Cap analogs and methods of use thereof

HK40138048APending Publication Date: 2026-09-25TRILINK BIOTECH LLC
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Patent Information

Application Number
HK62026124918
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-05-23
Filing Date
2026-06-16
Publication Date
2026-09-25
Estimated Expiration
2044-07-31

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Abstract

Described herein are novel cap analogs and compositions, and methods of using the same. Also described herein is an RNA molecule comprising a 5'-cap, wherein the 5'-cap includes a 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 cap analog or RNA molecule comprising the cap analog as described herein.
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Description

Abstract This article describes novel cap analogs and compositions of formula (I), and methods of using them. This article also describes RNA molecules comprising a 5'-cap, wherein the 5'-cap comprises a cap analog as described herein. This article further describes methods for inducing therapeutic effects in subjects, the methods comprising administering to the subject a cap analog as described herein or an RNA molecule comprising the cap analog. (I) wherein N is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a natural, modified, or non-natural nucleoside; provided that N1 is not a modified or unmodified G nucleoside.

Claims

WHAT IS CLAIMED IS:

1. 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: N1is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, natural, modified, or unnatural nucleoside; with the proviso that N1is not a modified or unmodified G nucleoside; each B1is independently a natural, modified, or unnatural nucleoside base; each X1is independently -O-, -CH2-, -CX2-, -CHX-, -N(R101)-, -BH-, or -S-; each Y1is independently O, S, or Se; each Z1is independently -OH, -SH, -BH3, substituted or unsubstituted -O-alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted orunsubstituted -O-aryl; each R1is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR1A, -NR1AR1B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; R5is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR5A, -NR5AR5B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 R1and R5together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R1B, R5A, and R5Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -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; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R101is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H,-SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2,-OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; n is an integer from 0 to 3; m is an integer from 0 to 8; and X is -Cl, -Br, -I or –F.

2. The compound of claim 1, which is a compound of formula (IA):, 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; 3. The compound of claim 1, which is a compound of formula (IB):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: R2is independently hydrogen, –C(O)R2A, –C(O)OR2A, –OR2A, 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; R3is independently hydrogen, –C(O)R3A, –C(O)OR3A, –OR3A, 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 R2and R3together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R4is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR4A, -NR4AR4B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 R2A, R3A, R4A, and R4B, is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -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; and R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

4. The compound of claim 1, which is a compound of formula (IC):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.

5. The compound of claim 1, which is 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.

6. The compound of claim 1, which is a compound of formula (IE):, 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.

7. The compound of claim 1, which is 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.

8. The compound of claim 1, which is a compound of formula (IG):, 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.

9. The compound of claim 1, which is a compound of formula (IH):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: R2is independently hydrogen, –C(O)R2A, –C(O)OR2A, –OR2A, 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; R3is independently hydrogen, –C(O)R3A, –C(O)OR3A, –OR3A, 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 R2and R3together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; and each R2Aand R3Ais independently hydrogen, -CX3, -CHX2, -CH2X,-C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ^ ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -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.

10. The compound of any one of claims 1-9, wherein N1is A, C, or U.

11. The compound of claim 10, wherein N1is A or U.

12. The compound of claim 11, wherein N1is A.

13. The compound of any one of claims 1-9, wherein N1is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

14. The compound of claim 13, wherein N1is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkyl.

15. The compound of claim 14, wherein N1is substituted alkyl or substituted heteroaryl.1 wherein N1.

17. The compound of any one of claims 1-16, wherein each B1is independently A, m6A, G, C, or U.

18. The compound of any one of claims 3-6 or 9-17, wherein each B1is independently G.

19. The compound of any one of claims 3-6 or 9-17, wherein each B1is independently U.

20. The compound of any one of claims 1-3 or 9-19, wherein each R1is independently hydrogen, halogen, or -OR1A.

21. The compound of claim 20, wherein each R1is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

22. The compound of claim 21, wherein each R1is independently methoxy.

23. The compound of any one of claims 3, 4, or 9-22, wherein R2is independently hydrogen or substituted or unsubstituted alkyl.

24. The compound of claim 23, wherein R2is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

25. The compound of claim 24, wherein R2is independently hydrogen or methyl.

26. The compound of any one of claims 3, 4, or 9-25, wherein R3is independently hydrogen or substituted or unsubstituted alkyl.

27. The compound of claim 26, wherein R3is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

28. The compound of claim 27, wherein R3is independently hydrogen or methyl.

29. The compound of any one of claims 3-8 or 10-28, wherein R4is hydrogen, halogen, or -NR4AR4B.

30. The compound of claim 29, wherein R4is hydrogen, -F, -NHMe, -NH2, or -NMe2.

31. The compound of claim 30, wherein R4is hydrogen or -NHMe.

32. The compound of claim 31, wherein R4is hydrogen.

33. The compound of any one of claims 1-32, wherein each R5is independently hydrogen.

34. The compound of any one of claims 1-19 or 23-32, wherein at least one R1forms a ring together with the R5within four atoms of said R1and the atoms to which they are connected, thereby forming a locked nucleic acid (LNA).

35. The compound of any one of claims 1-34, wherein each X1is independently -O-, -CH2-, -CF2-, or -S-.

36. The compound of claim 35, wherein each X1is independently -O-.

37. The compound of any one of claims 1-36, wherein each Y1is independently O or S.

38. The compound of claim 37, wherein each Y1is independently O.

39. The compound of any one of claims 1-38, wherein each Z1is independently -OH or -SH.

40. The compound of claim 39, wherein each Z1is independently -OH.

41. The compound of any one of claims 1 or 10-40, wherein m is 0 or 1.

42. The compound of any one of claims 1-41, wherein n is 1.

43. A compound of the following 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.

44. A compound of the following 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. 4, 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.

46. A compound of the following 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.

47. A compound of the following 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.

48. A compound of the following 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.

49. The compound of any one of claims 1-48, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt.

50. The compound of claim 49, wherein the pharmaceutically acceptable salt is a sodium salt.

51. An RNA molecule comprising a 5’-cap, wherein the 5’-cap comprises a compound of any one of claims 1-50.

52. The RNA molecule of claim 51, wherein the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.

53. A pharmaceutical composition comprising a compound of any one of claims 1-50 and a pharmaceutically acceptable excipient.

54. A pharmaceutical composition comprising an RNA molecule of claim 51 and a pharmaceutically acceptable excipient.

55. An initiating capped oligonucleotide primer of the following formula: Apppm6A2’OMepG.

56. An initiating capped oligonucleotide primer of the following formula: Ph-4-Bu-pppm6A2’OMepG.

57. An initiating capped oligonucleotide primer of the following formula: Ph-4-Bu-pppA2’OMepG.

58. An initiating capped oligonucleotide primer of the following formula: Thiamine-pppA2’OMepG.

59. An initiating capped oligonucleotide primer of the following formula: Thiamine-pppm6A2’OMepG.

60. An initiating capped oligonucleotide primer of the following formula: ApppA2’OMepG.

61. An RNA molecule comprising the initiating capped oligonucleotide primer, stereoisomer, or a pharmaceutically acceptable salt thereof, of any one of claims 55-60.

62. The RNA molecule of claim 61, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt.

63. The RNA molecule of claim 62, wherein the pharmaceutically acceptable salt is a sodium salt.

64. The RNA molecule of claim 63, wherein the RNA molecule is a messenger RNA (mRNA) molecule or a self-amplifying RNA (saRNA) molecule.

65. A pharmaceutical composition comprising an RNA molecule comprising the initiating capped oligonucleotide primer, stereoisomer, or a pharmaceutically acceptable salt thereof, of any one of claims 55-60, and a pharmaceutically acceptable excipient.

66. A method of inducing a therapeutic effect in a subject, comprising administering to the subject an RNA molecule according to claim 51 or 61 or a pharmaceutical composition according to claim 53 or 65.

67. A method of administering to a subject a therapeutic dose unit of an mRNA molecule comprising a 5’-cap, wherein the 5’-cap comprises a compound of any one of claims 1-50.

68. The RNA molecule of claim 51 or 61, for use in therapy.

69. The mRNA molecule comprising a 5’-cap, wherein the 5’-cap comprises a compound of any one of claims 1-50, for use in therapy.

70. A method of inhibiting eIF4E in a mammal comprising administering a compound of any one of claims 1-50, an RNA molecule of claim 51 or 61, or a pharmaceutical composition of claim 53 or 65.

71. 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: N1is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, natural, modified, or unnatural nucleoside; with the proviso that N1is not a modified or unmodified G nucleoside; each B1is independently a natural, modified, or unnatural nucleoside base;each X1is independently -O-, -CH2-, -CX2-, -CHX-, -N(R101)-, -BH-, or -S-; each Y1is independently O, S, or Se; each Z1is independently -OH, -SH, -BH3, substituted or unsubstituted -O-alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted -O-aryl; each R1is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR1A, -NR1AR1B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; R5is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR5A, -NR5AR5B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 R1and R5together with the carbon atoms to which they are connected form a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; each R1A, R1B, R5A, and R5Bis independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -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; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R101is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2,-OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; n is an integer from 0 to 3; m is an integer from 0 to 8; and X is -Cl, -Br, -I or –F; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

72. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (IA), 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; into a mixture comprising a polynucleotide template and an RNA polymerase underconditions 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.

73. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (IB)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: R2is independently hydrogen, –C(O)R2A, –C(O)OR2A, –OR2A, 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; R3is independently hydrogen, –C(O)R3A, –C(O)OR3A, –OR3A, 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 R2and R3together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R4is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR4A, -NR4AR4B, -COOH, -CONH2,-NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 R2A, R3A, R4A, and R4B, is independently hydrogen, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -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; and R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

74. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (IC)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; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

75. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer 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; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

76. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (IE), 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; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

77. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer 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; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

78. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (IG), 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; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

79. A method for preparing a fully templated RNA molecule comprising: introducing the initiating capped oligonucleotide primer of formula (IH)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: R2is independently hydrogen, –C(O)R2A, –C(O)OR2A, –OR2A, 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; R3is independently hydrogen, –C(O)R3A, –C(O)OR3A, –OR3A, 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 R2and R3together with the nitrogen atom to which they are connected form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; and each R2Aand R3Ais independently hydrogen, -CX3, -CHX2, -CH2X,-C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ^ ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; into a mixture comprising a polynucleotide template and an RNA polymerase 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.

80. The method of any one of claims 71-79, wherein B1, R1, R2, R3, R4, R5, N1, X1, Y1, Z1, m and n are as defined in any one of claims 1-42.