl 2 ,-OCHBr 2 , -OCHI2, -OCHF2, -OCH2CI, -OCH2Br,
  • n is an integer from 0 to 3; and X is -Cl.
  • the compound of formula (I) is not: or an enantiomer, a mixture of enantiomers, a mixture of two or more di stereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a complex formation as described above is a prerequisite for the initiation of an in vitro transcription.
  • a complex as described herein contains any one of the compounds (formulas or structures) or initiating capped oligonucleotide primers described below, including in embodiments, and a DNA template.
  • R 1 is independently hydrogen, substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • alky l
  • a substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1 is independently substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 1 when R 1 is independently substituted, it is substituted with at least one substituent group.
  • R 1 when R 1 is independently substituted, it is substituted with at least one size-limited substituent group.
  • R 1 when R 1 is independently substituted, it is substituted with at least one lower substituent group.
  • R 1 is independently hydrogen or substituted or unsubstituted alkyl.
  • R 1 is independently hydrogen or substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci- Ce alkyl, or C1-C4 alkyl).
  • R 1 is independently hydrogen.
  • R 1 is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 1 is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.
  • R 1 is independently hydrogen. In embodiments. R 1 is independently methyl. In embodiments, R 1 is independently ethyl. In embodiments. R 1 is independently propyl. In embodiments, R 1 is independently isopropyl. In embodiments, R 1 is independently butyl. In embodiments, R 1 is independently isobutyl. In embodiments, R 1 is independently t-butyl. In embodiments, R 1 is independently pentyl. In embodiments, R 1 is independently isopentyl. In embodiments, R 1 is independently hexyl.
  • R 2 is independently hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl
  • a substituted R 2 (e.g., substituted alkyl, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2 is independently substituted with a plurality' of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally 7 be different.
  • R 2 when R 2 is independently substituted, it is substituted with at least one substituent group.
  • R 2 when R 2 is independently substituted, it is substituted with at least one size-limited substituent group.
  • R 2 when R 2 is independently substituted, it is substituted with at least one lower substituent group.
  • R 2 is independently hydrogen or substituted or unsubstituted alkyl.
  • R 2 is independently hydrogen or substituted (e.g. with a substituent group, a sizelimited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci- Ce alkyl, or C1-C4 alkyl).
  • R 2 is independently hydrogen.
  • R 2 is independently 7 unsubstituted alkyl (e g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 2 is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 2 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopenty l, or hexyl.
  • R 1 is hydrogen and R 2 is hydrogen.
  • R 3 is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g..).
  • alkyl e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g.
  • cycloalkyl e.g., C?-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted aryl e.g..
  • Ce-Cio aryl, C10 aryl, or phenyl substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 3 when R 3 is substituted, it is substituted with at least one substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one size-limited substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one lower substituent group.
  • R 3 is hydrogen or substituted or unsubstituted alkyl.
  • R 3 is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 3 is hydrogen.
  • R 3 is unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopentyl, or hexyl.
  • R 3 is hydrogen. In embodiments, R-' is methyl. In embodiments, R is ethyl. In embodiments, R 3 is propyl. In embodiments, R 3 is isopropyl. In embodiments. R 3 is butyl. In embodiments, R 3 is isobutyl. In embodiments, R 3 is t-butyl. In embodiments, R 3 is pentyl. In embodiments, R 3 is isopentyd. In embodiments, R 3 is hexyl.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyd e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkyd e.g., Cs-Cs cy cloalkyl, Cs-Ce cy cloalkyd, or C5-C6 cycloalkyl
  • substituted e.
  • a substituted R 7 (e.g., substituted alkyd, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyd, substituted ary l, and/or substituted heteroary ! is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wdierein if the substituted R 7 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or low er substituent group may optionally be different.
  • R 7 when R 7 is substituted, it is substituted with at least one substituent group.
  • R 7 when R 7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 7 is substituted, it is substituted with at least one lower substituent group.
  • R 7 is independently hydrogen, halogen, or -OR 7A . In embodiments. R 7 is independently hydrogen. In embodiments, R 7 is independently halogen. In embodiments, R 7 is independently -OR 7A . In embodiments, R 7 is independently chloro. In embodiments, R 7 is independently bromo. In embodiments, R 7 is independently iodo. In embodiments, R 7 is independently fluoro.
  • R 7A is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 7A is hydrogen. In embodiments, R 7A is substituted alkyl. In embodiments, R 7A is an unsubstituted alkyl.
  • R 7A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexyl.
  • R 7A is hydrogen.
  • R 7A is methyl.
  • R 7A is ethyl.
  • R 7A is propyl.
  • R 7A is isopropyl.
  • R 7A is butyl. In embodiments, R 7A is isobutyl. In embodiments, R 7A is t-butyl. In embodiments. R 7A is pentyl. In embodiments, R 7A is hexyl.
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted aryl e.g., C6-C10 aryl, C10 aryl, or phenyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroai 4, or 5 to 6 membered heteroary l.
  • a substituted R 11 (e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 11 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 11 when R 11 is substituted, it is substituted with at least one substituent group.
  • R 11 when R 11 is substituted, it is substituted with at least one size-limited substituent group.
  • R 11 when R 11 is substituted, it is substituted with at least one lower substituent group.
  • R 11 is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In embodiments, R 11 is independently hydroxy. In embodiments, R 11 is independently methoxy. In embodiments, R 11 is independently ethoxy. In embodiments, R 11 is independently propoxy. In embodiments, R 11 is independently butoxy. In embodiments, R 11 is independently t- butoxy.
  • R 11A is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 11A is hydrogen. In embodiments, R 11A is substituted alkyl. In embodiments, R 11A is an unsubstituted alkyd.
  • R 11A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cs alkyl, or C1-C4 alkyl).
  • a substituted R 11A (e.g., substituted alky 1, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 11A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 11A when R 11A is substituted, it is substituted with at least one substituent group.
  • R 11A when R 11A is substituted, it is substituted with at least one size-limited substituent group.
  • R 11A when R 11A is substituted, it is substituted with at least one lower substituent group.
  • R 11A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 11A is hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobuty l, t-butyl, pentyl, isopentyl, hexyl.
  • R 11A is hydrogen.
  • R 11A is methyl.
  • R 11A is ethyl.
  • R 11A is propyl.
  • R 11A is isopropyl.
  • R 11A is butyl.
  • R 11A is isobutyl.
  • R 11A is t-butyl.
  • R 11A is pentyl.
  • R 11A is hexyl.
  • a substituted R 19 (e.g., substituted alkyl. substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 19 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 19 when R 19 is substituted, it is substituted with at least one substituent group.
  • R 19 when R 19 is substituted, it is substituted with at least one size-limited substituent group.
  • R 19 when R 19 is substituted, it is substituted with at least one lower substituent group.
  • each R 19 is hydrogen.
  • R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene. In embodiments, R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene. In embodiments, R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.
  • R 7 and R 19 together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., Cs-Cs cycloalkylene, C3-C6 cycloalkylene, or Cs-Ce cycloalkylene).
  • a substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkylene e.g., Cs-Cs cycloalkylene, C3-C6 cycloalkylene, or Cs-Ce cycloalkylene.
  • heterocycloalkylene formed by the joining of R 7 and R 19 together with the carbon atoms to which they are connected when substituted, it is substituted with at least one size-limited substituent group. In embodiments, when heterocycloalkylene formed by the joining of R 7 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.
  • cycloalkylene formed by the joining of R 7 and R 19 together with the carbon atoms to which they are connected when cycloalkylene formed by the joining of R 7 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when cycloalkylene formed by the joining of R 7 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.
  • R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments. R 7 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted 4 membered heterocycloalkylene.
  • R 7 and R 19 together with the carbon atoms to which they are connected form a substituted 4 membered heterocycloalkylene. In embodiments, R 7 and R 19 together with the carbon atoms to which they are connected form an unsubstituted 4 membered heterocycloalkylene.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene. In embodiments, R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene. In embodiments, R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • a substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heterocycloalkylene e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., Cs-Cs cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • a substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkylene e.g., Cs-Cs cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene.
  • a substituted heterocycloalkylene formed by the joining of R 11 and R 19 together with the carbon atoms to w hich they are connected is substituted with at least one substituent group, size-limited substituent group, or low er substituent group; wherein if the substituted heterocycloalkylene is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, sizelimited substituent group, and/or low er substituent group may optionally be different.
  • when heterocycloalkylene formed by the joining of R 11 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one substituent group.
  • heterocycloalkylene formed by the joining of R 11 and R 19 together with the carbon atoms to which they are connected when substituted, it is substituted with at least one size-limited substituent group. In embodiments, when heterocycloalkylene formed by the joining of R 11 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.
  • cycloalkylene formed by thejoining of R 11 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when cycloalkylene formed by the joining of R 11 and R 19 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.
  • R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments. R 11 and R 19 together with the carbon atoms to which they are connected form a substituted or unsubstituted 4 membered heterocycloalkylene.
  • R 11 and R 19 together w ith the carbon atoms to which they are connected form a substituted 4 membered heterocycloalkylene. In embodiments, R 11 and R 19 together with the carbon atoms to which they are connected form an unsubstituted 4 membered heterocycloalkylene.
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl
  • substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted aryl e.g., Cs-Cio aryl, C10 aryl, or phenyl
  • substituted e.g., with a substituent group, with a substituent group,
  • each R 1A , R 2A . R 3A , R 7A . R 11A . R 11B . R 19A . and R 19B is independently substituted with one or more substituent groups.
  • each R 1A , R 2A , R 3A , R 7A , R 11A , R 11B , R 19A , and R 19B is independently substituted with one or more size-limited substituent groups.
  • each R 1A , R 2A , R 3A , R 7A , R 11A , R 11B , R 19A , and R 19B is independently substituted with one or more lower substituent groups.
  • R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 member
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 7A and R 7B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a heterocycloalkyl formed by the joining of R 7A and R 7B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heterocycloalkyl formed by the joining of R 7A and R 7B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 7A and R 7B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 7A and R 7B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one low er substituent group. In embodiments, when a heteroaryl formed by the joining of R 7A and R 7B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a low er substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted e.g., with a substituent group, a size-limited substituent group or a low er substituent group
  • unsubstituted heterocycloalkyl e.g.,
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 11A and R 11B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality 7 of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may’ optionally be different.
  • a heterocycloalkyl formed by the joining of R 11A and R 11B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 11A and R 11B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 11A and R 11B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 11A and R 11B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formed
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 19A and R 19B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a heterocycloalkyl formed by the joining of R 19A and R 19B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • B 1 , B 2 , and B 3 are each independently a natural, modified, or unnatural nucleoside base. In embodiments, B 1 , B 2 , and B 3 are each independently a natural nucleoside base. In embodiments, B 1 . B 2 . and B 3 are each independently a modified nucleoside base. In embodiments, B 1 , B 2 , and B 3 are each independently an unnatural nucleoside base.
  • B 1 , B 2 , and B 3 are each independently adenine, guanine, cytosine, uracil, or thymine.
  • B 1 is adenine.
  • B 1 is guanine.
  • B 1 is cytosine.
  • B 1 is uracil.
  • B 1 is thymine.
  • B 2 is adenine.
  • B 2 is guanine.
  • B 2 is cytosine.
  • B 2 is uracil.
  • B 2 is thymine.
  • B' is adenine.
  • B 3 is guanine.
  • B 3 is cytosine.
  • B 3 is uracil.
  • B 3 is thymine.
  • B 1 includes, but is not limited to, pyrazolo[3,4-d]pyrimidines, 5- methylcytosine (5-me-C). 5-hydroxymethyl cytosine, xanthine, hypoxanthine. 2-aminoadenine.
  • B 2 includes, but is not limited to, pyrazolo[3,4-d]pyrimidines, 5- methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6- methyl and other alkyl derivatives of adenine and guanine.
  • irmdazo[l,5-a]1.3.5 triazinones 9-deazapurines, imidazo[4,5- d]pyrazines, thiazolo[4,5-d]pyrimidines, pyrazin-2-ones, 1,2,4-triazine, pyridazine; and 1,3,5 triazine.
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • Ring A is a substituted or unsubstituted heterocycloalkylene. In embodiments, Ring A is a substituted heterocycloalkylene. In embodiments, Ring A is an unsubstituted heterocycloalkylene.
  • Ring A is a substituted or unsubstituted heteroarylene. In embodiments, Ring A is a substituted heteroarylene. In embodiments, Ring A is an unsubstituted heteroarylene.
  • Ring A is a 3 to 10 membered substituted heterocycloalkylene. In embodiments. Ring A is a 3 membered substituted heterocycloalkylene. In embodiments, Ring A is a 4 membered substituted heterocycloalkylene. In embodiments, Ring A is a 5 membered substituted heterocycloalkylene. In embodiments, Ring A is a 6 membered substituted heterocycloalkylene. In embodiments, Ring A is a 7 membered substituted heterocycloalkylene. In embodiments. Ring A is a 8 membered substituted heterocycloalkylene. In embodiments, Ring A is a 9 membered substituted heterocycloalkylene. In embodiments. Ring A is a 10 membered substituted heterocycloalkylene.
  • Ring A is a 3 to 10 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 3 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 4 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 5 membered unsubstituted heterocycloalkylene. In embodiments. Ring A is a 6 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 7 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 8 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 9 membered unsubstituted heterocycloalkylene. In embodiments, Ring A is a 10 membered unsubstituted heterocycloalkylene.
  • Ring A is a substituted or unsubstituted tetrahydrofuranylene. In embodiments. Ring A is a substituted tetrahydrofuranylene. In embodiments, Ring A is an unsubstituted tetrahydrofuranylene. In embodiments, Ring A is a substituted or unsubstituted morpholinylene. In embodiments, Ring A is a substituted morpholinylene. In embodiments, Ring A is an unsubstituted morpholinylene.
  • X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-,
  • X 1 is -O-, -CH2-, or -CX2-. In embodiments, X 1 is -O-, -CH2-, or - CF2-. In embodiments, X 1 is -O-. In embodiments, X 1 is -CH2-. In embodiments, X 1 is -CX2-. In embodiments, XHs -CF2-. In embodiments, XHs -N(R 101 )-. In embodiments, X' is -NH-. In embodiments, X 1 is -BH-. In embodiments, X 1 is -S-.
  • X 2 is -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-. In embodiments, X 2 is -O-, -CH2-, -CF2-, -NH-, -BH-, or -S-. In embodiments, X 2 is -O-, -CH2-, or -NH-. In embodiments. X 2 is -CH2- or -NH-.
  • X 2 is -O-. In embodiments, X 2 is -CH2-. In embodiments, X 2 is -CX2-. In embodiments, X 2 is -CF2-. In embodiments, X 2 is -N(R 101 )-. In embodiments, X 2 is -NH-. In embodiments, X 2 is -BH-. In embodiments, X 2 is -S-.
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se. In embodiments, Y 1 , Y 2 , Y 3 , and Y 4 , are each independently O, S, or Se. In embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , are each independently O or S. In embodiments, Y 1 , Y 2 , Y 3 , and Y 4 , are each independently O or S. In embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , are each independently O. In embodiments.
  • Y 1 . Y 2 . Y 3 . and Y 4 are each independently O. In embodiments. Y 1 is O. In embodiments, Y 1 is S. In embodiments, Y 1 is Se. In embodiments, Y 2 is O. In embodiments, Y 2 is S. In embodiments, Y 2 is Se. In embodiments, Y 3 is O. In embodiments, Y 3 is S. In embodiments, Y 3 is Se. In embodiments, Y 4 is O. In embodiments, Y 4 is S. In embodiments, Y 4 is Se. In embodiments, Y 5 is O or S. In embodiments, Y 5 is O. In embodiments, Y 5 is S. In embodiments, Y 5 is Se.
  • R 101 is hydrogen, oxo, halogen, -CCk, -CBn, -CF3, -CI3, -CHCI2, -CHBr 2 , -CHF2, -CHI 2 , - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2.
  • X is -Cl, -Br, -I or -F. In embodiments, X is -Cl. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is F.
  • n is an integer from 0 to 3. In embodiments, n is 1 or 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. [00319] In embodiments, the compound of formula (I) is not:
  • an enantiomer a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • B' is a natural nucleoside base
  • R 4 is independently hydrogen, -C(O)R 4A . -C(O)OR 4A . -OR 4A . substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 5 is independently hydrogen, -C(O)R 5A . -C(O)OR 5A , -OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • R 6 is hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CHBn, -CHF2, -CHI 2 , - CH2CL -CH 2 Br, -CH2F, -CH2I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3, -OCBr 3 , -OCI3, -OCHCI2, -OCHBr 2 , -OCHI2, -OCHF2, -OCH2CI, -
  • R 14 is hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CHCh, -CHBr2, -CHF2, -CHI 2 . - CH2CI. -CH 2 Br, -CH2F, -CH2I, -CN, -OR 14A , -NR 14A R 14B , -COOH. -CONH2.
  • each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14B is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH2, -COOH, -CONH2.
  • R 1 , R 2 , R 3 , R 7 , R 11 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , n, and Ring A are each as defined herein, including in embodiments.
  • R 4 is independently hydrogen. -C(O)R 4A . -C(O)OR 4A , -OR 4A . substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g..).
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l
  • substituted e.g., substituted with at least one substituent group, size
  • a substituted R 4 (e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l, and/or substituted heteroaryl) is independently substituted with at least one substituent group
  • R 4 is independently hydrogen or methyl.
  • R 5 is independently hydrogen, -C(O)R 5A , substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In embodiments, R 5 is independently hydrogen.
  • R 5 is independently hydrogen.
  • R 5 is independently unsubstituted cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 5 is independently substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) cycloalkyl (e.g., Cs-Cs cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 5 is independently substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 5 is independently hydrogen. -C(O)NHCH2CH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl. pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 is independently hydrogen, -C(O)NHCH2CH3, methyl, isopropyl, or cyclopropyl.
  • R 5 is independently hydrogen or methyl.
  • R 5 is independently hydrogen. In embodiments. R 5 is independently -C(O)NHCH2CH3. In embodiments, R 5 is independently methyl. In embodiments, R 5 is independently ethyl. In embodiments, R 5 is independently propyl. In embodiments, R 5 is independently isopropyl. In embodiments, R 5 is independently buty l. In embodiments, R 5 is independently isobutyl. In embodiments, R 5 is independently t-butyl. In embodiments, R 5 is independently pentyl. In embodiments. R 5 is independently hexyl. In embodiments. R 5 is independently cyclopropyl. In embodiments, R 3 is independently cyclobutyl. In embodiments, R 5 is independently cyclopentyl. In embodiments, R 5 is independently cyclohexyl.
  • R 4 is independently hydrogen or methyl; or (ii) R 5 is independently hydrogen or methyl.
  • R 6 is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CHCb, -CH Bn.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • substituted e.g..
  • cycloalkyd e.g., Cs-Cs cycloalkyl, Cs-Ce cycloalkyl, or Cs-Ce cycloalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl.
  • ary 1 e.g., Ce-Cio ary 1, Cio aryl, or pheny l
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 member
  • a substituted R 6 (e.g., substituted alkyl, substituted heteroalky 1, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary 1, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 6 when R 6 is substituted, it is substituted with at least one substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one size-limited substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one lower substituent group.
  • R 6 is hydrogen, halogen, or -NR 6A R 6B .
  • R 6 is hydrogen.
  • R 6 is halogen.
  • R 6 is -NR 6A R 6B .
  • R 6 is -Cl.
  • R 6 is -Br.
  • R 6 is -I.
  • R 6 is -F.
  • R 6 is -NHMe.
  • R 6 is -NH2.
  • R 6 is -NMe2.
  • R 6 is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R 6 is hydrogen. -NH2, or -NHMe. In embodiments, R 6 is hydrogen or -NHMe.
  • R 6A is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 6A is hydrogen. In embodiments, R 6A is substituted alkyd. In embodiments, R 6A is an unsubstituted alkyl. In embodiments, R 6B is hydrogen or substituted or unsubstituted alky 1. In embodiments. R 6B is hydrogen. In embodiments, R 6B is substituted alkyl. In embodiments, R 6B is an unsubstituted alkyl.
  • R 6A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl).
  • R 6B is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • a substituted R 6A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 6A is substituted, it is substituted with at least one substituent group.
  • R 6A when R 6A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 6A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 6B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 6B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 6B when R 6B is substituted, it is substituted with at least one substituent group. In embodiments, when R 6B is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R 6B is substituted, it is substituted with at least one lower substituent group.
  • R 6A is hydrogen or substituted or unsubstituted alkyl.
  • R 6A is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 6A is hydrogen.
  • R 6A is unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 6A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexyl.
  • R 6A is hydrogen.
  • R 6A is methyl.
  • R 6A is ethyl.
  • R 6A is propyl.
  • R 6A is isopropyl.
  • R 6A is butyl.
  • R 6A is isobuty 1.
  • R 6A is t-butyl.
  • R 6A is pentyl.
  • R 6A is hexyl.
  • R 6B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl.
  • R 6B is hydrogen.
  • R 6B is methyl.
  • R 6B is ethyl.
  • R 6B is propyl.
  • R 6B is isopropyl.
  • R 6B is butyl.
  • R 6B is isobutyl.
  • R 6B is t-butyl.
  • R 6B is pentyl.
  • R 6B is hexyl.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g..
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6
  • a substituted R 14 (e.g., substituted alkyd, substituted heteroalky 1, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary 1. and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 14 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 14 when R 14 is substituted, it is substituted with at least one substituent group.
  • R 14 when R 14 is substituted, it is substituted with at least one size-limited substituent group.
  • R 14 when R 14 is substituted, it is substituted with at least one lower substituent group.
  • R 14 is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R 14 is hydrogen or -NH2. In embodiments, R 14 is hydrogen.
  • R 14A is hydrogen or substituted or unsubstituted alkyl. In embodiments. R 14A is hydrogen. In embodiments, R 14A is substituted alkyl. In embodiments, R 14A is an unsubstituted alkyl. In embodiments, R 14B is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 14B is hydrogen. In embodiments, R 14B is substituted alkyl. In embodiments, R 6B is an unsubstituted alkyd.
  • R 14A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cs alkyl, or C1-C4 alkyl).
  • R 14B is hydrogen, substituted (e g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky 1 (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • a substituted R 14A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 14A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 14A is substituted, it is substituted with at least one substituent group.
  • R 14A when R 14A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 14A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 14B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, substituted aryl, and/or substituted heteroaryl
  • R 14B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 14B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 14A is hydrogen or substituted or unsubstituted alkyl. In embodiments. R 14A is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alky l, or C1-C4 alkyd). In embodiments, R 14A is hydrogen. In embodiments, R 14A is unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 14A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 14B is hydrogen or substituted or unsubstituted alky l.
  • R 14B is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 14B is hydrogen.
  • R 14B is unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Ce alkyl, or C1-C4 alkyl). In embodiments. R 14B is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd).
  • alkyl e.g., Ci-Cs alkyl. Ci-Ce alkyl, or C1-C4 alkyd.
  • R ,4A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl.
  • R 14A is hydrogen.
  • R 14A is methyl.
  • R 14A is ethyl.
  • R 14A is propyl.
  • R 14A is isopropyl.
  • R 14A is butyl.
  • R 14A is isobuty 1.
  • R 14A is t-butyl.
  • R 14A is pentyl.
  • R14 6A is hexyl.
  • R 14B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl.
  • R 14B is hydrogen.
  • R 14B is methyl.
  • R 14B is ethyl.
  • R 14B is propyl.
  • R 14B is isopropyl.
  • R 14B is butyl.
  • R 14B is isobutyl.
  • R 14B is t-butyl.
  • R 14B is pentyd.
  • R 14B is hexyl.
  • -OCXs. -OCHX2, -OCH2X substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd), substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd), substituted (e.g.
  • cycloalkyl e.g., Cs-Cs cycloalkyd, C3-C6 cycloalkyd, or C5-C6 cycloalkyd
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • substituted e.g.
  • aryl e.g., Ce-Cio aryl, C10 ary 1, or phenyl
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryd, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14B is independently substituted with one or more substituent groups. In embodiments, each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14B is independently substituted with one or more size-limited substituent groups. In embodiments, each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14B is independently substituted with one or more lower substituent groups.
  • R 6A and R 6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g.
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryd is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a heterocycloalkyl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heterocycloalkyl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heteroaryl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom when a heteroaryl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heteroaryl formed by the joining of R 6A and R 6B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.
  • R 14A and R 14B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g.
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 14A and R 14B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a heterocycloalkyl formed by the joining of R 14A and R 14B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heterocycloalkyl formed by the joining of R 14A and R 14B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 14A and R 14B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 14A and R 14B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formed by the joining of R 14A and R 14B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • X is -Cl, -Br, -I or -F. In embodiments. X is -Cl. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is -F.
  • R 8 is independently hydrogen, halogen, -CCh, -CBrs, -CFs, -Ch, -CHCh, -CH Bn. -CHF2, -CHI2, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 8A . -NR 8A R 8B , -COOH, -CONH2, -NO2.
  • R 8 is independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -Ch, -CHCh, -CHBn, -CHF2, -CHI2, - CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN, -OR 8 A , -NR 8 A R 8 B , -COOH, -CONH2, -NCh, -SH, -SO3H, -SO4H, -SO 2 NH 2 . -NHNH2, -ONH2, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO2H, -NHC(O)R 8 A .
  • R 9 is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CHCI2, -CHBrc, -CHF2, -CHI 2 , -CH 2 C1, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO4H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H.
  • R 10 is hydrogen, halogen, -CCls, -CBr 3 , -CF3, -CI3, -CHC1 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 C1, -CH 2 Br, -CH 2 F, -CH 2 I, -CN.
  • R 8A and R 8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 8 A and R 8 B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 9A and R 9B substituents bonded to the same nitrogen atom may optionally be
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 and n, are each as defined herein, including in embodiments.
  • R 8 is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CHCI2. -CHBr 2 , -CHF2, -CHI2, -CN, -OR 8A , -NR 8A R 8B , -CONH2. -COOH. -NHC(O)R 8A , -NO2.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkyl e.g., Cs-Cs cycloalkyl, C -C6 cycloalkyl, or Cs-Ce cycloalkyl
  • substituted e.g., substituted
  • a substituted R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8 when R 8 is substituted, it is substituted with at least one substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one size-limited substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one lower substituent group.
  • R 8 is independently hydrogen, halogen, -OR 8A , or -NHC(O)R 8A .
  • R 8 is independently hydrogen.
  • R 8 is independently halogen.
  • R 8 is independently -OR 8A .
  • R 8 is independently -NHC(O)R 8A .
  • R 8 is independently chloro.
  • R 8 is independently bromo.
  • R 8 is independently iodo.
  • R 8 is independently fluoro.
  • R 8 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.
  • R 8 is independently hydrogen, hydroxy, or methoxy. In embodiments, R 8 is independently hydroxy or methoxy. In embodiments, R 8 is independently hydrogen or hydroxy.
  • R 8 is independently hydrogen. In embodiments, R 8 is independently hydroxy. In embodiments, R 8 is independently methoxy. In embodiments, R 8 is independently ethoxy. In embodiments, R 8 is independently propoxy. In embodiments, R 8 is independently butoxy. In embodiments, R 8 is independently t-butoxy.
  • R 8A is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 8A is hydrogen. In embodiments, R 8A is a substituted alkyl. In embodiments. R 8A is an unsubstituted alkyl.
  • R 8A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl).
  • a substituted R 8A (e.g.. substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8A is substituted with a plurality' of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8A when R 8A is substituted, it is substituted with at least one substituent group.
  • R 8A when R 8A is substituted, it is substituted with at least one size-limited substituent group.
  • R 8A when R 8A is substituted, it is substituted with at least one lower substituent group.
  • R 8A is hydrogen or substituted or unsubstituted alkyl.
  • R 8A is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cg alkyd, or C1-C4 alkyl).
  • R 8A is hydrogen.
  • R 8A is unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd).
  • R 8A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 8A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyd, isopent d, or hexyl.
  • R 8A is hydrogen.
  • R 8A is methyl.
  • R 8A is ethyl.
  • R 8A is propyl.
  • R 8A is isopropyl.
  • R 8A is butyl.
  • R 8A is isobutyl.
  • R 8A is t-butyl.
  • R 8A is pentyl.
  • R 8A is isopentyl.
  • R 8A is hexyl.
  • R 8 is independently hydrogen, halogen, -CCh, -CBn, -CF3, -Ch, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CHCI2. -CHBn, -CHF2, -CHI2, -CN, -OR 8 A , -NR 8 A R 8 B , -CONH2, -COOH, -NHC(O)R 8 A . -NO2, -SH, substituted (e.g...
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyd.
  • a substituted R 8 (e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8 when R 8 is substituted, it is substituted with at least one substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one size-limited substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one lower substituent group.
  • R 8 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.
  • R 8 is independently hydrogen, hydroxy, or methoxy. In embodiments. R 8 is independently hydroxy or methoxy. In embodiments, R 8 is independently hydrogen or hydroxy.
  • R 8 is independently hydrogen. In embodiments, R 8 is independently hydroxy. In embodiments, R 8 is independently methoxy. In embodiments, R 8 is independently ethoxy. In embodiments, R 8 is independently propoxy. In embodiments, R 8 is independently butoxy. In embodiments, R 8 is independently t-butoxy.
  • R 8 A is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 8 A is hydrogen. In embodiments, R 8 A is a substituted alkyl. In embodiments. R 8 A is an unsubstituted alkyl.
  • R 8 A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-C 6 alkyl, or C1-C4 alkyl).
  • a substituted R 8 A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8 A is substituted with a plurality’ of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 8 A when R 8 A is substituted, it is substituted with at least one substituent group.
  • R 8 A when R 8 A is substituted, it is substituted with at least one size-limited substituent group.
  • R 8 A when R 8 A is substituted, it is substituted with at least one lower substituent group.
  • R 8 A is hydrogen or substituted or unsubstituted alkyl.
  • R 8 A is hydrogen or substituted (e.g.. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl).
  • R 8 A is hydrogen.
  • R 8 A is unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd).
  • R 8 A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 8 A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyd, or hexyl.
  • R 8 A is hydrogen.
  • R 8 A is methy l.
  • R 8 A is ethyl.
  • R 8 A is propyl.
  • R 8 A is isopropyl.
  • R 8 A is buty l.
  • R 8 A is isobutyl.
  • R 8 A is t-butyl.
  • R 8 A is pentyl.
  • R 8 A is isopentyl.
  • R 8 A is hexyl.
  • R 9 is independently hydrogen, halogen, -CCls, -CB . -CF3, -CI3, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CHCI2. -CHBr 2 , -CHF2, -CHI2, -CN, -OR 9A , -NR 9A R 9R , -CONH2. -COOH. -NHC(O)R 9A , -NO2.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with at least one substituent group, sizelimited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • substituted cycloalkyd e.g., C3-C8 cycloalkyd, C3-C6 cycloalkyl, or C5-C6 cycloalkyd
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted aryl e.g., Ce-Cio ary l, C10 aryl, or phenyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • a substituted R 9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 9 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 9 when R 9 is substituted, it is substituted with at least one substituent group.
  • R 9 when R 9 is substituted, it is substituted with at least one size-limited substituent group.
  • R 9 when R 9 is substituted, it is substituted with at least one lower substituent group.
  • R 9 is independently hydrogen, halogen, -OR 9A , or -NHC(O)R 9A .
  • R 9 is independently hydrogen.
  • R 9 is independently halogen.
  • R 9 is independently -OR 9A .
  • R 9 is independently -NHC(O)R 9A .
  • R 9 is independently chloro.
  • R 9 is independently bromo.
  • R 9 is independently iodo.
  • R 9 is independently fluoro.
  • R 9 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.
  • R 9 is independently hydrogen. In embodiments. R 9 is independently hydroxy. In embodiments. R 9 is independently methoxy. In embodiments, R 9 is independently ethoxy. In embodiments, R 9 is independently propoxy. In embodiments, R 9 is independently butoxy. In embodiments, R 9 is independently t-butoxy.
  • R 9A is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 9A is hydrogen. In embodiments, R 9A is a substituted alkyl. In embodiments, R 9A is an unsubstituted alkyl.
  • R 9A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-C 6 alkyl, or C1-C4 alkyl).
  • a substituted R 9A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or low er substituent group; wherein if the substituted R 9A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or low er substituent group may optionally be different.
  • R 9A when R 9A is substituted, it is substituted with at least one substituent group.
  • R 9A when R 9A is substituted, it is substituted with at least one size-limited substituent group.
  • R 9A when R 9A is substituted, it is substituted with at least one lower substituent group.
  • R 9A is hydrogen or substituted or unsubstituted alkyl. In embodiments. R 9A is hydrogen or substituted (e.g.. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alky l, or C1-C4 alkyd). In embodiments, R 9A is hydrogen. In embodiments, R 9A is unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 9A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl.
  • R 9A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, penty l, isopenty l, or hexyl.
  • R 9A is hydrogen.
  • R 9A is methyl.
  • R 9A is ethyl.
  • R 9A is propyl.
  • R 9A is isopropyl.
  • R 9A is butyl.
  • R 9A is isobutyl.
  • R 9A is t-butyl.
  • R 9A is pentyd.
  • R 9A is isopentyl.
  • R 9A is hexyl.
  • R 8 and R 9 together with the carbon atoms to w hich they are connected form a substituted or unsubstituted heterocycloalkylene.
  • R 8 and R 9 together with the carbon atoms to which they are connected form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • R 8 and R 9 together with the carbon atoms to w hich they are connected form a substituted or unsubstituted heterocycloalkylene.
  • R 8 and R 9 together with the carbon atoms to which they are connected form a substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • R 8 and R 9 together with the carbon atoms to which they are connected form a substituted 5 membered heterocycloalkylene. In embodiments, R 8 and R 9 together with the carbon atoms to which they are connected form an unsubstituted 5 membered heterocycloalkylene. In embodiments, R 8 and R 9 together with the carbon atoms to which they are connected form a substituted 6 membered heterocycloalk lene. In embodiments, R 8 and R 9 together with the carbon atoms to which they are connected form an unsubstituted 6 membered heterocycloalkylene.
  • R 8 and R 9 together with the carbon atoms to which they are connected form a substituted 5 membered heterocycloalkylene. In embodiments, R 8 and R 9 together with the carbon atoms to which they are connected form an unsubstituted 5 membered heterocycloalkylene. In embodiments, R 8 and R 9 together with the carbon atoms to which they are connected form a substituted 6 membered heterocycloalkylene. In embodiments, R 8 and R 9 together with the carbon atoms to which they are connected form an unsubstituted 6 membered heterocycloalkylene.
  • R 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene. In embodiments, R 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene. In embodiments, R 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted heterocycloalkylene.
  • a substituted heterocycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkylene is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, sizelimited substituent group, and/or lower substituent group may optionally be different.
  • when heterocycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one substituent group.
  • heterocycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected when substituted, it is substituted with at least one size-limited substituent group. In embodiments, when heterocycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.
  • cycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected when cycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when cycloalkylene formed by the joining of R 8 and R 10 together with the carbon atoms to which they are connected is substituted, it is substituted with at least one lower substituent group.
  • R 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, R 8 and R 10 together with the carbon atoms to which they are connected form a substituted or unsubstituted 4 membered heterocycloalkylene.
  • R 8 and R 10 together with the carbon atoms to which they are connected form a substituted 4 membered heterocycloalkylene. In embodiments, R 8 and R 10 together with the carbon atoms to which they are connected form an unsubstituted 4 membered heterocycloalkylene.
  • R 8 and R 10 together with the carbon atoms to which they are connected form a substituted 4 membered heterocycloalkylene. In embodiments, R 8 and R 10 together with the carbon atoms to which they are connected form an unsubstituted 4 membered heterocycloalkylene.
  • R 8 and R 10 or R 8 and R 10 together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).
  • R 8 and R 10 together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).
  • R 8 and R 10 together with the carbon atoms to which they are connected form a locked nucleic acid (LNA).
  • each R 8A , R 8B , R 8 A , R 8 B , R 9A . R 9B , R 10A , and R 10B is independently hydrogen.
  • a substituent group e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd
  • substituted e.g.
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • substituted e.g.
  • aryl e.g., Ce-Cio aryl, C10 and, or phenyl
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered hctcroaryl.
  • each R 8A , R 8B , R 8 A , R 8 B , R 9A . R 9B , R 10A , and R 10B is independently- substituted with one or more substituent groups.
  • each R 8A , R 8B , R 8 A , R 8 B , R 9A , R 9B , R 10A , and R 10B is independently substituted with one or more lower substituent groups.
  • R 8A and R 8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g.. 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g.
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 8 A and R 8 B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 member
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 8A and R 8B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 8 A and R 8 B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaiyl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a heterocycloalkyl formed by the joining of R 8A and R 8B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 8A and R 8B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 8A and R 8B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size- limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 8A and R 8B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.
  • a heterocycloalkyl formed by the joining of R 8 A and R 8 B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 8 A and R 8 B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 8 A and R 8 B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when a heterocycloalky l formed by the joining of R 8 A and R 8 B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.
  • R 9A and R 9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyd (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyd e.g., 3 to 8 member
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a heterocycloalkyl formed by the joining of R 9A and R 9B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when a heterocycloalkyd formed by the joining of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.
  • R 10A and R 10B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 member
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 10A and R 10B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a heterocycloalkyl formed by the joining of R 10A and R 10B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 10A and R 10B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 10A and R 10B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 10A and R 1OB substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group.
  • each X is independently-Cl, -Br, -I or -F. In embodiments, X is independently -Cl. In embodiments, X is independently -Br. In embodiments, X is independently -I. In embodiments, X is independently -F.
  • R 12 is independently hydrogen. -C(O)R 12A , -C(O)OR 12A , -OR 12A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl:
  • R 13 is independently hydrogen. -C(O)R 13A , -C(O)OR 13A , -OR 13A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; or R 12 and R 13 together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted hctcrocyclyl; each R 12A and R 13A is independently hydrogen, -CX3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, X, and n, are each as defined herein, including in embodiments.
  • R 12 is independently hydrogen, -C(O)R 12A , -C(O)OR 12A , -0R 12A . substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g.. 2 to 8 membered heteroalkyl,
  • substituted e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd
  • substituted e.g., substituted
  • ary l e.g., Ce-Cio aryl, C10 ary 1, or phenyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g.. 5 to
  • a substituted R 12 (e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 12 is independently substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 12 when R 12 is independently substituted, it is substituted with at least one substituent group.
  • R 12 when R 12 is independently substituted, it is substituted with at least one size-limited substituent group.
  • R 12 when R 12 is independently substituted, it is substituted with at least one lower substituent group.
  • R 12 is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 12 is independently hydrogen or substituted (e g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l). In embodiments, R 12 is independently hydrogen. In embodiments. R 12 is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 12 is independently substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or Ci- C 4 alky l).
  • R 12 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.
  • R 12 is independently hydrogen or methyl.
  • R 12 is independently hydrogen. In embodiments, R 12 is independently methyl. In embodiments, R 12 is independently ethyl. In embodiments, R 12 is independently propyl. In embodiments, R 12 is independently isopropyl. In embodiments, R 12 is independently butyl. In embodiments, R 12 is independently isobutyl. In embodiments, R 12 is independently t-butyl. In embodiments, R 12 is independently pentyl. In embodiments, R 12 is independently isopentyl. In embodiments, R 12 is independently hexyl.
  • R 13 is independently hydrogen, -C(O)R 13A , -C(O)OR 13A , -OR 13A , substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g.. 2 to 8 membered heteroalkyl,
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substituted with
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or low er substituent group
  • unsubstituted aryl e.g.. Ce-Cio aryl, C10 a d. or phenyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • a substituted R 13 (e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; w herein if the substituted R 13 is independently substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 13 when R 13 is independently substituted, it is substituted with at least one substituent group.
  • R 13 when R 13 is independently substituted, it is substituted with at least one size-limited substituent group.
  • R 13 when R 13 is independently substituted, it is substituted with at least one lower substituent group.
  • R 13 is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 13 is independently hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R 13 is independently hydrogen. In embodiments, R 13 is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments.
  • R 13 is independently substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or Ci- C 4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or Ci- C 4 alkyl.
  • R 13 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.
  • R 13 is independently hydrogen or methyl.
  • R 13 is independently hydrogen. In embodiments, R 13 is independently methyl. In embodiments, R 13 is independently ethyl. In embodiments, R 13 is independently propyl. In embodiments, R 13 is independently isopropyl. In embodiments, R 13 is independently butyl. In embodiments, R 13 is independently isobutyl. In embodiments, R 13 is independently t-butyl. In embodiments. R 13 is independently pentyl. In embodiments. R 13 is independently isopentyl. In embodiments, R 13 is independently hexyl.
  • each R 12A and R 13A is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH 2 , -CN. -OH, -NH 2 , -COOH. -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO2NH2, -NHNH2.
  • a substituent group e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, Cs-Ce cycloalkyl, or C5-C6 cycloalkyl
  • substituted e.g.
  • a substituent group e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • substituted e.g. with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted aryl e.g., Cs-Cio aryl. C10 aryl, or phenyl
  • substituted e.g.
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaiyl.
  • each R 12A and R 13A is independently substituted with one or more substituent groups. In embodiments, each R 12A and R 13A is independently substituted with one or more size-limited substituent groups. In embodiments, each R 12A and R 13A is independently substituted with one or more lower substituent groups.
  • X 1 . X 2 . Y 1 . Y 2 , Y 3 , Y 4 , Y 5 , B 3 . and n are each as defined herein, including in embodiments.
  • R 15 is hydrogen, halogen, -CCh, -CBr 3 , -CF3, -Ch, -CHCI2, -CHBr 2 , -CHF2, -CHI 2 , -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CN.
  • R 16 is independently hydrogen, -C(O)R 16A , -C(O)OR 16A , -OR 16A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R 15A , R 15B , and R 16A is independently hydrogen, -CX3, -CHX2, -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO2NH2, -NHNH2, -ONH2.
  • -OCX3, -OCHX2, -OCH2X substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 15A and R 15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A, and n, are each as defined herein, including in embodiments.
  • R 15 is hydrogen, halogen, -CCh, -CBrs. -CF3, -Ch, -CH2CI, -CH 2 Br, -CH2F, -CH2I. -CHCh, -CH Bn. -CHF2, -CHI 2 . -CN. -OR 15A . -NR 15A R 15B , -NO2. -SH.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkyl e.g..
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkyl e.g., Cs-Cs cycloalkyl, C3-C6
  • Cio aryl, or phenyl substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl)- [00459]
  • a substituted R 15 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • the substituted R 13 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 15 when R 15 is substituted, it is substituted with at least one substituent group. In embodiments, when R 13 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 15 is substituted, it is substituted with at least one lower substituent group.
  • R 15 is hydrogen, halogen, or -NR 15A R 15B .
  • R 15 is hydrogen.
  • R 15 is halogen.
  • R 15 is -NR 15A R 15B .
  • R 15 is -Cl.
  • R 15 is -Br.
  • R 15 is -I.
  • R 15 is -F.
  • R 15 is -NHMe.
  • R 15 is -NH2.
  • R 15 is -NMe2.
  • R 15 is hydrogen. -F, -NHMe, -NH2, or -NMe2. In embodiments, R 15 is hydrogen, -NHMe, or -NH2.
  • R 15A is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 15A is hydrogen. In embodiments, R 15A is substituted alkyl. In embodiments, R 15A is an unsubstituted alkyl. In embodiments, R 15B is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 15B is hydrogen. In embodiments, R 13B is substituted alkyl. In embodiments, R 15B is an unsubstituted alkyl.
  • R 15A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Cg alkyl, or C1-C4 alkyl).
  • R 13B is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Cg alkyl, or C1-C4 alkyl).
  • a substituted R 15A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 15A is substituted with a plurality' of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 15A is substituted, it is substituted with at least one substituent group.
  • R 15A when R 15A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 15A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 15B e g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 15B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 15B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 15B when R 15B is substituted, it is substituted with at least one substituent group. In embodiments, when R 15B is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R 15B is substituted, it is substituted with at least one lower substituent group.
  • R 15A is hydrogen or substituted or unsubstituted alkyl.
  • R 15A is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl).
  • R 13A is hydrogen.
  • R 15A is unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 15A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 15B is hydrogen or substituted or unsubstituted alky l.
  • R 15B is hydrogen or substituted (e g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alky l).
  • R 15B is hydrogen.
  • R 15B is unsubstituted alkyl (e.g., Ci-Cs alkyl. Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R 15B is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • alkyl e.g., Ci-Cs alkyl. Ci-Ce alkyl, or C1-C4 alkyl.
  • R 15A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobuty l, t-butyl, pentyl, isopentyl, hexyl.
  • R 15A is hydrogen.
  • R 15A is methyl.
  • R 15A is ethyl.
  • R 15A is propyl.
  • R 15A is isopropyl.
  • R 15A is butyl.
  • R 15A is isobutyl.
  • R 15A is t-butyl.
  • R 15A is pentyl.
  • R 15A is hexyl.
  • R 15B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl. pentyl, isopentyl, hexyl.
  • R 15B is hydrogen.
  • R 13B is methyl.
  • R 13B is ethyl.
  • R 15B is propyl.
  • R 15B is isopropyl.
  • R 15B is butyl.
  • R 15B is isobutyl.
  • R 15B is t-butyl.
  • R 15B is penty l.
  • R 15B is hexyl.
  • R 16 is independently hydrogen, -C(O)R 16A , -C(O)OR 16A , -OR 16A , substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alky l, Ci-Ce alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g.. 2 to 8 membered heteroalkyl,
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., Ci-Cs alky l, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., substitute
  • aryl e.g.. Ce-Cio aryl, C10 ary l, or phenyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g.
  • a substituted R 16 (e.g., substituted alkyd, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; w herein if the substituted R 16 is independently substituted with a plurality 7 of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 16 when R 16 is independently substituted, it is substituted with at least one substituent group.
  • R 16 when R 16 is independently substituted, it is substituted with at least one size-limited substituent group.
  • R 16 when R 16 is independently substituted, it is substituted with at least one lower substituent group.
  • R 16 is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, R 16 is independently hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments, R 16 is independently hydrogen. In embodiments, R 16 is independently unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl). In embodiments.
  • R 16 is independently substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or Ci- C 4 alkyl).
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or Ci- C 4 alkyl.
  • R 16 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.
  • R 16 is independently hydrogen. In embodiments, R 16 is independently methyl. In embodiments, R 16 is independently ethyl. In embodiments, R 16 is independently propyl. In embodiments, R 16 is independently isopropyl. In embodiments, R 16 is independently buty l. In embodiments, R 16 is independently isobutyl. In embodiments, R 16 is independently t-butyl. In embodiments. R 16 is independently pentyl. In embodiments, R 16 is independently isopentyl. In embodiments, R 16 is independently hexyl.
  • each R 15A , R 15B , and R 16A is independently substituted with one or more substituent groups. In embodiments, each R 15A . R 15B . and R 16A is independently substituted with one or more size-limited substituent groups. In embodiments, each R 15A , R 15B , and R 16A is independently substituted with one or more lower substituent groups.
  • R 15A and R 15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heterocycloalkyl e.g., 3 to 8 member
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 15A and R 15B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a heterocycloalkyl formed by the joining of R 15A and R 15B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heterocycloalkyl formed by the joining of R 15A and R 15B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 15A and R 15B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 15A and R 15B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one low er substituent group. In embodiments, when a heteroaryl formed by the joining of R 15A and R 15B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heteroaryl formed by the joining of R 13A and R 15B substituents bonded to the same nitrogen atom when a heteroaryl formed by the joining of R 13A and R 15B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • R 17 is hydrogen, halogen, -CCh, -CBr 3 , -CF3, -Ch, -CHC1 2 , -CHBr 2 , -CHF 2 , -CHI 2 , - CH 2 C1, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 17A , -NR 17A R 17B , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO4H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H.
  • R 18 is independently hydrogen, -C(O)R 18A , -C(O)OR 18A , -OR 18A , substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R 17A . R 17B . and R 18A . is independently hydrogen, -CX3, -CHX 2 .
  • R 17A and R 17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. and wherein: R 1 , R 2 , R 3 , R 7 , R 11 , R 15 . R 16 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A. and n are each as defined herein, including in embodiments.
  • R 17 is hydrogen, halogen, -CCls, -CBn. -CF3, -CI3, -CH2CI, -CH 2 Br, -CH2F, -CH2I, -CHCh, -CHBr 2 . -CHF2, -CHI2, -CN, -OR 17A . -NR 17A R 17B , -NO2.
  • -SH substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyd), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalky l (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g.
  • R 17 is hy drogen, halogen, or -NR 17A R 17B .
  • R 17 is hydrogen.
  • R 17 is halogen.
  • R 17 is -NR 17A R 17B .
  • R 17 is -Cl.
  • R 17 is -Br.
  • R 17 is -I.
  • R 17 is -F.
  • R 17 is -NHMe.
  • R 17 is -NH2.
  • R 17 is -NMe2.
  • R 17 is hydrogen, -F, -NHMe, -NH2, or -NMe2. In embodiments, R 17 is hydrogen. -NHMe, or -NH2.
  • R 17A is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 17A is hydrogen. In embodiments, R 17A is substituted alkyl. In embodiments, R 17A is an unsubstituted alkyl. In embodiments, R 17B is hydrogen or substituted or unsubstituted alkyl. In embodiments. R 17B is hydrogen. In embodiments, R 17B is substituted alkyl. In embodiments, R 17B is an unsubstituted alkyl.
  • R 17A is hydrogen, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17B is hydrogen, substituted (e.g.. substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17B when R 17B is substituted, it is substituted with at least one substituent group. In embodiments, when R 17B is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R 17B is substituted, it is substituted with at least one lower substituent group-
  • R 17A is hydrogen or substituted or unsubstituted alkyl.
  • R 17A is hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17A is hydrogen.
  • R 17A is unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17A is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17B is hydrogen or substituted or unsubstituted alkyl.
  • R 17B is hydrogen or substituted (e.g.. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alky l, Ci-Ce alkyl, or C1-C4 alkyd).
  • R 17B is hydrogen.
  • R 17B is unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17B is substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 17A is hydrogen, methyl, ethyl, propyl, isopropyl, buty l, isobutyl, t-butyl, penty l, isopentyd, hexyl.
  • R 17A is hydrogen.
  • R 17A is methyl.
  • R 17A is ethyl.
  • R 17A is propyl.
  • R 17A is isopropyl.
  • R 17A is butyl.
  • R 17A is isobutyl.
  • R 17A is t-butyl.
  • R 17A is pentyl.
  • R 17A is hexyl.
  • R 17B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, penty l, isopentyd, hexyl.
  • R 17B is hydrogen.
  • R 17B is methyl.
  • R 17B is ethyl.
  • R 17B is propyl.
  • R 17B is isopropyl.
  • R 17B is butyl.
  • R 17B is isobutyl.
  • R 17B is t-butyl.
  • R 17B is pentyl.
  • R 17B is hexyl.
  • R 18 is independently hydrogen, -C(O)R 18A , -C(O)OR 18A , -OR 18A , substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyd, or C1-C4 alkyd), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyd, 2 to 6 membered heteroalkyd, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8
  • 3 to 8 membered heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., Cs-Cio aryl, Cio aryl, or phenyl), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g., Cs-Cio aryl, Cio aryl, or phenyl
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • a substituted R 18 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is independently substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 18 is independently substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 18 when R 18 is independently substituted, it is substituted with at least one substituent group.
  • R 18 when R 18 is independently substituted, it is substituted with at least one size-limited substituent group.
  • R 18 when R 18 is independently substituted, it is substituted with at least one lower substituent group.
  • R 18 is independently hydrogen or substituted or unsubstituted alkyl.
  • R 18 is independently hydrogen or substituted (e.g., with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 18 is independently hydrogen.
  • R 18 is independently unsubstituted alkyl (e.g.. Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl).
  • R 18 is independently substituted (e.g., with a substituent group, a sizelimited substituent group or a lower substituent group) alkyl (e.g., Ci-Cs alkyd, Ci-Ce alkyl, or Ci- C 4 alky l).
  • alkyl e.g., Ci-Cs alkyd, Ci-Ce alkyl, or Ci- C 4 alky l.
  • R 18 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyd, or hexyl.
  • R 18 is independently hydrogen. In embodiments, R 18 is independently methyl. In embodiments, R 18 is independently ethyl. In embodiments, R 18 is independently propyl. In embodiments. R 18 is independently isopropyl. In embodiments, R 18 is independently butyl. In embodiments, R 18 is independently isobutyl. In embodiments, R 18 is independently t-butyl. In embodiments, R 18 is independently penty l. In embodiments, R 18 is independently isopentyl. In embodiments, R 18 is independently hexyl. [00501] In embodiments, each R 17A . R 17B . and R 18A is independently hydrogen.
  • alkyl e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl
  • substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • substituted e.g., with a substituent group, a size-limited substituent group
  • aryl e.g.. Ce-Cio aryl, C10 aryl, or phenyl
  • substituted e.g., with a substituent group, a size-limited substituent group or a lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • each R 17A , R 17B , and R 18A is independently substituted with one or more substituent groups. In embodiments, each R 17A , R 17B , and R 18A is independently substituted with one or more size-limited substituent groups. In embodiments, each R 17A , R 17B , and R 18A is independently substituted with one or more lower substituent groups.
  • R 17A and R 17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g. with a substituent group, a size-limited substituent group or a lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), or substituted (e.g.
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • a substituted heterocycloalkyl or substituted heteroaryl formed by the joining of R 17A and R 17B substituents bonded to the same nitrogen atom is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a heterocycloalkyl formed by the joining of R 17A and R 17B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a heterocycloalkyl formed by the joining of R 17A and R 17B substituents bonded to the same nitrogen atom when a heterocycloalkyl formed by the joining of R 17A and R 17B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a heterocycloalkyl formed by the joining of R 17A and R 17B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one lower substituent group. In embodiments, when a heteroaryl formed by the joining of R 17A and R 17B substituents bonded to the same nitrogen atom is substituted, it is substituted with at least one substituent group.
  • a compound of formula (IU) (IU); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hy drate thereof; wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 18 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 18 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • R 14 , R 17 , R 18 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • a compound of formula (IBB) (IBB); or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 8 , R 9 , R 10 , R 11 , R 14 , R 17 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , and n are each as defined herein, including in embodiments.
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

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Abstract

La présente invention décrit de nouveaux analogues de coiffe de trétranucléotide et de trinucléotide, leurs procédés de production et leurs méthodes d'utilisation. L'invention concerne également des molécules d'ARN présentant une coiffe en 5', la coiffe en 5' comprenant un analogue de coiffe de tétranucléotide ou de trinucléotide tel que décrit ici. L'invention décrit en outre des méthodes d'induction d'un effet thérapeutique chez un sujet, les méthodes comprenant une étape d'administration au sujet d'une molécule d'ARN comprenant l'analogue de coiffe de trinucléotide.
PCT/US2024/045502 2023-09-06 2024-09-06 Analogues de coiffe et leurs méthodes d'utilisation Pending WO2025054401A2 (fr)

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