COBURN GLEN (US)
CHU GUO-HUA (US)
CONDON STEPHEN M (US)
BOYD STEVEN A (US)
PEVEAR DANIEL C (US)
WO2002088159A1 | 2002-11-07 | |||
WO2012158811A2 | 2012-11-22 | |||
WO2018067241A1 | 2018-04-12 | |||
WO2022119784A1 | 2022-06-09 | |||
WO2022089614A1 | 2022-05-05 |
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CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II); wherein: X is hydrogen or -CN; G is ; R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; each R15a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R15a on the same atom are taken together to form an oxo; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26; R26 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26 b cRd, - S NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R26a on the same atom are taken together to form an oxo; or two R26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo; pro vided that when G is and X is -CN, or G is and X is hydrogen; then at least one of R11, R12 or R15 is not hydrogen. 2. The compound of claim 1, wherein X is hydrogen. 3. The compound of claim 1, wherein X is -CN. 4. The compound of any one of claims 1-3, wherein R13 is hydrogen. 5. The compound of any one of claims 1-3, wherein R13 is C1-C6alkyl. 6. The compound of any one of claims 1-5, wherein R14 is -OH. 7. The compound of any one of claims 1-5, wherein R14 is fluoro. 8. The compound of any one of claims 1-7, wherein G is 9. The compound of any one of claims 1-7, wherein G is . 10. The compound of any one of claims 1-7, wherein G is . 11. The compound of any one of claims 1-7, wherein G is 12. The compound of any one of claims 1-11, wherein: R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. 13. The compound of any one of claims 1-11, wherein: R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. 14. The compound of any one of claims 1-11, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, CH O C( O)R26 CH O C( O)OR26 15. The compound of any one of claims 1-11, wherein: R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. 16. The compound of any one of claims 1-11, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. 17. The compound of any one of claims 1-11, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. 18. The compound of any one of claims 1-11, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. 19. The compound of any one of claims 1-18, wherein R11 is hydrogen, -C(=O)R21, or C1-C6alkyl optionally substituted with one or more R11a. 20. The compound of any one of claims 1-19, wherein R11 is hydrogen or -C(=O)R21. 21. The compound of any one of claims 1-20, wherein R11 is hydrogen. 22. The compound of any one of claims 1-20, wherein R11 is -C(=O)R21. 23. The compound of any one of claims 1-22, wherein R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. 24. The compound of any one of claims 1-23, wherein R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 25. The compound of any one of claims 1-24, wherein R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 26. The compound of any one of claims 1-25, wherein R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl. 27. The compound of any one of claims 1-26, wherein R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl. 28. The compound of any one of claims 1-26, wherein R12 is hydrogen or -C(=O)R22. 29. The compound of any one of claims 1-26, wherein R12 is hydrogen, or -C(=O)OR22. 30. The compound of any one of claims 1-26, wherein R12 is hydrogen or C1-C6alkyl. 31. The compound of any one of claims 1-30, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. 32. The compound of any one of claims 1-31, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 33. The compound of any one of claims 1-32, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). 34. The compound of any one of claims 1-33, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 35. The compound of any one of claims 1-30, wherein R22 is C1-C6alkyl or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. 36. The compound of any one of claims 1-30, wherein each R22a is independently halogen, -CN, - OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 37. The compound of any one of claims 1-36, wherein each R22a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 38. The compound of any one of claims 1-36, wherein each R22a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 39. The compound of any one of claims 1-36, wherein each R22a is independently halogen, - OC(=O)Ra, or -NRcRd. 40. The compound of any one of claims 1-39, wherein R15 is hydrogen, -C(=O)R25, or -CH2-O- C(=O)R25. 41. The compound of any one of claims 1-40, wherein R15 is hydrogen or -C(=O)R25. 42. The compound of any one of claims 1-41, wherein R15 is -C(=O)R25. 43. The compound of any one of claims 1-41, wherein R15 is hydrogen. 44. The compound of any one of claims 1-43, wherein R25 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a. 45. The compound of any one of claims 1-43, wherein R25 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), or C1-C6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R25a. 46. The compound of any one of claims 1-43, wherein R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R25a. 47. The compound of any one of claims 1-46, wherein each R25a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 48. The compound of any one of claims 1-46, wherein each R25a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 49. The compound of any one of claims 1-48, wherein R16 is -C(=O)R26. 50. The compound of any one of claims 1-49, wherein R26 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R26a. 51. The compound of any one of claims 1-49, wherein R26 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. 52. The compound of any one of claims 1-49, wherein R26 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R26a. 53. The compound of any one of claims 1-52, wherein each R26a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 54. The compound of any one of claims 1-52, wherein each R26a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 55. A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (III); wherein: X is hydrogen or -CN; G ; R1 s y rogen, - , - , or 1- 6a y op ona y su s uted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a; each R16a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R16a on the same atom are taken together to form an oxo; R26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R26a on the same atom are taken together to form an oxo; or two R26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo; provided that when G hydrogen; then at least one of R11, R12, or R16 is not hydrogen. 56. The compound of claim 55, wherein X is hydrogen. 57. The compound of claim 55, wherein X is -CN. 58. The compound of any one of claims 55-57, wherein R13 is hydrogen. 59. The compound of any one of claims 55-57, wherein R13 is C1-C6alkyl. 60. The compound of any one of claims 55-59, wherein R14 is -OH. 61. The compound of any one of claims 55-59, wherein R14 is fluoro. 62. The compound of any one of claims 55-61, wherein G is . 63. The compound of any one of claims 55-61, wherein G is . 64. The compound of any one of claims 55-61, wherein G is . 65. The compound of any one of claims 55-61, wherein G i . 66. The compound of any one of claims 55-65, wherein: R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 67. The compound of any one of claims 55-65, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 68. The compound of any one of claims 55-65, wherein: R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 69. The compound of any one of claims 55-65, wherein: R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 70. The compound of any one of claims 55-65, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 71. The compound of any one of claims 55-65, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 72. The compound of any one of claims 55-65, wherein: R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. 73. The compound of any one of claims 52-69, wherein R11 is hydrogen, -C(=O)R21, or C1-C6alkyl optionally substituted with one or more R11a. 74. The compound of any one of claims 55-73, wherein R11 is hydrogen or -C(=O)R21. 75. The compound of any one of claims 55-73, wherein R11 is hydrogen. 76. The compound of any one of claims 55-73, wherein R11 is -C(=O)R21. 77. The compound of any one of claims 55-76, wherein R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. 78. The compound of any one of claims 55-76, wherein R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 79. The compound of any one of claims 55-76, wherein R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 80. The compound of any one of claims 55-79, wherein R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl. 81. The compound of any one of claims 55-79, wherein R12 is -C(=O)R22, -C(=O)OR22, or C1- C6alkyl. 82. The compound of any one of claims 55-79, wherein R12 is hydrogen or -C(=O)R22. 83. The compound of any one of claims 55-79, wherein R12 is hydrogen, or -C(=O)OR22. 84. The compound of any one of claims 55-79, wherein R12 is hydrogen or C1-C6alkyl. 85. The compound of any one of claims 55-79, wherein R12 is -C(=O)OR22. 86. The compound of any one of claims 55-85, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. 87. The compound of any one of claims 55-85, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 88. The compound of any one of claims 55-85, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). 89. The compound of any one of claims 55-85, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 90. The compound of any one of claims 55-85, wherein R22 is C1-C6alkyl or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. 91. The compound of any one of claims 55-90, wherein each R22a is independently halogen, -CN, - OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 92. The compound of any one of claims 55-90, wherein each R22a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 93. The compound of any one of claims 55-90, wherein each R22a is independently halogen, -OH, - ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 94. The compound of any one of claims 55-90, wherein each R22a is independently halogen, - OC(=O)Ra, or -NRcRd. 95. The compound of any one of claims 55-94, wherein R15 is -C(=O)R25. 96. The compound of any one of claims 55-95, wherein R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R25a. 97. The compound of any one of claims 55-95, wherein R25 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R25a. 98. The compound of any one of claims 55-95, wherein R25 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R25a. 99. The compound of any one of claims 55-95, wherein each R25a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 100. The compound of any one of claims 55-99, wherein each R25a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 101. The compound of any one of claims 55-99, wherein R16 is hydrogen, -C(=O)R26, or -CH2-O- C(=O)R26. 102. The compound of any one of claims 55-99, wherein R16 is hydrogen or -C(=O)R26. 103. The compound of any one of claims 55-99, wherein R16 is -C(=O)R26. 104. The compound of any one of claims 55-99, wherein R16 is hydrogen. 105. The compound of any one of claims 55-99, wherein R16 is -CH2-O-C(=O)R26. 106. The compound of any one of claims 55-105, wherein R26 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a. 107. The compound of any one of claims 55-105, wherein R26 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), or C1-C6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R26a. 108. The compound of any one of claims 55-105, wherein R26 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R26a. 109. The compound of any one of claims 55-108, wherein each R26a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 110. The compound of any one of claims 55-108, wherein each R26a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 111. A compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (IV); wherein: X is hydrogen or -CN; G is ; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. 112. The compound of claim 111, wherein X is hydrogen. 113. The compound of claim 111, wherein X is -CN. 114. The compound of any one of claims 111-113, wherein R13 is hydrogen. 115. The compound of any one of claims 111-113, wherein R13 is C1-C6alkyl. 116. The compound of any one of claims 111-115, wherein R14 is -OH. 117. The compound of any one of claims 111-115, wherein R14 is fluoro. 118. The compound of any one of claims 111-117, wherein R12 is -C(=O)R22, -C(=O)OR22, or C1- C6alkyl. 119. The compound of any one of claims 111-117, wherein R12 is -C(=O)R22. 120. The compound of any one of claims 111-117, wherein R12 is -C(=O)OR22. 121. The compound of any one of claims 111-117, wherein R12 is C1-C6alkyl. 122. The compound of any one of claims 111-121, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. 123. The compound of any one of claims 111-121, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 124. The compound of any one of claims 111-121, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). 125. The compound of any one of claims 111-121, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 126. The compound of any one of claims 111-121, wherein R22 is C1-C6alkyl or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. 127. The compound of any one of claims 111-126, wherein each R22a is independently halogen, -CN, - OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 128. The compound of any one of claims 111-126, wherein each R22a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 129. The compound of any one of claims 111-126, wherein each R22a is independently halogen, -OH, - ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 130. The compound of any one of claims 111-126, wherein each R22a is independently halogen, - OC(=O)Ra, or -NRcRd. 131. The compound of any one of claims 111-130, wherein R15 is -C(=O)R25. 132. The compound of any one of claims 111-130, wherein R15 is -C(=O)OR25. 133. The compound of any one of claims 111-130, wherein R15 is -CH2-O-C(=O)R25. 134. The compound of any one of claims 111-133, wherein R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R25a. 135. The compound of any one of claims 111-133, wherein R25 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R25a. 136. The compound of any one of claims 111-133, wherein R25 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R25a. 137. The compound of any one of claims 111-136, wherein each R25a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 138. The compound of any one of claims 111-136, wherein each R25a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 139. A compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (V); wherein: X is hydrogen or -CN; G is ; R12 is -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a; each R16a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R16a on the same atom are taken together to form an oxo; R26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R26a on the same atom are taken together to form an oxo; or two R26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. 140. The compound of claim 139, wherein X is hydrogen. 141. The compound of claim 139, wherein X is -CN. 142. The compound of any one of claims 139-141, wherein R13 is hydrogen. 143. The compound of any one of claims 139-141, wherein R13 is C1-C6alkyl. 144. The compound of any one of claims 139-143, wherein R14 is -OH. 145. The compound of any one of claims 139-143, wherein R14 is fluoro. 146. The compound of any one of claims 139-145, wherein R12 is -C(=O)R22, -C(=O)OR22, or C1- C6alkyl. 147. The compound of any one of claims 139-146, wherein R12 is -C(=O)R22. 148. The compound of any one of claims 139-146, wherein R12 is -C(=O)OR22. 149. The compound of any one of claims 139-146, wherein R12 is C1-C6alkyl. 150. The compound of any one of claims 139-149, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. 151. The compound of any one of claims 139-149, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 152. The compound of any one of claims 139-149, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). 153. The compound of any one of claims 139-149, wherein R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 154. The compound of any one of claims 139-149, wherein R22 is C1-C6alkyl or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. 155. The compound of any one of claims 139-154, wherein each R22a is independently halogen, -CN, - O Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C( alkyl, or C1-C6haloalkyl. 156. The compound of any one of claims 139-154, wherein each R22a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 157. The compound of any one of claims 139-154, wherein each R22a is independently halogen, -OH, - ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 158. The compound of any one of claims 139-154, wherein each R22a is independently halogen, - OC(=O)Ra, or -NRcRd. 159. The compound of any one of claims 139-158, wherein R15 is hydrogen. 160. The compound of any one of claims 139-158, wherein R15 is -C(=O)R25. 161. The compound of any one of claims 139-158, wherein R15 is -C(=O)OR25. 162. The compound of any one of claims 139-161, wherein R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R25a. 163. The compound of any one of claims 139-161, wherein R25 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R25a. 164. The compound of any one of claims 139-161, wherein R25 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R25a. 165. The compound of any one of claims 139-164, wherein each R25a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 166. The compound of any one of claims 139-164, wherein each R25a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 167. The compound of any one of claims 139-166, wherein R16 is -C(=O)R26. 168. The compound of any one of claims 139-166, wherein R16 is -C(=O)OR26. 169. The compound of any one of claims 139-168, wherein R26 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a. 170. The compound of any one of claims 139-169, wherein R26 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). 171. The compound of any one of claims 139-168, wherein R26 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). 172. The compound of any one of claims 139-168, wherein R26 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). 173. The compound of any one of claims 139-168, wherein R26 is C1-C6alkyl or C1-C6aminoalkyl. 174. The compound of any one of claims 139-173, wherein each R26a is independently halogen, -CN, - OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 175. The compound of any one of claims 139-173, wherein each R26a is independently halogen, -CN, - OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 176. The compound of any one of claims 139-173, wherein each R26a is independently halogen, -OH, - ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. 177. The compound of any one of claims 139-173, wherein each R26a is independently -OC(=O)Ra, or -NRcRd. 178. A compound of Formula (VIa), (VIb), or (VIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (VIa) Formula (VIb) Formula (VIc); wherein: X is hydrogen or -CN; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a; each R16a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R16a on the same atom are taken together to form an oxo; R26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R26a on the same atom are taken together to form an oxo; or two R26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. 179. A compound selected from a compound found in table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 180. A pharmaceutical composition comprising the compound of any one of claims 1-179, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier. 181. A method of treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-179, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 180. 182. The method of claim 181, further comprising administering at least one antiviral agent in combination with the compound of any one of claims 1-179, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 180. 183. The method of claim 181 or 182, wherein the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), "African Swine Fever Viruses," Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papiloma virus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Poxviridae, Potyviridae, Reoviridae, Retroviridae, Rhabdoviridae, Tectiviridae, Togaviridae, pox, papilloma, corona, influenza, sendai virus (SeV), sindbis virus (SINV), vaccinia viruses, West Nile, Hanta, viruses which cause the common cold, and any combination thereof. 184. The method of any one of claims 181-183, wherein the viral infection is caused by coronavirus disease 2019 (SARS-CoV-2). 185. The method of any one of claims 181-183, wherein the viral infection is caused by a Ebolavirus. 186. The method of claim 185, wherein the Ebolavirus is Zaira Ebolavirus (Ebola virus). 187. The method of any one of claims 181-186, wherein the at least one antiviral agent is remdesivir, ribavirin, favipiravir, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, idoxuridine, edoxudine, trifluridine, vidarabine, brivudine, acyclovir, ganciclovir, valaciclovir, cidofovir, valganciclovir, penciclovir, famciclovir, zidovudine, didanosine, zalcitabine, stavudine, abacavir, lamivudine, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, adefovir, entecavir, telbivudine, sofosbuvir, or a mixture thereof. 188. The method of any one of claims 181-186, wherein the at least one antiviral agent is molnupiravir. 189. The method of any one of claims 181-186, wherein the at least one antiviral agent is a ribonucleic acid (RNA)-dependent RNA polymerase inhibitor, a checkpoint inhibitor or PD- 1/PD-L1 inhibitor, a therapeutic vaccine, an RNA interference (RNAi) therapeutic, an antisense- based therapeutic, an coronavirus entry inhibitor, a TLR agonist; an RIG-I agonist, or an interferon. |
Step 1. Synthesis of 2-(octadecyloxy)ethyl dihydrogen phosphate (6.2). [00337] To a solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (100 mg, 0.317 mmol) in THF (3 mL) and triethylamine (64 mg, 0.635 mmol) was added phosphoryl trichloride (97 mg, 0.635 mmol) in THF (1 mL), the solution was stirred at 0 °C for 1 h, then water was added and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with ethyl ether (5 mL x 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 6.2 (80 mg, 57% yield) as a yellow solid. MS (ESI): m/z calcd. for C20H43O5P 394.53, found 393.0 [M-H]-. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 6.4 Hz, 2H), 4.11 - 3.96 (m, 3H), 3.48 - 3.37 (m, 4H), 2.45 (s, 3H), 1.51 (quint, J = 6.4 Hz, 2H), 1.29 - 1.24 (m, 30H), 0.88 (t, J = 6.8 Hz, 3H). Step 2. Synthesis of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol e-4-carbonitrile (6.4). [00338] To a solution of 6.3 (prepared according to Siegel, D., et al., J. Med. Chem.2017, 60, 1648−1661, 2 g, 0.006 mol) and 2,2-dimethoxypropane (3.45 g, 0.033 mol) in acetone (50 mL) was added sulfuric acid (0.90 g, 98%) dropwise at 25 °C for 0.5 h, then heated to 45 °C for 0.5 h. The reaction mixture was quenched by NaHCO3 (sat. aqueous, 10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH/DCM from 0% to 5%) to obtain 6.4 (2.3 g, 96% yield) as a white solid. MS (ESI): m/z calcd. for C15H17N5O4331.33, found 332.0 [M+H] + . Step 3. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-(octadecyloxy)ethyl) hydrogen phosphate (6.5). [00339] To a solution of 6.4 (262 mg, 0.663 mmol), 6.2 (200 mg, 0.603 mmol) and 4- dimethylaminopyridine (66 mg, 0.543 mmol) in pyridine (10 mL) was added DCC (249 mg, 1.207 mmol), the resulting mixture was stirred at 90 °C for 16 h. The solution was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC to afford 6.5 (150 mg, 33% yield) as a white solid. MS (ESI): m/z calcd. for C35H58N5O8P 707.85, found 706.3 [M-H]-. Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (2-(octadecyloxy)ethyl) hydrogen phosphate (6). [00340] To a solution of 6.5 (150 mg, 0.211 mmol) in THF (5 mL) was added HCl (0.3 mL, 12 M aqueous) dropwise at 0 °C, the mixture was stirred at 25 °C for 16 h. The reaction was quenched by NaHCO3 (sat. aqueous, 5 mL), concentrated under reduced pressure and purified by prep-HPLC to afford the title compound (120.88 mg, 84% yield) as a white solid. MS (ESI): m/z calcd. for C32H54N5O8P 667.78, found 666.4 [M-H]-. 1 H NMR (400 MHz, MeOD) δ 7.91 (s, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.95 (d, J = 5.2 Hz, 1H), 4.85 (d, J = 5.2 Hz, 1H), 4.36 - 4.32 (m, 1H), 4.27 (t, J = 5.2 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.90 - 3.81 (m, 2H), 3.48 - 3.45 (m, 2H), 3.40 - 3.35 (m, 2H), 1.55 - 1.48 (m, 2H), 1.29 - 2.25 (m, 30H), 0.92 (t, J = 6.4 Hz, 3H). 31 P NMR (162 MHz, CD 3 OD) δ 0.36. Example 7. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) hydrogen phosphate (Compound 7).
Step 1. Synthesis of (S)-2-hydroxy-3-(octadecyloxy)propyl 4-methylbenzenesulfonate (7.2). [00341] To a solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (7.1, 1.0 g, 4.39 mmol) and octadecan-1-ol (1.7 g, 6.1 mmol) in dry DCM (20 mL) was added boron trifluoride etherate (8 drops) dropwise at 25 °C under N 2 . The reaction mixture was stirred at 25 °C for 16 h, then the solution was concentrated to dryness. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 20%) to give 7.2 (1.4 g, 63% yield) as a white solid. MS (ESI): mass calcd. for C28H50O5S, 498.34, m/z found 499 [M+H] + . Step 2. Synthesis of (R)-2-(benzyloxy)-3-(octadecyloxy)propyl 4-methylbenzenesulfonate (7.3). [00342] To a solution of 7.2 (1.0 g, 2.01 mmol) in 1,4-dioxane (20 mL) was added benzyl 2,2,2- trichloroacetimidate (1.0 g, 3.98 mmol) under N2, followed by trifluoromethanesulfonic acid (9 drops). The reaction mixture was stirred at 25 °C for 1 h. TLC showed complete consumption of 7.2. The reaction mixture was diluted with DCM (60 mL) and washed with saturated aqueous NaHCO3 (20 mL x 2), followed by water (20 mL), then the organic phase was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 20%) to give 7.3 (0.85 g, 80% purity, 60% yield) as a colorless oil, and used directly in the next step. Step 3. Synthesis of (R)-2-(benzyloxy)-3-(octadecyloxy)propan-1-ol (7.4). [00343] To a solution of 7.3 (0.70 g, 1.19 mmol) in dry DMF (2.5 mL) and dry DMSO (10 mL) was added cesium acetate (0.48 g, 2.50 mmol) under N2. The reaction mixture was stirred at 60 °C for 16 h. TLC showed complete consumption of starting material 7.3. The reaction mixture was quenched with water (15 mL) and extracted with ether (10 mL x 3). The organic phase was separated and washed with water (12 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness, re-evaporated with toluene. The residue was dissolved with ether (10 mL) and LiAlH4 (90 mg, 2.4 mmol) was added at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and 3 h at 25 °C. TLC showed complete consumption of intermediate. The reaction mixture was quenched by very slow addition of water (5.0 mL). The mixture was filtered through celite. The mixture was separated and the aqueous phase was extracted with DCM (3.0 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 20%) to give 7.4 (0.34 g, 52% yield) as a milk white oil. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.27 (m, 5H), 4.73 - 4.61 (dd, J = 36.0, 11.6 Hz, 2H), 3.78 - 3.52 (m, 5H), 3.44 (td, J = 6.8, 1.6 Hz, 2H), 1.57 (quint, J = 7.2 Hz, 2H), 1.33 - 1.24 (m, 30H), 0.88 (t, J = 7.2 Hz, 3H). Step 4. Synthesis of (S)-2-(benzyloxy)-3-(octadecyloxy)propyl dihydrogen phosphate (7.5). [00344] To a solution of 7.4 (0.34 g, 0.77 mmol) in dry THF (8.0 mL) was added a solution of triethylamine (78 mg, 0.77 mmol) and pyridine (61 mg, 0.77 mmol) in dry THF (1.0 mL) under N2 at 0 °C. The reaction mixture was stirred for 5 min, and phosphoryl trichloride (0.24 g, 1.5 mmol) was added into the flask vessel dropwise at 0 °C. The reaction mixture was stirred for 4 h at 0 °C. Then water (5.0 mL) was added very slowly into the flask vessel. The reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was extracted with ether (10 mL x 3). The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness to give 7.5 (0.40 g, crude) as a milk white oil. MS (ESI): mass calcd. for C28H51O6P, 514.34, m/z found 513 [M-H]-. 1 H NMR (400 MHz, CDCl3) δ 7.35 - 7.26 (m, 5H), 6.18 (br, 5H), 4.67 (dd, J = 25.7, 11.8 Hz, 2H), 4.20 - 3.99 (m, 2H), 3.79 (quint, J = 4.8 Hz, 1H), 3.58 - 3.51 (m, 2H), 3.42 (td, J = 6.8, 1.9 Hz, 2H), 1.53 (quint, J = 6.4 Hz, 2H), 1.30 - 1.24 (m, 30H), 0.88 (t, J = 7.2 Hz, 3H). Step 5. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) hydrogen phosphate (7.6). [00345] To a solution of 7.5 (0.40 g, 0.77 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahy drofuro[3,4-d][1,3]dioxole-4-carbonitrile, 6.4 (0.23 g, 0.69 mmol), and DMAP (94 mg, 0.77 mmol) in pyridine (40 mL) was added DCC (0.24 mg, 1.2 mmol). The reaction mixture was stirred for 24 h at 90 °C under N 2 . The reaction mixture was concentrated to dryness and the residue was purified by Prep-HPLC [Gradient: 50-95% MeOH in water (0.1% NH3·H2O)] to give 7.6 (0.28 g, 43% yield) as a white solid. MS (ESI): mass calcd. for C 43 H 66 N 5 O 9 P, 827.46, m/z found 826 [M-H]-. 1 H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.40 - 7.12 (m, 6H), 7.08 (d, J = 4.7 Hz, 1H), 5.31 (d, J = 6.3 Hz, 1H), 5.07 (dd, J = 6.3, 2.5 Hz, 1H), 4.68 - 4.58 (m, 3H), 4.06 (t, J = 4.7 Hz, 2H), 3.97 - 3.86 (m, 2H), 3.74 (quint, J = 5.2 Hz, 1H), 3.58 - 3.48 (m, 2H), 3.43 (t, J = 6.8 Hz, 2H), 1.73 (s, 3H), 1.55 (quint, J = 6.8 Hz, 2H), 1.42 (s, 3H), 1.38 - 1.26 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). Step 6. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (2-(octadecyloxy)ethyl) hydrogen phosphate (7). [00346] To a solution of 7.6 (0.10 g, 0.12 mmol) in dry THF (5.0 mL) was added a solution of conc. aqueous HCl (0.05 mL) in dry THF (0.5 mL). The reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was evaporated to dryness with a stream of nitrogen. The residue was purified by prep- HPLC [Gradient: 50% - 95% MeOH in water (0.1% NH3·H2O)] to give the title compound (74% yield) as a white solid. MS (ESI): mass calcd. for C40H62N5O9P, 787.43, m/z found 786 [M-H]-. 1 H NMR (400 MHz, MeOD) δ 7.96 (s, 1H), 7.36 - 7.20 (m, 5H), 7.10 (d, J = 4.7 Hz, 2H), 4.79 (d, J = 5.2 Hz, 1H), 4.63 (q, J = 11.9 Hz, 2H), 4.37 - 4.33 (m, 1H), 4.26 (t, J = 5.4 Hz, 1H), 4.19 - 4.03 (m, 2H), 3.91 (tq, J = 10.9, 5.4 Hz, 2H), 3.73 (quint, J = 4.8 Hz, 1H), 3.57 - 3.45 (m, 2H), 3.41 (t, J = 6.0 Hz, 2H), 1.53 (quint, J = 6.8 Hz, 2H), 1.37 - 1.27 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). Example 8. Synthesis of 16-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphory l)oxy)hexadecanoic acid (Compound 8 Step 1. Synthesis of methyl 16-hydroxyhexadecanoate (8.2). [00347] To a solution of 16-hydroxyhexadecanoic acid (8.1, 50 mg, 0.183 mmol) in MeOH (4 mL) was added p-TSA (13 mg, 0.073 mmol), then the mixture was stirred at 25 °C for 16 h. The reaction was quenched by NaHCO3 (50 mg) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 30%) to obtain 8.2 (40 mg, 76% yield) as a white solid. MS (ESI): m/z calcd. for C17H34O3286.25, found 285.0 [M-H]-. Step 2. Synthesis of methyl 16-(phosphonooxy)hexadecanoate (8.3). [00348] To a solution of 8.2 (50 mg,0.174 mmol) in THF (3 mL) and triethylamine (35 mg, 0.349 mmol) was added a solution of phosphoryl trichloride (54 mg, 0.349 mmol) in THF (1 mL) dropwise, the solution was stirred at 0 °C for 1 h, then water was added and the resulting mixture was stirred at 25 °C for 16 h. The solution was extracted with ethyl ether (5 mL x 3). The combined organic phase was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 8.3 (50 mg, 70% yield) as a white solid. MS (ESI): m/z calcd. for C17H35O6P 366.43, found 365.0 [M-H]-. Step 3. Synthesis of methyl 16-(((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazi n-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(hydroxy)phosphoryl)oxy)hexadecanoate (8.4). [00349] To a solution of 8.3 (50 mg, 0.136 mmol), 4 (50 mg, 0.15 mmol) and 4-dimethylaminopyridine (15 mg, 0.122 mmol) in pyridine (5 mL) was added DCC (59 mg, 0.286 mmol), the resulting mixture was stirred at 90 °C for 16 h. The solution was concentrated under reduced pressure to a residue, which was purified by prep-HPLC to afford 8.4 (150 mg, 33% yield) as a white solid. MS (ESI): m/z calcd. for C 32 H 50 N 5 O 9 P 679.75, found 678.0 [M-H]-. Step 4. Synthesis of 16-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)ox y)hexadecanoic acid. [00350] To a solution of 8.4 (400 mg, 0.588 mmol) in THF (5 mL) was added HCl (5 mL, 12 M) dropwise at 0 °C, the mixture was stirred at 25 °C for 16 h. The reaction was quenched by NaHCO 3 (sat. aqueous, 10 mL) and concentrated under reduced pressure to get the crude product. The residue was redispersed in MeOH (5 mL) and purified by prep-HPLC to afford the title compound (85.0 mg, 23% yield) as a white solid. MS (ESI): m/z calcd. for C 28 H 44 N 5 O 9 P 625.66, found 624.3 [M-H]-. 1 H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 6.89 (d, J = 5.2 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H), 4.75 (d, J = 5.2 Hz, 1H), 4.25 - 4.20 (m, 1H), 4.16 (t, J = 5.2 Hz, 1H), 3.94 - 3.90 (m, 2H), 3.60 - 3.58 (m, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.51 - 1.48 (m, 2H), 1.38 - 1.35 (m, 2H), 1.25 - 1.12 (m, 22H). 31 P NMR (162 MHz, CD 3 OD) δ 0.54. Example 9. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahyd f 2 l th l 3 th lb t t C d 9 [00351] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and 3-methylbutyryl chloride. MS (ESI): mass calcd. for C17H21N5O5, 375.15, m/z found 376.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (br s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6 Hz, 1H), 5.37 (d, J = 6 Hz, 1H), 4.68 (d, J = 5.2 Hz, 1H), 4.3 (d, J = 6 Hz, 1H), 4.1-4.2 (m, 2H), 3.91 (m, 1H), 2.15 (m, 2H), 1.92 (m, 1H), 0.86 (m, 6H). Example 10. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 10). [00352] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and cyclohexylacetyl chloride. MS (ESI): mass calcd. for C20H25N5O5, 415.19, m/z found 416.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6 Hz, 1H), 5.37 (d, J = 6 Hz, 1H), 4.68 (d, J = 5.2 Hz, 1H), 4.22 (d, J = 6 Hz, 1H), 3.9-4.15 (m, 2H), 3.92 (m, 1H), 2.07 (m, 2H), 1.5 (br m, 6H), 1.0-1.2 (m, 3H), 0.86-1.1 (m, 2H). Example 11. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 12). [00353] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and phenylacetyl chloride. MS (ESI): mass calcd. for C20H19N5O5, 409.14, m/z found 410.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (br s, 2H), 7.95 (s, 1H), 7;.21-7.28 (m, 5H), 6.91 (d, J = 4.4 Hz, 1H), 6.79 (d, J = 4.4 Hz, 1H), 6.3 (br s, 1H), 5.39 (br s, 1H), 4.65 (d, J = 4.8 Hz, 1H), 4.35 (m, 1H), 3.9-4.2 (m, 2H), 3.67 (m, 2H). Example 12. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrof ran-2- l)meth l isob t rate (Com o nd 14) [00354] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and isobutyryl chloride. MS (ESI): mass calcd. for C16H19N5O5, 361.1, m/z found 362.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (br s, 3H), 6.90 (d, J = 4.8 Hz, 1H), 6.80 (d, J = 4.8 Hz, 1H), 6.31 (d, J = 6 Hz, 1H), 5.37 (d, J = 6 Hz, 1H), 4.68 (d, J = 5.2 Hz, 1H), 4.1-4.3 (m, 3H), 3.93 (m, 1H), 2.53 (m, 1H), 1.05 (m, 6H). Example 13. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl propionate (Compound 15). [00355] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and propanoyl chloride. MS (ESI): mass calcd. for C15H17N5O5, 347.1, m/z found 347.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6 Hz, 1H), 5.37 (d, J = 6 Hz, 1H), 4.68 (d, J = 5.2 Hz, 1H), 4.34 (d, J = 6 Hz, 1H), 3.9-4.2 (m, 2H), 3.91 (m, 1H), 2.3 (q, J = 7.6 Hz, 2H), 1.0 (t, J = 7.6 Hz, 3H). Example 14. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4- hydroxy-2-{[(3-methylbutanoyl)oxy]methyl}oxolan-3-yl (2S)-2-amino-3-methylbutanoate (Compound 19). Step 1. Synthesis of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 3-{[(2S)-2-{[(tert- butoxy)carbonyl]amino}-3-methylbutanoyl]oxy}-5-cyano-4-hydro xyoxolan-2-yl]methyl 3- methylbutanoate (19.1). [00356] To a solution of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano-3,4- dihydroxyoxolan-2-yl]methyl 3-methylbutanoate (9, 300 mg, 0.799 mmol) in THF (15 mL) was added (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoic acid (173.43 mg, 0.799 mmol), EDCI (459.62 mg, 2.397 mmol) and DMAP (292.91 mg, 2.397 mmol), the mixture was stirred at 25 o C for 16 h. The reaction was washed with EtOAc (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 19.1 (70 mg, 14% yield) as a white solid. MS (ESI): m/z calcd. for C 27 H 38 N 6 O 8 574.28, found 575.2 [M+H] + . Step 2. Synthesis of Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 - cyano-4-hydroxy-2-{[(3-methylbutanoyl)oxy]methyl}oxolan-3-yl (2S)-2-amino-3-methylbutanoate (19). [00357] To a solution of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 3-{[(2S)-2- {[(tert-butoxy)carbonyl]amino}-3-methylbutanoyl]oxy}-5-cyano -4-hydroxyoxolan-2-yl]methyl 3- methylbutanoate (19.1, 100 mg, 0.174 mmol) in THF (5 mL) was added HCl in dioxane (4M, 3 mL), the mixture was stirred at 25 o C for 4 h. the mixture was stirred at 25 o C for 16 h. The reaction was concentrated in vacuo and purified by prep-HPLC to afford 19 (35.89 mg, 39% yield) as a white solid. MS (ESI): m/z calcd. for C22H30N6O6474.22, found 475.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93- 7.90 (br, s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.62-6.60 (m, 1H), 5.12-5.10 (m, 2H), 4.45-4.43 (m, 1H), 4.27 (dd, J = 12.0, 4.4 Hz, 1H), 4.24 (dd, J = 12.0, 4.8 Hz, 1H), 3.23 (d, J = 5.2 Hz, 1H), 2.16-2.15 (m, 2H), 1.99-1.97 (m, 1H), 1.93-1.91 (m, 1H), 0.93-0.83 (m, 12H). Example 15. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-((pivaloyloxy)methoxy)tetrahydrofuran-2-yl)methyl 3-methylbutanoate (Compound 24). [00358] To a suspension of 9 (100 mg, 0.266 mmol), dibutyltin oxide (86.2 mg, 0.346 mmol) and tetrabutylammonium bromide (112 mg, 0.346 mmol) in DCE (1.0 mL) was added iodomethyl pivalate (161 mg, 0.666 mmol). The reaction mixture was stirred at 75 °C for 2 h under nitrogen. The reaction mixture was diluted with EA (5.0 mL) and washed with Sat. aq. Na 2 S 2 O 3 (3.0 mL × 2), followed by water (3.0 mL × 2), brine (3.0 mL). The organic phase was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by Prep-HPLC to give 24 (22.09 mg, 16% yield) as a white solid. MS (ESI): m/z calcd. for C23H31N5O7489.22, found 490.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.8 Hz, 1H), 6.50 (d, J = 6.0 Hz, 1H), 5.32 (dd, J = 23.2, 6.4 Hz, 2H), 5.00 – 4.95 (dd, J = 6.0, 4.8 Hz, 1H), 4.37 – 4.28 (m, 2H), 4.18 – 4.09 (m, 2H), 2.14 (d, J = 7.2 Hz, 2H), 1.97 – 1.86 (m, 1H), 1.11 (s, 9H), 0.86 (dd, J = 6.8, 4.0 Hz, 6H). Example 16. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-2- {[(2-cyclohexylacetyl)oxy]methyl}-4-hydroxyoxolan-3-yl (2S)-2-amino-3-methylbutanoate (Com o nd 27) Step 1. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-2-{[(2- cyclohexylacetyl)oxy]methyl}-4-hydroxyoxolan-3-yl (2S)-2-amino-3-methylbutanoate (27.1). [00359] The compound 27.1 was prepared according to the procedure of Example 19, Step 1, using 10 and (2S)-2-{[(tert-butoxy) carbonyl] amino}-3-methylbutanoic acid. MS (ESI): mass calcd. for C30H42N6O8, 614.31, m/z found 615.3 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-2-{[(2- cyclohexylacetyl)oxy]methyl}-4-hydroxyoxolan-3-yl (2S)-2-amino-3-methylbutanoate (27). [00360] The title compound 27 was prepared according to the procedure of Example 19, Step 2, using 27.1. MS (ESI): mass calcd. for C25H34N6O6, 514.25, m/z found 515.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92-7.90 (br, s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H), 5.12-5.09 (m, 2H), 4.44-4.40 (m, 1H), 4.29 (dd, J = 12.0, 3.6 Hz, 1H), 4.22 (dd, J = 12.0, 4.8 Hz, 1H), 3.23 (d, J = 5.2 Hz, 1H), 2.19 – 2.12 (m, 2H), 2.03 – 1.96 (m, 1H), 1.57-1.50 (m, 6H), 1.15-1.05 (m, 3H), 0.94-0.85 (m, 8H). Example 17. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-((3-methylbutanoyl)oxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 33). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (tert-butoxycarbonyl)-L-valinate (33.1). [00361] The title compound was prepared according to Example 16, Step 1, using intermediate acetonide 6.4. Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (33.2). [00362] To a solution of 33.1 (3.50 g, 6.6 mmol) in MeOH (70 mL) was added TsOH·H2O (2.51 g, 13.2 mmol) at 0 °C. The mixture was stirred at 0 o C for 30 minutes and then warmed up to 20 °C and stirred for 16 h. After completion, the mixture was concentrated in vacuo to afford a residue, the residue was purified by Prep-HPLC [Gradient: 40-60% ACN in water (0.1% FA)] to give 33.2 (1.25 g, 2.5 mmol, 37.8% yield) as a white solid. MS (ESI): m/z calcd. for C22H30N6O7, 490.22, found 491.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.05 (d, J = 70.8 Hz, 3H), 7.17 – 7.09 (m, 1H), 6.97 (d, J = 4.4 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 6.34 (s, 1H), 5.40 (s, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.38 – 4.18 (m, 3H), 3.98 – 3.83 (m, 2H), 1.96 (d, J = 6.8 Hz, 1H), 1.34 (d, J = 32.4 Hz, 9H), 0.82 (t, J = 6.0 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-((3-methylbutanoyl)oxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (33.3). [00363] To a solution of 33.2 (200 mg,0.40 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 3- methylbutanoyl chloride (0.25 mL, 2.0 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 33.3 (90 mg, 37.3% yield) as a white solid. MS (ESI): m/z calcd. for C27H38N6O8, 574.28, found 575.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br s, 3H), 7.16 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 5.17 – 4.99 (m, 2H), 4.49 – 4.44 (m, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.80 (dd, J = 44.0, 37.6 Hz, 1H), 2.26 (d, J = 7.2 Hz, 2H), 2.10 – 2.02 (m, 1H), 1.99 – 1.88 (m, 1H), 1.30 (d, J = 52.8 Hz, 9H), 0.93 (d, J = 6.8 Hz, 6H), 0.86 (d, J = 26.4 Hz, 1H), 0.78 (t, J = 6.8 Hz, 5H). Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-((3-methylbutanoyl)oxy)tetrahydrofuran-2-yl)methyl L-valinate (33). [00364] To a solution of 33.3 (60 mg, 0.104 mmol) in DCM (0.5 mL) was added HCl in 1,4-dioxane (0.5 mL, 4M) at 0 ℃, then the reaction was stirred at 20℃ for 1 hour. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 33 (37.6 mg, 71.1% yield) as a white solid. MS (ESI): m/z calcd. for C22H30N6O6, 474.22, found 475.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.64 (s, 1H), 5.15 – 5.07 (m, 2H), 4.47 (q, J = 4.4 Hz, 1H), 4.37 – 4.24 (m, 2H), 3.14 (d, J = 5.2 Hz, 1H), 2.26 (d, J = 7.2 Hz, 2H), 2.15 – 2.01 (m, 1H), 1.85 – 1.75 (m, 1H), 0.95 – 0.91 (m, 6H), 0.84 – 0.68 (m, 6H). Example 18. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl L-valinate (Compound 34). Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (34.1). [00365] The title compound was prepared according to the procedure of Example 33, Step 2, using 33.2 and 2-cyclohexylacetyl chloride. MS (ESI): m/z calcd. for C30H42N6O8, 614.31, found 615.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br s, 3H), 8.10 - 7.80 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 4.4 Hz, 2H), 6.87 (d, J = 4.4 Hz, 1H), 6.64 (d, J = 5.6 Hz, 1H), 5.08 (s, 2H), 4.45 (d, J = 3.2 Hz, 1H), 4.30 (s, 2H), 3.84 (t, J = 7.2 Hz, 1H), 2.25 (d, J = 6.8 Hz, 2H), 1.93 (dd, J = 13.2, 6.8 Hz, 1H), 1.75 - 1.55 (m, 6H), 1.37 (s, 7H), 1.25 - 1.11 (m 4H), 0.94 (d, J = 12.0 Hz, 2H), 0.77 (t, J = 7.2 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahyd f 2 l) th l L li t (34) [00366] The title compound was prepared according to the procedure of Example 33, Step 3, using 34.1. MS (ESI): m/z calcd. for C25H34N6O6, 514.25, found 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.63 (s, 1H), 5.16 – 5.04 (m, 2H), 4.47 (q, J = 4.4 Hz, 1H), 4.33 – 4.24 (m, 2H), 3.12 (d, J = 5.2 Hz, 1H), 2.26 (d, J = 6.8 Hz, 2H), 1.80 – 1.57 (m, 7H), 1.27 – 1.06 (m, 3H), 1.00 – 0.89 (m, 2H), 0.84 – 0.73 (m, 6H). Example 19. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(2-phenylacetoxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 36). Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(2-phenylacetoxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (36.1). [00367] The title compound was prepared according to the procedure of Example 33, Step 2, using 33.2 and 2-phenylacetyl chloride. MS (ESI): m/z calcd. for C 30 H 36 N 6 O 8 , 608.26, found 609.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 7.32 (d, J = 4.4 Hz, 4H), 7.28 – 7.23 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 4.4 Hz, 1H), 6.69 (d, J = 6.0 Hz, 1H), 5.11 (t, J = 5.2 Hz, 2H), 4.48 (d, J = 4.0 Hz, 1H), 4.33 – 4.24 (m, 2H), 3.88 – 3.66 (m, 3H), 1.91 (dt, J = 13.2, 6.8 Hz, 1H), 1.40 – 1.20 (m, 9H), 0.75 (dd, J = 8.8, 7.2 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(2-phenylacetoxy)tetrahydrofuran-2-yl)methyl L-valinate (36). [00368] The title compound was prepared according to the procedure of Example 33, Step 3, using 36.1. MS (ESI): m/z calcd. for C 25 H 28 N 6 O 6 , 508.21, found 509.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 7.32 (d, J = 4.0 Hz, 4H), 7.30 – 7.23 (m, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.69 (d, J = 6.4 Hz, 1H), 5.18 – 5.08 (m, 2H), 4.49 (q, J = 4.4 Hz, 1H), 4.28 (d, J = 4.4 Hz, 2H), 3.76 (q, J = 16.0 Hz, 2H), 3.10 (d, J = 5.2 Hz, 1H), 1.82 – 1.70 (m,, 1H), 0.78 (d, J = 6.8, 3H), 0.72 (d, J = 6.8 Hz, 3H). Example 20. Synthesis of ((2R,3S,4R,5R)-3-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]tria zin-7-yl)-5- cyano-4-h drox tetrah drofuran-2- l)meth l L-valinate (Com ound 37) Step 1. Synthesis of ((2R,3S,4R,5R)-3-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]tria zin-7-yl)-5-cyano- 4-hydroxytetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (37.1). [00369] The title compound was prepared according to the procedure of Example 33, Step 2, using 33.2 and acetyl chloride. 1 H NMR (400 MHz, DMSO) δ 7.93 (br s, 3H), 7.15 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 5.13 – 5.00 (m, 2H), 4.51 – 4.44 (m, 1H), 4.35 – 4.23 (m, 2H), 3.89 – 3.81 (m, 1H), 2.08 (s, 3H), 1.98 – 1.85 (m, 2H), 1.37 (s, 9H), 0.78 (t, J = 6.8 Hz, 6H). Step 2. Synthesis ((2R,3S,4R,5R)-3-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]tria zin-7-yl)-5-cyano-4- hydroxytetrahydrofuran-2-yl)methyl L-valinate (37). [00370] The title compound was prepared according to the procedure of Example 33, Step 3, using 37.1. MS (ESI): m/z calcd. for C19H24N6O6432.18, found 433.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.63 (d, J = 4.4 Hz, 1H), 5.16 – 4.99 (m, 2H), 4.52 – 4.46 (q, J = 4.4 Hz, 1H), 4.35 – 4.24 (m, 2H), 3.18 – 3.12 (m, 1H), 2.09 (s, 3H), 1.84 – 1.74 (m, 1H), 0.81 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H). Example 21. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(isobutyryloxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 38). Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(isobutyryloxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (38.1). [00371] The title compound was prepared according to the procedure of Example 33, Step 2, using 33.2 and 2-methylpropanoyl chloride. MS (ESI): m/z calcd. for C26H36N6O8560.26, found 561.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 7.16 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.4 Hz, 1H), 6.58 (d, J = 6.0 Hz, 1H), 5.17 – 5.07 (m, 2H), 4.46 (dd, J = 8.4, 4.8 Hz, 1H), 4.34 – 4.24 (m, 2H), 3.88 – 3.82 (m, 1H), 2.65 – 2.57 (m, 1H), 1.98 – 1.86 (m, 1H), 1.42 – 1.20 (m, 9H), 1.14 (t, J = 7.2 Hz, 6H), 0.77 (t, J = 7.2 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(isobutyryloxy)tetrahydrofuran-2-yl)methyl L-valinate (38). [00372] The title compound was prepared according to the procedure of Example 33, Step 3, using 38.1. MS (ESI): m/z calcd. for C21H28N6O6460.21, found 461.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.57 (d, J = 6.0 Hz, 1H), 5.18 – 5.08 (m, 2H), 4.50 – 4.43 (m, 1H), 4.37 – 4.23 (m, 2H), 3.12 (d, J = 4.0 Hz, 1H), 2.66 – 2.56 (m, 1H), 1.83 – 1.72 (m, 1H), 1.15 (t, J = 7.2 Hz, 6H), 0.77 (dd, J = 22.8, 6.8 Hz, 6H). Example 22. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 39).
Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (39.1). [00373] The title compound was prepared according to the procedure of Example 33, Step 2, using 33.2 and propionyl chloride. MS (ESI): m/z calcd. for C 25 H 34 N 6 O 8 , 546.24, found 547.30 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 3H), 7.16 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H), 5.17 – 5.03 (m, 2H), 4.47 (d, J = 4.4 Hz, 1H), 4.30 (d, J = 4.4 Hz, 2H), 3.80 (dd, J = 44.4, 37.6 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.93 (dt, J = 13.2, 6.4 Hz, 1H), 1.37 (s, 9H), 1.07 (t, J = 7.6 Hz, 3H), 0.78 (t, J = 6.8 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (39). [00374] The title compound was prepared according to the procedure of Example 33, Step 3, using 39.1. MS (ESI): m/z calcd. for C 20 H 26 N 6 O 6 , 446.19, found 447.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 5.18 – 5.05 (m, 2H), 4.49 (q, J = 4.4 Hz, 1H), 4.42 – 4.24 (m, 3H), 3.32 (d, J = 5.2 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.92 – 1.81 (m, 1H), 1.08 (t, J = 7.6 Hz, 3H), 0.86 – 0.75 (m, 6H). Example 23. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4- hydroxy-2-{[(2-phenylacetyl)oxy]methyl}oxolan-3-yl (2S)-2-amino-3-methylbutanoate (Compound 43 Step 1. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy- 2-{[(2-phenylacetyl)oxy]methyl}oxolan-3-yl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3- methylbutanoate (43.1). [00375] The compound 43.1 was prepared according to the procedure of Example 19, Step 1, using 12 and (2S)-2-{[(tert-butoxy) carbonyl] amino}-3-methylbutanoic acid. MS (ESI): mass calcd. for C30H36N6O8, 608.26, m/z found 608.3 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy- 2-{[(2-phenylacetyl)oxy]methyl}oxolan-3-yl (2S)-2-amino-3-methylbutanoate (43). [00376] The title compound 27 was prepared according to the procedure of Example 19, Step 2, using 43.1. MS (ESI): mass calcd. for C25H28N6O6, 508.21, m/z found 509.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br, s, 3H), 7.30 – 7.17 (m, 5H), 6.94 (d, J = 4.8 Hz, 1H), 6.84 (d, J = 4.8 Hz, 1H), 6.58 ( d, J = 5.6 Hz, 1H), 5.17 – 5.11(m, 1H), 5.08-5.07 (m, 1H), 4.46-4.44 (m,1H), 4.34 (dd, J = 12.0, 3.6 Hz, 1H), 4.25 (dd, J = 12.4, 5.2 Hz, 1H), 3.66 (s, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.00-1.97(m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). Example 24. Synthesis of {[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl} -5-cyano-4- hydroxy-2-{[(2-phenylacetyl)oxy]methyl}oxolan-3-yl]oxy}methy l 2,2-dimethylpropanoate (Compound 48). [00377] To a solution of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano-3,4- dihydroxyoxolan-2-yl]methyl 2-phenylacetate (12, 150 mg, 0.366 mmol) in DCE (10 mL) was added Tetrabutylammonium bromide (153.55 mg, 0.476 mmol), DBTO (118.60 mg, 0.476 mmol) and iodomethyl pivalate (221.67 mg, 0.916 mmol) under N2 atmosphere, the resulting mixture was stirred at 75 °C for 2 h. The reaction was washed with DCM (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 48 (12 mg, 6% yield) as a white solid. MS (ESI): m/z calcd. for C 26 H 29 N 5 O 7 523.21, found 524.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br, s, 3H), 7.29-7.24 (m, 3H), 7.23 – 7.18 (m, 2H), 6.94 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.48 (d, J = 6.4 Hz, 1H), 5.32 (d, J = 6.4 Hz, 1H), 5.26 (d, J = 6.4 Hz, 1H), 4.96 – 4.88 (t, J = 5.6 Hz, 1H), 4.34-4.30 (m, 2H), 4.16-4.13 (m, 2H), 3.65 (s, 2H), 1.10 (s, 9H). Example 25. Synthesis of (2R,3S,4R,5R)-2-(acetoxymethyl)-5-(4-aminopyrrolo[2,1-f][1,2 ,4]triazin- 7-yl)-5-cyano-4-hydroxytetrahydrofuran-3-yl 3-methylbutanoate (Compound 49). [00378] To a solution of 13 (100 mg, 0.30 mmol) in NMP (1.0 mL) was added HCl/dioxane (0.5 mL, 4 M). The mixture solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 3-methylbutanoyl chloride (0.29 mL, 2.4 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to obtain 49 (11.3 mg, 8.80% yield) as a white solid. MS (ESI): m/z calcd. for C19H23N5O6, 417.16, found 418.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 5.11 (m, 2H), 4.44 (dd, J = 8.8, 4.0 Hz, 1H), 4.31 (dd, J = 12.2, 3.6 Hz, 1H), 4.19 (dd, J = 12.2, 5.2 Hz, 1H), 2.27 (d, J = 7.2 Hz, 2H), 2.07 (dt, J = 13.6, 6.8 Hz, 1H), 2.00 (s, 3H), 0.94 (dd, J = 6.8, 0.8 Hz, 6H). Example 26. Synthesis of (2R,3S,4R,5R)-2-(acetoxymethyl)-5-(4-aminopyrrolo[2,1-f][1,2 ,4]triazin- 7-yl)-5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 50). [00379] The title compound was prepared according to the procedure of Example 49, Step 1, using Compound 13 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C22H27N5O6, 457.20, m/z found 458.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (br s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.62 – 6.53 (m, 1H), 5.12 – 5.07 (m, 2H), 4.43 (dd, J = 8.4, 4.4 Hz, 1H), 4.31 (dd, J = 12.0, 3.6 Hz, 1H), 4.19 (dd, J = 12.0, 5.2 Hz, 1H), 2.26 (d, J = 6.8 Hz, 2H), 2.00 (s, 3H), 1.81 – 1.58 (m, 6H), 1.28 – 1.10 (m, 3H), 1.01 – 0.90 (m, 2H). Example 27. Synthesis of (2R,3S,4R,5R)-2-[(acetyloxy)methyl]-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-5-cyano-4-hydroxyoxolan-3-yl (2S)-2-amino-3-methylbutanoate (Compound 51). Step 1. Synthesis of (2R,3S,4R,5R)-2-[(acetyloxy)methyl]-5-{4-aminopyrrolo[2,1-f] [1,2,4]triazin-7- yl}-5-cyano-4-hydroxyoxolan-3-yl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoate (51.1). [00380] The compound 51.1 was prepared according to the procedure of Example 19, Step 1, using 13 and (2S)-2-{[(tert-butoxy) carbonyl] amino}-3-methylbutanoic acid. MS (ESI): mass calcd. for C24H32N6O8, 532.23 m/z found 533.2 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-2-[(acetyloxy)methyl]-5-{4-aminopyrrolo[2,1-f] [1,2,4]triazin-7- yl}-5-cyano-4-hydroxyoxolan-3-yl (2S)-2-amino-3-methylbutanoate (51). [00381] The title compound 51 was prepared according to the procedure of Example 19, Step 2, using 51.1. MS (ESI): mass calcd. for C19H24N6O6, 432.18, m/z found 433.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.90 (br, s, 3H), 6.94 (d, J = 4.4 Hz, 1H), 6.88 (d, J = 4.8 Hz, 1H), 6.61-6.55 (m, 1H), 5.20 – 5.09 (m, 2H), 4.43-4.40 (m, 1H), 4.31 (dd, J = 12.0, 3.6 Hz, 1H), 4.20 (dd, J = 12.0, 5.2 Hz, 1H), 3.23 (d, J = 5.2 Hz, 1H), 2.05-2.02 (m, 1H), 2.00 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.86 (d, J =6.8 Hz, 3H). Example 28. Synthesis of (2R,3S,4R,5R)-2-(acetoxymethyl)-5-(4-aminopyrrolo[2,1-f][1,2 ,4]triazin- 7-yl)-5-cyano-4-hydroxytetrahydrofuran-3-yl 2-phenylacetate (Compound 52). [00382] The title compound was prepared according to the procedure of Example 17, using 13 and 2- phenylacetyl chloride. MS (ESI): m/z calcd. for C 22 H 21 N 5 O 6 451.15, found 452.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br s, 3H), 7.35 – 7.20 (m, 5H), 6.93 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 4.4 Hz, 1H), 6.66 (d, J = 6.0 Hz, 1H), 5.12 (p, J = 5.6 Hz, 2H), 4.46 (dd, J = 9.2, 4.0 Hz, 1H), 4.31 (dd, J = 12.0, 3.6 Hz, 1H), 4.17 (dd, J = 12.0, 5.2 Hz, 1H), 3.77 (q, J = 16.0 Hz, 2H), 1.98 (s, 3H). Example 29. Synthesis of ((2R,3S,4R,5R)-3-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]tria zin-7-yl)-5- cyano-4-hydroxytetrahydrofuran-2-yl)methyl acetate (Compound 53). [00383] To a solution of 6.3 (2.00 g, 6.90 mmol) in DMPU (6 mL) was added HCl/dioxane (2.6 mL, 4 M). The mixture solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and Acetyl chloride (0.98 mL, 13.8 mmol) was added at once. The reaction was stirred at 0 ℃ for 1 hour. The reaction was diluted with ACN (4.0 mL) and purified by prep-HPLC to obtain 53 (380 mg, 15.2% yield) as a white solid. MS (ESI): m/z calcd. for C16H17N5O6, 375.12, found 376.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.94 (br s, 3H), 6.93 (dd, J = 4.8, 2.0 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.63 – 6.58 (m, 1H), 5.09 – 5.04 (m, 2H), 4.49 – 4.36 (m, 1H), 4.37 – 4.24 (m, 1H), 4.17 (dt, J = 11.2, 5.6 Hz, 1H), 2.18 – 2.07 (m, 3H), 2.01 (d, J = 8.0 Hz, 3H). Example 30. Synthesis of (2R,3S,4R,5R)-2-(acetoxymethyl)-5-(4-aminopyrrolo[2,1-f][1,2 ,4]triazin- 7-yl)-5-cyano-4-hydroxytetrahydrofuran-3-yl isobutyrate (Compound 54). [00384] The title compound was prepared according to the procedure of Example 17, using 13 and isobutyryl chloride. MS (ESI): m/z calcd. for C18H21N5O6403.15, found 404.20 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.54 (d, J = 6.0 Hz, 1H), 5.18 – 5.08 (m, 2H), 4.50 – 4.41 (m, 1H), 4.31 (dd, J = 12.4, 4.0 Hz, 1H), 4.20 (dd, J = 12.0, 5.2 Hz, 1H), 2.63 (q, J = 6.8 Hz, 1H), 2.00 (s, 3H), 1.15 (dd, J = 7.2, 6.0 Hz, 6H). Example 31. Synthesis of (2R,3S,4R,5R)-2-(acetoxymethyl)-5-(4-aminopyrrolo[2,1-f][1,2 ,4]triazin- 7-yl)-5-cyano-4-hydroxytetrahydrofuran-3-yl propionate (Compound 55). [00385] The title compound was prepared according to the procedure of Example 17, using 13 and propionyl chloride. MS (ESI): m/z calcd. for C17H19N5O6389.13, found 390.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.58 (d, J = 4.8 Hz, 1H), 5.10 (p, J = 5.6 Hz, 2H), 4.45 (q, J = 4.0 Hz, 1H), 4.32 (dd, J = 12.0, 3.6 Hz, 1H), 4.18 (dd, J = 12.0, 5.2 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 2.00 (s, 3H), 1.08 (t, J = 7.6 Hz, 3H). Example 32. Synthesis of {[(2R,3S,4R,5R)-2-[(acetyloxy)methyl]-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-5-cyano-4-hydroxyoxolan-3-yl]oxy}meth yl 2,2-dimethylpropanoate (Compound 56) [00386] The compound 56 was prepared according to the procedure of Example 48, Step 1, using 13 and iodomethyl pivalate. MS (ESI): mass calcd. for C20H25N5O7, 447.18, m/z found 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br, s, 3H), 6.92 (d, J = 4.8 Hz, 1H), 6.83 (d, J = 4.8 Hz, 1H), 6.49 (d, J = 6.4 Hz, 1H), 5.35 (d, J = 6.4 Hz, 1H), 5.28 (d, J= 6.4 Hz, 1H), 5.02 – 4.93 (m, 1H), 4.39 – 4.25 (m, 2H), 4.19 – 4.06 (m, 2H), 2.00 (s, 3H), 1.11 (s, 9H). Example 33. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4- hydroxy-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl 3-methylbutanoate (Compound 57). [00387] The title compound was prepared according to the procedure of Example 17, using 15 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C21H27N5O6445.20, found 446.20 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 6.4 Hz, 1H), 5.17 – 5.12 (m, 1H), 5.10 – 5.05 (m, 1H), 4.46 (q, J = 4.4 Hz, 1H), 4.26 (qd, J = 12.0, 4.0 Hz, 2H), 2.54 (q, J = 6.8 Hz, 1H), 2.27 (d, J = 7.2 Hz, 2H), 2.07 (dt, J = 13.6, 6.8 Hz, 1H), 1.04 (dd, J = 6.8, 4.8 Hz, 6H), 0.94 (d, J = 6.4 Hz, 6H). Example 34. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 58). [00388] The title compound was prepared according to the procedure of Example 49, Step 1, using Compound 14 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C24H31N5O6, 485.23, m/z found 486.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 6.4 Hz, 1H), 5.16 – 5.11 (m, 1H), 5.07 (t, J = 6.0 Hz, 1H), 4.45 (q, J = 4.4 Hz, 1H), 4.25 (qd, J = 12.0, 4.4 Hz, 2H), 2.57 – 2.51 (m, 1H), 2.28 (d, J = 6.8 Hz, 2H), 1.82 – 1.58 (m, 6H), 1.23 – 0.90 (m, 11H). Example 35. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4- hydroxy-2-{[(2-methylpropanoyl)oxy]methyl}oxolan-3-yl (2S)-2-amino-3-methylbutanoate (Compound 59). Ste p 1. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy- 2-{[(2-methylpropanoyl)oxy]methyl}oxolan-3-yl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3- methylbutanoate (59.1). [00389] The compound 59.1 was prepared according to the procedure of Example 19, Step 1, using 14 and (2S)-2-{[(tert-butoxy) carbonyl] amino}-3-methylbutanoic acid. MS (ESI): mass calcd. for C 26 H 36 N 6 O 8 , 560.26 m/z found 561.2 [M+H] + . Step 2: Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy- 2-{[(2-methylpropanoyl)oxy]methyl}oxolan-3-yl (2S)-2-amino-3-methylbutanoate (59). [00390] The title compound 59 was prepared according to the procedure of Example 19, Step 2, using 59.1. MS (ESI): mass calcd. for C 21 H 28 N 6 O 6 , 460.21, m/z found 461.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.90 (br, s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.62 -6.60 (m, 1H), 5.14- 5.10 (m, 2H), 4.46-4.45 (m, 1H), 4.27 (d, J = 4.0 Hz, 1H), 4.24 (d, J = 4.8 Hz, 1H), 3.23 (d, J = 5.2 Hz, 1H), 2.53-2.51 (m, 1H), 1.99-1.90 (m, 1H), 1.06 – 1.00 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H).0.85 (d, J = 6.8 Hz, 3H). Example 36. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(2-phenylacetoxy)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 60). [00391] The title compound was prepared according to the procedure of Example 49, Step 1, using Compound 14 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C 24 H 25 N 5 O 6 , 479.18, m/z found 480.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br s, 3H), 7.33 – 7.29 (m, 4H), 7.29 – 7.24 (m, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.68 (d, J = 6.4 Hz, 1H), 5.13 (dt, J = 12.0, 5.6 Hz, 2H), 4.48 (q, J = 4.4 Hz, 1H), 4.30 – 4.18 (m, 2H), 3.77 (q, J = 15.8 Hz, 2H), 2.47 – 2.44 (m, 1H), 1.04 – 1.00 m, 6H). Example 37. Synthesis of ((2R,3S,4R,5R)-3-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]tria zin-7-yl)-5- cyano-4-hydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 61). [00392] The title c ompound was prepared according to the procedure of Example 17, using 15 and acetyl chloride. MS (ESI): m/z calcd. for C18H21N5O6403.15, found 404.00 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 5.07 (dt, J = 19.2, 5.2 Hz, 2H), 4.48 (q, J = 4.8 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.25 – 4.16 (m, 1H), 2.53 (q, J = 7.2 Hz, 1H), 2.09 (s, 3H), 1.05 (d, J = 4.8 Hz, 3H), 1.03 (d, J = 4.8 Hz, 3H). Example 38. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4- hydroxy-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate (Compound 62). [00393] The title compound was prepared according to the procedure of Example 17, using 15 and isobutyryl chloride. MS (ESI): m/z calcd. for C20H25N5O6431.18, found 432.05 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 6.57 (d, J = 6.4 Hz, 1H), 5.20 – 5.06 (m, 2H), 4.46 (q, J = 4.2 Hz, 1H), 4.25 (qd, J = 12.0, 4.0 Hz, 2H), 2.67 – 2.58 (m, 1H), 2.54 (q, J = 7.2 Hz, 1H), 1.15 (t, J = 7.2 Hz, 6H), 1.04 (dd, J = 6.8, 5.6 Hz, 6H). Example 39. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 63). [00394] The title compound was prepared according to the procedure of Example 17, using 15 and propionyl chloride. MS (ESI): m/z calcd. for C19H23N5O6417.16, found 418.05 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 5.16 – 5.11 (m, 1H), 5.09 – 5.04 (m, 1H), 4.47 (q, J = 4.4 Hz, 1H), 4.26 (qd, J = 12.0, 3.6 Hz, 2H), 2.54 (q, J = 6.8 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.10 – 1.02 (m, 9H). Example 40. Synthesis of (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -5-cyano-4- hydroxy-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl)oxy)me thyl pivalate (Compound 64). [00395] The title compound was prepared according to the procedure of Example 24, using 15 and iodomethyl pivalate. MS (ESI): m/z calcd. for C 22 H 29 N 5 O 6 475.21, found 476.30 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.50 (d, J = 6.4 Hz, 1H), 5.40 – 5.25 (m, 2H), 4.98 (dd, J = 6.0, 5.2 Hz, 1H), 4.41 – 4.23 (m, 2H), 4.23 – 4.07 (m, 2H), 2.47 (q, J = 7.2 Hz, 1H), 1.11 (s, 9H), 1.05 (q, J = 3.6 Hz, 6H). Example 41. Synthesis (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4- hydroxy-2-[(propanoyloxy)methyl]oxolan-3-yl 3-methylbutanoate (Compound 65). Step 1. Synthesis (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy-2- [(propanoyloxy)methyl]oxolan-3-yl 3-methylbutanoate (65). [00396] To a solution of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano-3,4- dihydroxyoxolan-2-yl]methyl propanoate (15, 80 mg, 0.230 mmol) in NMP (3 mL) was added HCl in dioxane (4 M, 0.1 mL), The reaction was stirred at 25 °C for 15 minutes. Then 3-methylbutanoyl chloride (138.18 mg, 1.151 mmol) was added to the above solution at 0 o C, the resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (1 mL) and purified by prep-HPLC to afford the title compound (38.0 mg, 37% yield) as a white solid. MS (ESI): m/z calcd. for C20H25N5O6431.18, found 432.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br, s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 5.11-5.06 (m, 2H), 4.45 (dd, J = 8.4, 4.8 Hz, 1H), 4.32 (dd, J = 12.0, 3.6 Hz, 1H), 4.21 (dd, J = 12.0, 5.2 Hz, 1H), 2.41 – 2.19 (m, 4H), 2.07-2.04 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H), 0.94 (dd, J = 6.8, 0.8 Hz, 6H). Example 42. Synthesis of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano-3- [(2-cyclohexyl l 4 h l 2 l h l [00397] The title compound 66 was prepared according to the procedure of Example 65, Step 1, using 15 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C23H29N5O6, 471.21, m/z found 472.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93-7.91 (br, s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 5.12-5.06 (m, 2H), 4.44 -4.43 (m, 1H), 4.31 (dd, J = 12.0, 4.0 Hz, 1H), 4.20 (dd, J = 12.0, 5.2 Hz, 1H), 2.31 – 2.24 (m, 4H), 1.79 – 1.60 (m, 6H), 1.21 – 0.93 (m, 8H). Example 43. Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4- hydroxy-2-[(propanoyloxy)methyl]oxolan-3-yl (2S)-2-amino-3-methylbutanoate (Compound 67). Step 1: Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy- 2-[(propanoyloxy)methyl]oxolan-3-yl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoate (67.1). [00398] The compound 67.1 was prepared according to the procedure of Example 19, Step 1, using 15 and (2S)-2-{[(tert-butoxy) carbonyl] amino}-3-methylbutanoic acid. MS (ESI): mass calcd. for C25H34N6O8, 546.24 m/z found 547.3 [M+H] + . Step 2: Synthesis of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-4-hydroxy- 2-[(propanoyloxy)methyl]oxolan-3-yl (2S)-2-amino-3-methylbutanoate (67). [00399] The title compound 67 was prepared according to the procedure of Example 19, Step 2, using 67.1. MS (ESI): mass calcd. for C20H26N6O6, 446.19, m/z found 447.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br, s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.61-6.52 (m, 1H), 5.13- 5.10 (m, 2H), 4.44-4.40 (m, 1H),4.32 (dd, J = 12.4, 4.0 Hz, 1H), 4.21 (dd, J = 12.0, 5.2 Hz, 1H), 3.25 (d, J = 5.2 Hz, 1H), 2.30-2.22 (m, 2H), 2.01-1.95 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H), 0.92 (d, J= 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). Example 44. Synthesis of [(2R,3S,4R,5R)-3-(acetyloxy)-5-{4-aminopyrrolo[2,1-f][1,2,4] triazin-7- yl}-5-cyano-4-hydroxyoxolan-2-yl]methyl propanoate (Compound 69). Step 1. Synthesis of [(2R,3S,4R,5R)-3-(acetyloxy)-5-{4-aminopyrrolo[2,1-f][1,2,4] triazin-7-yl}-5- cyano-4-hydroxyoxolan-2-yl]methyl propanoate (69). [00400] The title compound 69 was prepared according to the procedure of Example 65, Step 1, using 15 and AcCl. MS (ESI): m/z calcd. for C H N O 38913 f d 3901 [M H] 1 H NMR (400 MHz, DMSO) δ 7.93-7.90 (br, s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H), 5.07-5.05 (m, 2H), 4.46-4.45 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.20 (dd, J = 12.4, 5.2 Hz, 1H), 2.30-2.28 (m, 2H), 2.09 (s, 3H), 0.99 (t, J = 7.6 Hz, 3H). Example 45. Synthesis of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano-4- hydroxy-3-[(2-methylpropanoyl)oxy]oxolan-2-yl]methyl propanoate (Compound 70). [00401] The title compound 70 was prepared according to the procedure of Example 65, Step 1, using 15 and isobutyryl chloride. MS (ESI): mass calcd. for C 19 H 23 N 5 O 6 , 417.16, m/z found 418.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br, s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 5.20 – 5.06 (m, 2H), 4.45 (dd, J = 8.8, 4.0 Hz, 1H), 4.31 (dd, J = 12.0, 4.0 Hz, 1H), 4.21 (dd, J = 12.0, 5.2 Hz, 1H), 2.70 – 2.56 (m, 1H), 2.29 (d, J = 5.2 Hz, 2H), 1.15 (dd, J = 6.8, 6.4 Hz, 6H), 0.99 (t, J = 7.6 Hz, 3H). Example 46. Synthesis of [(2R,3S,4R,5R)-3-(acetyloxy)-5-{4-aminopyrrolo[2,1-f][1,2,4] triazin-7- yl}-5-cyano-4-hydroxyoxolan-2-yl]methyl propanoate (Compound 71). [00402] The title compound 71 was prepared according to the procedure of Example 65, Step 1, using 15 and propionyl chloride. MS (ESI): mass calcd. for C 18 H 21 N 5 O 6 , 403.15, m/z found 404.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br, s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 5.10-5.05 (m, 2H), 4.46 (dd, J = 8.4, 4.8 Hz, 1H), 4.33 (dd, J = 12.0, 3.6 Hz, 1H), 4.20 (dd, J = 12.0, 5.2 Hz, 1H), 2.40-2.38 (m, 2H), 2.35 – 2.24 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H). Example 47. Synthesis of {[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl} -5-cyano-4- hydroxy-2-[(propanoyloxy)methyl]oxolan-3-yl]oxy}methyl 2,2-dimethylpropanoate (Compound 72). Step 1: Synthesis o f {[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl} -5-cyano-4- hydroxy-2-[(propanoyloxy)methyl]oxolan-3-yl]oxy}methyl 2,2-dimethylpropanoate (72). [00403] The compound 72 was prepared according to the procedure of Example 48, Step 1, using 15 and iodomethyl pivalate. MS (ESI): mass calcd. for C21H27N5O7, 461.19, m/z found 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br, s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.8 Hz, 1H), 6.49 (d, J = 6.4 Hz, 1H), 5.35 (d, J = 6.4 Hz, 1H), 5.28 (d, J = 6.4 Hz, 1H), 4.97-4.96 (m, 1H), 4.39 – 4.28 (m, 2H), 4.19 – 4.08 (m, 2H), 2.28 -2.26(m, 2H), 1.11 (s, 9H), 1.00 (t, J = 7.6 Hz, 3H). Example 48. Synthesis of pentyl (7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)carbamate (Compound 81). Step 1. Synthesis of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -6-(((tert- butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3, 4-d][1,3]dioxole-4-carbonitrile (81.1). [00404] To a mixture of 6.4 (4.00 g, 12.1 mmol) and imidazole (2.06 g, 30.2 mmol) in DMF (20 mL) was added TBSCl (2.19 g, 14.5 mmol) slowly at 0 ℃. The mixture was then stirred at 20℃, for 16 hours. TLC showed that the starting material was consumed completely. After completion, the mixture was quenched with water (300 mL) and extracted with Ethyl acetate (200 mL×3). The organic layer was then dried over sodium sulphate and concentrated in vacuo to afford a residue. The residue was purified by flash column chromatography (SiO2, Ethyl acetate/Petroleum ether = 0-30%) to obtain 81.1 as a colorless oil (4.8 g, 88.4% yield) which was confirmed by 1 H NMR and LCMS. MS (ESI): mass calcd. for C21H31N5O4Si, 445.21, m/z found 446.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 5.33 (d, J = 6.4 Hz, 1H), 4.85 (dd, J = 6.4, 2.8 Hz, 1H), 4.37 (dd, J = 7.6, 4.8 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 3.70 (dd, J = 4.8, 1.2 Hz, 2H), 1.63 (s, 3H), 1.37 (s, 3H), 0.76 (s, 9H), -0.03 (s, 3H), -0.08 (s, 3H). Step 2. Synthesis of pentyl (7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl) -4-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2, 1-f][1,2,4]triazin-4-yl)carbamate (81.2). [00405] A mixture 81.1 (200 mg,0.45 mmol), DMAP ( 274.15 mg, 2.24 mmol) and DIEA (0.37 mL, 2.24 mmol) in DCM (2 mL) was added pentyl chloroformate (0.19 mL, 1.35 mmol) at 0 ℃ under N 2 , then the reaction was stirred at 20 ℃ for 16 hours. The reaction mixture was poured into 50 mL of water and the organic layer was separated. The aqueous was extracted with DCM (50 mL) twice. The organic phase was washed with brine water (50 mL x3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by flash column chromatography (Petroleum ether / ethyl acetate from 0% to 8%) to obtain 81.2 as a white solid (125 mg, 44.8% yield) MS (ESI): m/z calcd. for C27H41N5O6Si, 559.28, found 560.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.40 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 5.30 (d, J = 6.2 Hz, 1H), 4.86 (dd, J = 6.2, 2.4 Hz, 1H), 4.44 (d, J = 2.4 Hz, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3.70 (d, J = 4.4 Hz, 2H), 1.70 – 1.63 (m, 5H), 1.39 – 1.32 (m, 7H), 0.89 (t, J = 7.2 Hz, 3H), 0.73 (s, 9H), -0.08 (d, J = 17.6 Hz, 6H). Step 3. Synthesis of pentyl (7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)carbamate. [00406] To solution of 81.2 (65.0 mg, 0.12 mmol) in THF (1 mL) was added HCl (1 mL, 6M) at 0℃, then the reaction was stirred at 20 ℃ for 1 hour. The reaction was diluted with ACN (1.0 mL) and purified by prep-HPLC to obtain 81 (22.8 mg, 48.5% yield) as a white solid. MS (ESI): m/z calcd. for C18H23N5O6, 405.16, found 406.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32 (s, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.21 (d, J = 6.4 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.70 – 4.55 (m, 1H), 4.16 (t, J = 6.8 Hz, 2H), 4.07 (dd, J = 9.2, 4.4 Hz, 1H), 3.95 (dd, J = 10.8, 5.2 Hz, 1H), 3.69 – 3.60 (m, 1H), 3.56 – 3.47 (m, 1H), 1.67 (p, J = 7.2 Hz, 2H), 1.41 – 1.30 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H). Example 49. Synthesis of (2S)-2-amino-N-{7-[(2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl }-3-methylbutanamide (Compound 83).
Step 1. Synthesis of tert-butyl N-[(1S)-1-({7-[(3aR,4R,6R,6aR)-6-{[(tert- butyldimethylsilyl)oxy]methyl}-4-cyano-2,2-dimethyl-dihydro- 3aH-furo[3,4-d][1,3]dioxol-4- yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}carbamoyl)-2-methylprop yl]carbamate (83.1) [00407] To a solution of (3aR,4R,6R,6aR)-4-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl} -6-{[(tert- butyldimethylsilyl)oxy]methyl}-2,2-dimethyl-dihydro-3aH-furo [3,4-d][1,3]dioxole-4-carbonitrile (81.1, 200 mg, 0.4488 mmol) in THF (10 mL) was added (2S)-2-{[(tert-butoxy)carbonyl]amino}-3- methylbutanoic acid (146.08 mg, 0.6732 mmol), HOBT (90.96 mg, 0.6732 mmol), EDCI (129.05 mg, 0.6732 mmol ) and DIEA (174.01 mg, 1.3464 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was extracted with EA (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE from 2% to 20%) to obtain 83.1 as a white solid (190 mg, 59% yield). MS (ESI): mass calcd. for C31H48N6O7Si, 644.34, m/z found 645.3 [M+H] + . Step 2. Synthesis of (2S)-2-amino-N-{7-[(2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl }-3-methylbutanamide (83). [00408] To a solution of tert-butyl N-[(1S)-1-({7-[(3aR,4R,6R,6aR)-6-{[(tert- butyldimethylsilyl)oxy]methyl}-4-cyano-2,2-dimethyl-dihydro- 3aH-furo[3,4-d][1,3]dioxol-4- yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}carbamoyl)-2-methylprop yl]carbamate (83.1, 100 mg, 0.155 mmol) in THF (3 mL) was added HCl (12M, 1 mL) at 0 °C, the mixture was stirred at 25 °C for 6 h. The reaction was concentrated in vacuo and purified by prep-HPLC to afford the salt-forming compound. The compound was basified by NaHCO3 (sat. aqueous, 1 mL) and purified by prep-HPLC to obtain 83 as a white solid (9.85 mg, 12% yield). MS (ESI): mass calcd. for C17H22N6O5, 390.17, m/z found 391.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.21 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.23 (d, J = 4.4 Hz, 1H), 7.13 (s, 1H), 6.89 (d, J = 4.8 Hz, 1H), 6.12 (d, J =6.0 Hz, 1H), 5.20 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.64-4.60 (m, 2H), 4.05-4.01 (m, 1H), 3.94-3.90 (m, 1H), 3.74 – 3.59 (m, 1H), 3.57 – 3.47 (m, 1H), 2.18-2.05 (m, 1H), 0.96-0.85 (m, 6H). Example 50. Synthesis of (S)-2-amino-N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)-3-(4- fluorophenyl)propenamide (Compound 84). Step 1. Synthesis of tert-butyl ((S)-1-((7-((3aR,4R,6R,6aR)-6-(((tert- butyldimethylsilyl)oxy)methyl)-4-cyano-2,2-dimethyltetrahydr ofuro[3,4-d][1,3]dioxol-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-3-(4-fluoropheny l)-1-oxopropan-2-yl)carbamate (84.2). [00409] To a solution of 81.1 (2.00 g, 4.5 mmol), 84.1 (1.28 g, 4.5 mmol) and DIPEA (0.87 g, 6.7 mmol) in dry DMF (20 mL) was added HATU (2.57 g, 6.7 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into ice water (40 mL) and extracted with EA (20 mL × 2). The combined organic phase was washed with water (15 mL), followed by brine (15 mL × 3), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% EA in PE) to give 84.2 (2.47 g, 78% yield) as a white solid. MS (ESI): m/z calcd. for C35H47FN6O7Si 710.33, found 711.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 8.51 (s, 1H), 7.42 (dd, J = 8.0, 5.6 Hz, 2H), 7.33 – 7.20 (m, 2H), 7.15 – 7.07 (m, 3H), 5.31 (d, J = 6.0 Hz, 1H), 4.87 (dd, J = 6.0, 2.4 Hz, 1H), 4.49 – 4.44 (m, 1H), 3.71 (d, J = 4.4 Hz, 1H), 3.12 – 3.00 (m, 1H), 2.86 – 2.75 (m, 1H), 1.66 (s, 3H), 1.38 (s, 3H), 1.32 (s, 9H), 0.73 (s, 9H), -0.07 (d, J = 18.0 Hz, 6H). Step 2. Synthesis of (S)-2-amino-N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)-3-(4- fluorophenyl)propanamide (84). [00410] To a solution of 84.2 (50 mg, 0.07 mmol) in dry THF (0.5 mL) was added Conc. HCl (0.25 mL, 12 M) dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was basified with aq. NaHCO 3 at 0 °C and adjust pH to 8. LC-MS showed peak shifting and the new peak has a same MS, which maybe different salt form with different pH value. The organic solvent was removed with flowing nitro Th id dil t d ith ACN d ified by prep- HPLC to afford the title compound 84 (4.52 mg, 14% yield) as a white solid. MS (ESI): m/z calcd. for C21H21FN6O5456.16, found 457.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.56 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.42 – 7.34 (m, 2H), 7.17 (s, 1H), 7.09 – 7.02 (m, 3H), 6.86 (d, J = 4.4 Hz, 1H), 6.11 (d, J = 6.0 Hz, 1H), 5.22 (d, J = 4.0 Hz, 1H), 4.98 – 4.85 (m, 2H), 4.60 (t, J = 5.6 Hz, 1H), 4.04 (dd, J = 9.2, 4.4 Hz, 1H), 3.93 (dd, J = 10.4, 5.2 Hz, 1H), 3.66 – 3.59 (m, 1H), 3.53 – 3.45 (m, 1H), 3.18 (dd, J = 14.0, 4.0 Hz, 1H), 3.02 (dd, J = 13.6, 11.2 Hz, 1H). 19 F NMR (377 MHz, DMSO) δ -116.76. Example 51. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)benzamide (Compound 85). Step 1. Synthesis of N-(7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methy l)-4-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)benzamide (85.1). [00411] To a solution of 81.1 (2.00 g, 4.50 mmol) and DMAP (820 mg, 6.75 mmol) in dry DCM (20 mL) was added benzoyl chloride (950 mg, 6.75 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The mixture was washed with water (10 mL×2), followed by brine (10 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% EA in PE) to give 85.1 (1.99 g, 80% yield) as a white solid. MS (ESI): m/z calcd. for C28H35N5O5Si 549.24, found 550.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 8.65 - 7.84 (m, 3H), 7.66 (t, J = 6.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.22 - 6.94 (m, 2H), 5.34 (d, J = 6.4 Hz, 1H), 4.88 (dd, J = 6.0, 2.8 Hz, 1H), 4.46 (d, J = 2.0 Hz, 1H), 3.72 (d, J = 4.8 Hz, 2H), 1.66 (s, 3H), 1.38 (s, 3H), 0.75 (s, 9H), -0.03 (s, 3H), -0.07 (s, 3H). Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)benzamide (85). [00412] To a solution of 85.1 (0.10 g, 0.18 mmol) in MeOH (1.0 mL) was added aq. HCl (1.0 mL, 6 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The organic solvent was removed with flowing nitrogen. The residue was purified by prep-HPLC to afford the title compound 85 (23.55 mg, 33% yield) as a white solid. MS (ESI): m/z calcd. for C19H17N5O5395.12, found 396.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.36 (s, 1H), 8.65 – 7.85 (m, 3H), 7.70 – 7.61 (m, 1H), 7.59 – 7.52 (m, 2H), 7.27 – 7.04 (m, 2H), 6.24 (d, J = 6.4 Hz, 1H), 5.26 (d, J = 5.6 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.12 – 4.06 (m, 1H), 3.97 (dd, J = 10.4, 5.2 Hz, 1H), 3.69 – 3.62 (m, 1H), 3.56 – 3.48 (m, 1H). Example 52. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl acetate (Compound 87). [00413] To a solution of pentyl 81 (80 mg, 0.19 mmol) in DMPU (1 mL) was added 4 M dioxane HCl (0.2 mL) dropwise at 0 ℃. The mixture was then stirred for 30 min and added acetyl chloride (0.2 mL) dropwise and stirred for another 30 min. After completion, the mixture was purified by prep-HPLC to afford 87 (30 mg, 33.6% yield) as a white solid. MS (ESI): m/z calcd. for C20H25N5O7, 447.18, found 448.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 8.34 (s, 1H), 7.29 (d, J = 4.4 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.40 (d, J = 6.0 Hz, 1H), 5.44 (d, J = 6.0 Hz, 1H), 4.68 (t, J = 5.6 Hz, 1H), 4.32 (dd, J = 12.0, 2.8 Hz, 1H), 4.28 – 4.23 (m, 1H), 4.20 – 4.11 (m, 3H), 3.93 (q, J = 6.0 Hz, 1H), 2.01 (s, 3H), 1.67 (p, J = 6.8 Hz, 2H), 1.41 – 1.28 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H). Example 53. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl 2- cyclohexylacetate (Compound 88). [00414] To a solution of 81 (60.0 mg, 0.16 mmol) in DMPU (1 mL) was added HCl/dioxane (0.2 mL, 4 M). The mixture solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0℃ and 2-cyclohexylacetyl chloride (0.11 mL, 0.74 mmol) was added at once. The reaction was stirred at 0 ℃ for 2 hours. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to obtain 88 (28.8 mg, 36.6% yield) as a white solid. MS (ESI): m/z calcd. for C26H35N5O7, 529.25, found 530.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.33 (s, 1H), 7.29 (d, J = 4.0 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 5.43 (d, J = 6.0 Hz, 1H), 4.83 – 4.58 (m, 1H), 4.33 – 4.28 (m, 1H), 4.27 – 4.22 (m, 1H), 4.20 – 4.13(m, 3H), 3.95 (dd, J = 11.2, 6.0 Hz, 1H), 2.18 – 2.05 (m, 2H), 1.71 – 1.55 (m, 8H), 1.40 – 1.30 (m, 4H), 1.22 – 1.05 (m, 3H), 0.92 – 0.80 (m, 5H). Example 54. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl 2- phenylacetate (Compound 89). [00415] The title compound was prepared according to the procedure of Example 88, Step 1, using Compound 81 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C26H29N5O7, 523.21, m/z found 524.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.33 (s, 1H), 7.33 – 7.19 (m, 6H), 6.97 (d, J = 4.8 Hz, 1H), 6.40 (d, J = 6.0 Hz, 1H), 5.45 (d, J = 5.6 Hz, 1H), 4.64 (t, J = 5.6 Hz, 1H), 4.34 (dd, J = 12.0, 2.4 Hz, 1H), 4.29 – 4.25 (m, 1H), 4.24 – 4.14 (m, 3H), 3.97 – 3.91 (m, 1H), 3.66 (s, 2H), 1.73 – 1.60 (m, 2H), 1.44 – 1.29 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H). Example 55. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl propionate (Compound 91). [00416] The title compound was prepared according to the procedure of Example 88, Step 1, using Compound 81 and propionyl chloride. MS (ESI): mass calcd. for C21H27N5O7, 461.19, m/z found 462.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.33 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 5.43 (d, J = 6.0 Hz, 1H), 4.86 – 4.46 (m, 1H), 4.33 (dd, J = 12.0, 2.8 Hz, 1H), 4.28 – 4.22 (m, 1H), 4.19 – 4.13 (m, 3H), 3.94 (dd, J = 11.6, 6.0 Hz, 1H), 2.35 – 2.24 (m, 2H), 1.71 – 1.63(m, 2H), 1.46 – 1.26 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). Example 56. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 92). [00417] The title compound was prepared according to the procedure of Example 87, Step 1, using Compound 81 and 2-methylpropanoyl chloride. MS (ESI): mass calcd. for C 22 H 29 N 5 O 7 , 475.21, m/z found 476.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.33 (s, 1H), 7.27 (d, J = 4.4 Hz, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.41 (d, J = 6.4 Hz, 1H), 5.42 (d, J = 6.0 Hz, 1H), 4.68 (t, J = 5.6 Hz, 1H), 4.33 – 4.23 (m, 2H), 4.20 – 4.14 (m, 3H), 3.95 (dd, J = 11.2, 6.0 Hz, 1H), 2.52 (s, 1H), 1.71 –1.62 (m, 2H), 1.41 – 1.29 (m, 4H), 1.04 (m, 6H), 0.89 (t, J = 7.2 Hz, 3H). Example 57. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl 3- methylbutanoate (Compound 93). [00418] The title compound was prepared according to the procedure of Example 87, Step 1, using Compound 81 and 3-methylbutanoyl chloride. MS (ESI): mass calcd. for C23H31N5O7, 489.22, m/z found 490.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.33 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 5.43 (d, J = 5.2 Hz, 1H), 4.68 (t, J = 5.6 Hz, 1H), 4.34 – 4.28 (m, 2H), 4.20 – 4.13 (m, 3H), 3.94 (dd, J = 11.6, 6.0 Hz, 1H), 2.17– 2.12 (m,, 2H), 1.95 – 1.85 (m, 1H), 1.73 – 1.62 (m, 2H), 1.42 – 1.29 (m, 4H), 0.94 – 0.81 (m, 9H). Example 58. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 97).
Step 1. Synthesis of tert-butyl ((S)-1-((7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)amino)-3-(4- fluorophenyl)-1-oxopropan-2-yl)carbamate (97.1). [00419] To a solution of 84.2 (1.40 g, 1.97 mmol) in dry THF (15 mL) was added TBAF (3.0 mL, 1 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and at 25 °C for another 5 h. The mixture was quenched with Sat. aq. NH4Cl (15 mL) and extracted with EA (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 35% EA in PE) to 97.1 (820 mg, 70% yield) as a yellow solid. MS (ESI): m/z calcd. for C29H33FN6O7596.24, found 597.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 8.51 (s, 1H), 7.43 (dd, J = 8.4, 6.0 Hz, 2H), 7.33 – 7.06 (m, 5H), 5.36 (d, J = 6.4 Hz, 1H), 5.02 (t, J = 5.6 Hz, 1H), 4.94 – 4.79 (m, 2H), 4.40 – 4.33 (m, 1H), 3.59 – 3.45 (m, 2H), 3.10 (dd, J = 13.2, 3.2 Hz, 1H), 2.81 (dd, J = 13.2, 11.2 Hz, 1H), 1.65 (s, 3H), 1.38 (s, 3H), 1.34 – 1.20 (m, 9H). Step 2. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-phenylacetate (97.2). [00420] To a solution of 97.1 (200 mg, 0.335 mmol) and DIPEA (86.5 mg, 0.669 mmol) in dry DCM (1.5 mL) was added 2-phenylacetyl chloride (77.6 mg, 0.502 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with EA (5.0 mL) and washed with water (2.5 mL), followed by brine (2.5 mL), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 30% EA in PE) to give 97.2 (122 mg, 85% yield) as a white solid. MS (ESI): m/z calcd. for C37H39FN6O8714.28, found 715.2 [M+H] + . Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-phenylacetate (97). [00421] To a solution of 97.2 (50.0 mg, 0.07 mmol) in THF (0.4 mL) and water (0.2 mL) was added HCl/1,4-dioxane (0.3 mL, 4 M) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was adjusted pH to 8 with Sat. aq. NaHCO3 at 0 °C. The organic solvent was removed with flowing nitrogen. The residue was purified by prep-HPLC to afford the title compound (4.41 mg, 11% yield) as a white solid. MS (ESI): m/z calcd. for C 29 H 27 FN 6 O 6 574.20, found 575.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.58 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.39 (dd, J = 8.4, 6.0 Hz, 2H), 7.32 – 7.13 (m, 6H), 7.11 – 7.01 (m, 3H), 6.78 (d, J = 4.8 Hz, 1H), 6.33 (s, 1H), 5.43 (s, 1H), 4.98 – 4.89 (m, 1H), 4.63 (t, J = 5.2 Hz, 1H), 4.33 (d, J = 10.8 Hz, 1H), 4.25 – 4.15 (m, 2H), 3.96 – 3.87 (m, 1H), 3.66 (s, 2H), 3.22 – 3.15 (m, 1H), 3.07 – 2.98 (m, 1H). 19 F NMR (377 MHz, DMSO) δ -116.75. Example 59. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 3-methylbutanoate (Compound 101). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3-methylbutanoate (101.1). [00422] To a solution of 97.1 (200 mg, 0.335 mmol) and DIPEA (64.9 mg, 0.502 mmol) in dry DCM (2.0 mL) was added 3-methylbutanoyl chloride (60.5 mg, 0.502 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The organic solvent was removed with flowing nitrogen. The residue was purified by prep-HPLC to give 101.1 (62.2 mg, crude) as a white solid. MS (ESI): m/z calcd. for C 34 H 41 FN 6 O 8 680.30, found 681.4 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 3-methylbutanoate (101). [00423] To a solution of 101.1 (62.2 mg, crude) in THF (0.6 mL) was added aq. HCl (0.3 mL, 12 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The organic solvent was removed with flowing nitrogen. The residue was purified by prep-HPLC to afford the title compound (4.32 mg, 8.5% yield) as a white solid. MS (ESI): m/z calcd. for C26H29FN6O6540.21, found 541.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.69 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.47 (t, J = 6.4 Hz, 2H), 7.15 – 6.99 (m, 3H), 6.89 (d, J = 3.6 Hz, 1H), 6.09 (d, J = 6.0 Hz, 1H), 5.48 – 5.30 (m, 1H), 5.19 (d, J = 4.8 Hz, 1H), 4.93 – 4.81 (m, 1H), 4.65 – 4.53 (m, 1H), 4.08 – 3.99 (m, 1H), 3.97 – 3.90 (m, 1H), 3.65 – 3.59 (m, 1H), 3.51 – 3.48 (m, 1H), 3.18 – 3.13 (m, 1H), 3.05 – 2.97 (m, 1H), 2.41 (d, J = 6.8 Hz, 2H), 2.11 – 2.00 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -116.44. Example 60. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl acetate (Compound 103). [00424] To a solution of 85 (80.0 mg, 0.20 mmol) in DMPU (0.5 mL) was added HCl/dioxane (0.1 mL, 4 M). The mixture solution was stirred at 0 °C for 15 minutes. Then acetyl chloride (47.6 mg, 0.61 mmol) was added at 0 °C. The resulting mixture was stirred at 20 °C for another 2 hours. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to afford the title compound (21.1 mg, 23.8% yield) as a white solid. MS (ESI): m/z calcd. for C21H19N5O6437.13, found 438.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 8.39 (s, 1H), 8.07 (s, 2H), 7.66 (t, J = 6.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.17 (d, J = 4.4 Hz, 1H), 7.06 (s, 1H), 6.43 (d, J = 6.0 Hz, 1H), 5.46 (d, J = 5.6 Hz, 1H), 4.79 – 4.61 (m, 1H), 4.39 – 4.24 (m, 2H), 4.22 – 4.12 (m, 1H), 4.01 – 3.93 (m, 1H), 2.02 (s, 3H). Example 61. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 105) [00425] The title compound was prepared according to the procedure of Example 88, Step 1, using Compound 85 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C27H23N5O6, 513.16, m/z found 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.36 (s, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.36 – 7.19 (m, 5H), 7.16 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 5.46 (d, J = 5.6 Hz, 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.36 (dd, J = 12.0, 2.4 Hz, 1H), 4.32 – 4.26 (m, 1H), 4.22 (dd, J = 12.0, 5.2 Hz, 1H), 3.99 – 3.94 (m, 1H), 3.68 (s, 2H). Example 62. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl propionate (Compound 107). [00426] The title compound was prepared according to the procedure of Example 88, Step 1, using Compound 85 and propionyl chloride. MS (ESI): mass calcd. for C22H21N5O6, 451.15, m/z found 452.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.81 (s, 1H), 8.37 (s, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 6.44 (d, J = 6.0 Hz, 1H), 5.45 (d, J = 6.0 Hz, 1H), 4.78 – 4.62 (m, 1H), 4.35 (dd, J = 12.0, 2.8 Hz, 1H), 4.31 – 4.25 (m, 1H), 4.21 – 4.15 (m, 1H), 3.96 (dd, J = 11.6, 6.0 Hz, 1H), 2.34 – 2.26 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). Example 63. Synthesis ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 108). [00427] The title compound was prepared according to the procedure of Example 103, Step 1, using Compound 85 and 2-methylpropanoyl chloride. MS (ESI): mass calcd. for C23H23N5O6, 465.16, m/z found 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 8.37 (s, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 4.4 Hz, 1H), 6.44 (d, J = 6.0 Hz, 1H), 5.45 (d, J = 5.6 Hz, 1H), 4.70 (t, J = 5.2 Hz, 1H), 4.37- 4.14 (m, 3H), 4.02 - 3.93 (m, 1H), 2.55 - 2.51 (m, 1H), 1.05 (dd, J = 6.8, 2.4 Hz, 6H). Example 64. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 109). [00428] The title compound was prepared according to the procedure of Example 103, Step 1, using Compound 85 and 3-methylbutanoyl chloride. MS (ESI): mass calcd. for C 24 H 25 N 5 O 6 , 479.18, m/z found 480.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.38 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 4.4 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.45 (d, J = 6.0 Hz, 1H), 4.71 (s, 1H), 4.37– 4.25 (m, 2H), 4.18 (dd, J = 12.0, 5.2 Hz, 1H), 3.99–3.94 (m, 1H), 2.51 (s, 2H), 2.00 – 1.83 (m, 1H), 0.86 (dd, J = 6.8, 3.2 Hz, 6H). Example 65. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl L-valinate (Compound 110). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl (tert-butoxycarbonyl)-L-valinate (110.1) [00429] To a solution of 6.4 (1.00 g, 3 mmol) in THF (15 mL) was added (2S)-2-{[(tert- butoxy)carbonyl] amino}-3-methylbutanoic acid (0.65 g, 3 mmol), HOBt (0.41 g, 3 mmol) and DIEA (0.58 g, 4.5 mmol) at 0 °C, the mixture was then stirred at 0 °C for 5 min. Then added EDCI slowly into the mixture and stirred for 16 hours. After completion, the mixture was washed with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a residue. The residue was purified with prep-HPLC to afford 110.1 (230 mg, 10.4% yield) as a white solid. MS (ESI): m/z calcd. for C35H51N7O10, 729.37, found 730.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.47 (s, 1H), 7.20 (d, J = 4.4 Hz, 1H), 7.17 – 6.70 (m, 3H), 5.42 (d, J = 6.4 Hz, 1H), 4.92 (dd, J = 6.4, 2.8 Hz, 1H), 4.63 (s, 1H), 4.42 (s, 1H), 4.25 (dd, J = 12.0, 3.6 Hz, 1H), 4.14 (dd, J = 12.0, 6.4 Hz, 1H), 3.71 (dd, J = 46.0, 38.8 Hz, 1H), 2.09 (dd, J = 13.2, 6.8 Hz, 1H), 1.79 (dd, J = 13.6, 6.8 Hz, 1H), 1.66 (s, 3H), 1.45 – 1.23 (m, 21H), 0.94 (dd, J = 14.4, 6.8 Hz, 6H), 0.76 (dd, J = 15.2, 6.8 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl L-valinate (110). [00430] To a solution of 110.1 (100 mg, 0.13 mmol) in DCM (5 mL) was added 1 mL HCl/dioxane (5 mL) dropwise at 0 ℃. The mixture was then stirred at 0 ℃ for 2 hours. After completion, the mixture was dried through a nitrogen stream to afford a residue. The residue was purified with prep-HPLC to afford 110 (15 mg.22.1% yield) as a white solid. MS (ESI): m/z calcd. for C22H31N7O6, 489.23, found 490.15 [M+H] + . 1 H NMR (400 MHz, DMSO) 8.23 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.13 (s, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 5.40 (d, J = 5.6 Hz, 1H), 4.72 – 4.61 (m, 2H), 4.37 – 4.22 (m, 3H), 3.94 (q, J = 4.8 Hz, 1H), 3.30 (s, 1H), 2.23 – 2.13 (m, 1H), 1.92 – 1.80 (m, 1H), 0.96 (dd, J = 6.8, 4.0 Hz, 6H), 0.83 (dd, J = 16.4, 6.8 Hz, 6H). Example 66. Synthesis of [(2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo [2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 2-cyclohexylacetate (Compound 11 Step 1. Synthesis of tert-butyl ((S)-1-((7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (112.1). [00431] To a solution of tert-butyl N-[(1S)-1-({7-[(3aR,4R,6R,6aR)-6-{[(tert- butyldimethylsilyl)oxy]methyl}-4-cyano-2,2-dimethyl-dihydro- 3aH-furo[3,4-d][1,3]dioxol-4- yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}carbamoyl)-2-methylprop yl]carbamate (83.1, 450 mg, 0.697 mmol) in THF(5 mL) was added TBAF in THF (1M 35 L) h i i d 25 °C for 2 h. The reaction was extracted with EA (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE from 2% to 50%) to obtain 112.1 as a white solid (320 mg, 82% yield). MS (ESI): mass calcd. for C25H34N6O7, 530.25, m/z found 531.2 [M+H] + . Step 2. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl 2-cyclohexylacetate (112.2). [00432] The compound 112.2 was prepared according to the procedure of Example 1, Step 4, using 112.1 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C33H46FN6O8, 654.34, m/z found 655.3 [M+H] + . Step 3. Synthesis of [(2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo [2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 2-cyclohexylacetate (112). [00433] To a solution of [(3aR,4R,6R,6aR)-6-{4-[(2S)-2-{[(tert-butoxy)carbonyl]amino} -3- methylbutanamido]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-6-cyano- 2,2-dimethyl-dihydro-3aH-furo[3,4- d][1,3]dioxol-4-yl]methyl 2-cyclohexylacetate (112.2, 80 mg, 0.122 mmol) in THF (2 mL) and water (1 mL) was added HCl in dioxane (4 M, 2 mL), the mixture was stirred at 25 °C for 6 h. The reaction was concentrated in vacuo and purified by prep-HPLC to afford the salt-forming compound. The compound was filtered, and the filter cake was washed with water (5 mL x 3). Then the product was dried by lyophilization to give the title compound (26.02 mg, 41%) as a white solid. MS (ESI): mass calcd. for C25H34N6O6, 514.25, m/z found 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.22 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.55 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.13 (s, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 6.0 Hz, 1H), 4.65-4.63 (m, 2H), 4.35 – 4.26 (m, 1H), 4.22-4.20 (m, 1H), 4.16 (dd, J = 12.0, 5.2 Hz, 1H), 3.92-3.90 (m, 1H), 2.17-2.14 (m, 3H), 1.61-1.59 (m, 6H), 1.14-1.06 (m, 3H), 0.96 (dd, J = 6.8, 4.0 Hz, 6H), 0.90 – 0.87 (m, 2H). Example 67. Synthesis of (2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo[ 2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 2-phenylacetate (Compound 113). Step 1. Synthesis of [(3aR,4R,6R,6aR)-6-{4-[(2S)-2-{[(tert-butoxy)carbonyl]amino} -3- methylbutanamido]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-6-cyano- 2,2-dimethyl-dihydro-3aH-furo[3,4- d][1,3]dioxol-4-yl]methyl 2-phenylacetate (113.1). [00434] The compound 113.1 was prepared according to the procedure of Example 1, Step 4, using 112.1 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C33H40N6O8, 648.29, m/z found 649.3 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo[ 2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 2-phenylacetate (113). [00435] The compound 113 was prepared according to the procedure of Example 112, Step 3, using 113.1. MS (ESI): mass calcd. for C25H28N6O6, 508.21, m/z found 509.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.27 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.58 (s, 1H), 7.32 – 7.21 (m, 6H), 7.12 (s, 1H), 6.79 (d, J = 4.4 Hz, 1H), 6.40 (d, J = 5.2 Hz, 1H), 5.49 (d, J = 5.2 Hz, 1H), 4.65 (t, J = 8.0 Hz, 2H), 4.34 (dd, J = 11.6, 2.4 Hz, 1H), 4.28 – 4.15 (m, 2H), 3.94-3.92 (m, 1H), 3.66 (s, 2H), 2.20-2.15 (m, 1H), 0.96 (dd, J = 6.8, 4.4 Hz, 6H). Example 68. Synthesis of [(2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo [2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 2-methylpropanoate (Compound 116). Step 1. Synthesis of [(3aR,4R,6R,6aR)-6-{4-[(2S)-2-{[(tert-butoxy)carbonyl]amino} -3- methylbutanamido]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-6-cyano- 2,2-dimethyl-dihydro-3aH-furo[3,4- d][1,3]dioxol-4-yl]methyl 2-methylpropanoate (116.1). [00436] The compound 116.1 was prepared according to the procedure of Example 1, Step 4, using 112.1 and 2-methylpropanoyl chloride. MS (ESI): mass calcd. for C29H40N6O8, 600.29, m/z found 601.3 [M+H] + . Step 2: Synthesis of [(2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo [2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 2-methylpropanoate (116). [00437] The compound 116 was prepared according to the procedure of Example 112, Step 3, using 116.1. MS (ESI): mass calcd. for C21H28N6O6, 460.21, m/z found 461.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.21 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.13 (s, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.34-6.25 (m, 1H), 5.39-5.25 (m, 1H), 4.66-4.62 (m, 2H), 4.31 (dd, J = 12.0, 2.4 Hz, 1H), 4.23-4.21 (m, 1H), 4.16 (dd, J = 12.0, 5.2 Hz, 1H), 3.95 (d, J = 5.2 Hz, 1H), 2.53-2.50 (m, 1H), 2.18-2.15 (m, 1H), 1.05 (dd, J = 7.2, 2.8 Hz, 6H), 0.96 (dd, J = 6.8, 3.2 Hz, 6H). Example 69. Synthesis of [(2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo [2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 3-methylbutanoate (Compound 117). Step 1. Synthesis of [(3aR,4R,6R,6aR)-6-{4-[(2S)-2-{[(tert-butoxy)carbonyl]amino} -3- methylbutanamido]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-6-cyano- 2,2-dimethyl-dihydro-3aH-furo[3,4- d][1,3]dioxol-4-yl]methyl 3-methylbutanoate (117.1). [00438] The compound 117.1 was prepared according to the procedure of Example 1, Step 4, using 117.1 and 3-methylbutanoyl chloride. MS (ESI): mass calcd. for C30H42N6O8, 614.31, m/z found 615.3 [M+H] + . Step 2. Synthesis of [(2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo [2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]meth yl 3-methylbutanoate (117). [00439] The compound 117 was prepared according to the procedure of Example 112, Step 1, using 117.1 and 3-methylbutanoyl chloride. MS (ESI): mass calcd. for C22H30N6O6, 474.22, m/z found 475.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.23 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.13 (s, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 5.40 (d, J = 6.0 Hz, 1H), 4.69 – 4.60 (m, 2H), 4.33 (dd, J = 12.0, 2.4 Hz, 1H), 4.26 – 4.19 (m, 1H), 4.16 (dd, J = 12.0, 5.6 Hz, 1H), 3.93-3.92 (m, 1H), 2.18-2.15 (m, 3H), 1.98 – 1.87 (m, 1H), 0.96 (dd, J = 6.8, 3.6 Hz, 6H), 0.87 (dd, J = 6.8, 2.4 Hz, 6H). Example 70. Synthesis of (2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo[ 2,1- f][1,2,4]triazin-7-yl}-5-cyano-4-hydroxy-2-(hydroxymethyl)ox olan-3-yl (2S)-2-amino-3- methylbutanoate (Compound 129). Step 1. Synthesis of (2R,3S,4R,5R)-5-{4-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3- methylbutanamido]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-2-({1-[t ert- butyl(hydroxy)phenylsilyl]phenyl}methyl)-5-cyano-4-hydroxyox olan-3-yl (2S)-2-{[(tert- butoxy)carbonyl]amino}-3-methylbutanoate (129.1). [00440] The compound 129.1 was prepared according to the procedure of Example 83., Step 1, using 129.1 and (2S)-2-cyclohexylpropanoic acid. MS (ESI): mass calcd. for C48H65N7O10Si, 927.46, m/z found 928.5 [M+H] + . Step 2. (2R,3S,4R,5R)-5-{4-[(2S)-2-amino-3-methylbutanamido]pyrrolo[ 2,1-f][1,2,4]triazin-7-yl}-5- cyano-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl (2S)-2-amino-3-methylbutanoate (129). [00441] To a solution of (2R,3S,4R,5R)-5-{4-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3- methylbutanamido]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-2-{[(ter t-butyldiphenylsilyl)oxy]methyl}-5-cyano- 4-hydroxyoxolan-3-yl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoate (129.2, 100 mg, 0.107 mmol) in THF (2 mL) was added HCl in dioxane (4 M, 3 mL) and TBAF in THF(1 M, 4 mL), the mixture was stirred at 25 °C for 16 h. The reaction was concentrated in vacuo and purified by prep-HPLC to afford the salt-forming compound. The compound was basified by NaHCO3 (sat. aqueous, 1 mL) and purified by prep-HPLC to obtain 129 as a white solid (11.58 mg, 22% yield). MS (ESI): mass calcd. for C22H31N7O6, 489.23, m/z found 490.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.26 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.26 (d, J = 4.4 Hz, 1H), 7.14 (s, 1H), 6.90 (d, J = 4.4 Hz, 1H), 6.4-6.45 (m, 1H), 5.19 (dd, J = 5.6, 3.6 Hz, 1H), 5.02-5.00 (m, 2H), 4.66 (t, J = 8.0 Hz, 1H), 4.25-4.23 (m, 1H), 3.59- 3.55 (m, 2H), 3.23 (d, J = 5.2 Hz, 1H), 2.18-2.14 (m, 1H), 2.0-1.98 (m, 1H), 0.97 – 0.85 (m, 12H). Example 71. Synthesis of [(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluor o-3- hydroxy-4-methyloxolan-2-yl]methyl (2S)-2-amino-3-methylbutanoate (Compound 176). Step 1. Synthesis of ([(2R,3R,4R,5R)-5-[2-amino-6-(methylamino) purin-9-yl]-4-fluoro-3-hydroxy- 4-methyloxolan-2-yl] methyl (2S)-2-{[(tert-butoxy) carbonyl]amino}-3-methylbutanoate methane (176.1). [00442] The compound 176.1 was prepared according to the procedure of Example 19, Step 1, using 3.3 and (2S)-2-{[(tert-butoxy) carbonyl] amino}-3-methylbutanoic acid. MS (ESI): mass calcd. for C22H34FN7O6, 511.26 m/z found 512.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.81 (s, 1H), 7.30 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.03-6.00 (m, 3H), 5.80 (d, J = 6.8 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.37(dd, J = 12.0, 7.2 Hz, 1H), 4.06 (t, J = 8.0 Hz, 1H), 3.86 (t, J = 8.0 Hz, 1H), 3.30-3.25 (m, 1H),2.87 (s, 3H), 2.02- 1.98 (m, 1H), 1.36 (s, 9H), 1.09 (d, J = 22.4 Hz, 3H), 0.86 (dd, J = 6.8, 2.4 Hz, 6H). Step 2. Synthesis of [(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluor o-3-hydroxy-4- methyloxolan-2-yl]methyl (2S)-2-amino-3-methylbutanoate (176). [00443] The title compound 176 was prepared according to the procedure of Example 19, Step 2, using 176.1. MS (ESI): mass calcd. for C17H26FN7O4, 411.20, m/z found 412.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.83 (s, 1H), 7.34 (s, 1H), 6.12 – 5.97 (m, 3H), 5.82-5.80 (m, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.34 (dd, J = 12.4, 6.4 Hz, 2H), 4.10 – 4.05 (m, 1H), 3.18 ((d, J = 5.2 Hz, 1H), 2.87 (s, 3H), 1.86-1.83 (m, 1H), 1.10 (d, J = 22.4 Hz, 3H), 0.85 (dd, J = 17.2, 6.8 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ - 159.87 (s, 1H). Example 72. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-f luoro-3- hydroxy-4-methyltetrahydrofuran-2-yl)methyl propionate (Compound 180). [00444] The title compound was prepared according to the procedure of Example 3, Step 3, using propanoyl chloride. MS (ESI): mass calcd. for C15H21FN6O4, 368.16, m/z found 369.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.32 (br s, 1H), 6.0-6.05 (m, 3H), 5.76 (br d, J = 6.8 Hz, 1H), 4.29-4.47 (m, 4H), 4.04 (m, 1H), 2.87 (br s, 3H), 2.34-2.40 (m, 2H), 1.02-1.14 (m, 6H). Example 73. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-2-(( 2- cyclohexylacetoxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3 -yl 3-methylbutanoate (Compound 183). [00445] To a solution of 175 (100 mg, 0.22 mmol) in NMP was added 4 M HCl/dioxane (0.1 mL) dropwise at 0 o C. The mixture was then stirred at 0 o C for 30 minutes. After that, 3-methylbutanoyl chloride was added into the mixture slowly. The reaction mixture was stirred at 20 o C for 16 hours. After completion, the mixture was purified by prep-HPLC to afford 183 (12 mg, 9.9% yield) as a white solid. MS (ESI): m/z calcd. for C 25 H 37 FN 6 O 5 , 520.28, found 521.20 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.95 (s, 3H), 4.45 (d, J = 9.2 Hz, 1H), 4.33 (dd, J = 15.2, 6.0 Hz, 2H), 2.87 (s, 3H), 2.37 – 2.31 (m, 2H), 2.21 (d, J = 6.4 Hz, 2H), 2.03 (dt, J = 13.6, 6.8 Hz, 1H), 1.62 (dd, J = 21.2, 10.4 Hz, 6H), 1.24 – 1.09 (m, 6H), 0.93 (dt, J = 17.2, 8.4 Hz, 8H). 19 F NMR (377 MHz, DMSO) δ -156.31 (s, 1F). Example 74. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 3-methylbutanoate (Compound 185). [00446] The title compound was prepared according to the procedure of Example 183, using 177 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C25H31FN6O5514.23, found 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.48 – 7.13 (m, 6H), 6.13 (d, J = 19.6 Hz, 1H), 6.04 – 5.74 (m, 3H), 4.51 – 4.43 (m, 1H), 4.41 – 4.28 (m, 2H), 3.72 (d, J = 2.8 Hz, 2H), 2.87 (s, 3H), 2.34 – 2.30 (m, 2H), 2.06 – 1.97 (m, 1H), 1.14 (d, J = 23.2 Hz, 3H), 0.94 (dd, J = 6.8, 1.2 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -156.01. Example 75. Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2-amino-6-(methylamino)-9 H- purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl 3-methylbutanoate (Compound 186). [00447] The title compound was prepared according to the procedure of Example 183, using 178 and 3-methylbutanoyl chloride. MS (ESI): m/z calcd. for C19H27FN6O5438.20, found 439.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.05 (d, J = 70.8 Hz, 3H), 7.17 – 7.09 (m, 1H), 6.97 (d, J = 4.4 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 6.34 (s, 1H), 5.40 (s, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.38 – 4.18 (m, 3H), 3.98 – 3.83 (m, 2H), 1.96 (d, J = 6.8 Hz, 1H), 1.34 (d, J = 32.4 Hz, 9H), 0.82 (t, J = 6.0 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -156.17 (s, 1F). Example 76. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-((propionyloxy)methyl)tetrahydrofuran-3-yl 3-methylbutanoate (Compound 188). [00448] The title compound was prepared according to the procedure of Example 183, using 180 and 3-methylbutanoyl chloride. MS (ESI): m/z calcd. for C 20 H 29 FN 6 O 5 452.22, found 453.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.2 Hz, 1H), 5.90 (s, 3H), 4.46 (d, J = 9.6 Hz, 1H), 4.39 – 4.27 (m, 2H), 2.87 (s, 3H), 2.39 – 2.30 (m, 4H), 2.10 – 1.97 (m, 1H), 1.15 (d, J = 22.8 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H), 0.94 (dd, J = 6.8, 2.0 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ - 156.26. Example 77. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3-( 2- cyclohexylacetoxy)-4-fluoro-4-methyltetrahydrofuran-2-yl)met hyl 3-methylbutanoate (Compound 190). [00449] The title compound was prepared according to the procedure of Example 183, Step 1, using Compound 174 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C 25 H 37 FN 6 O 5 , 520.28, m/z found 521.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 6.02 – 5.74 (m, 3H), 4.44 (t, J = 8.4 Hz, 1H), 4.37 – 4.23 (m, 2H), 2.87 (s, 3H), 2.33 (d, J = 6.8 Hz, 2H), 2.22 (d, J = 6.8 Hz, 2H), 1.98 (dt, J = 13.6, 6.8 Hz, 1H), 1.76 – 1.58 (m, 6H), 1.27 – 1.10 (m, 6H), 1.05 – 0.93 (m, 2H), 0.90 (dd, J = 6.8, 2.4 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -156.30. Example 78. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-2-(( 2- cyclohexylacetoxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3 -yl 2-cyclohexylacetate (Compound 191). [00450] The title compound was prepared according to the procedure of Example 183, Step 1, using Compound 175 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C28H41FN6O5, 560.31, m/z found 561.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 6.05 – 5.80 (m, 3H), 4.47 – 4.41 (m, 1H), 4.35 – 4.27 (m, 2H), 2.87 (s, 3H), 2.33 (d, J = 6.8 Hz, 2H), 2.21 (d, J = 6.8 Hz, 2H), 1.74 – 1.61 (m, 11H), 1.26 – 1.10 (m, 10H), 1.02 – 0.86 (m, 4H). 19 F NMR (376 MHz, DMSO) δ -156.30. Example 79. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3-( 2- cyclohexylacetoxy)-4-fluoro-4-methyltetrahydrofuran-2-yl)met hyl 2-phenylacetate (Compound 193). [00451] The title compound was prepared according to the procedure of Example 183, Step 1, using Compound 177 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C28H35FN6O5, 554.27, m/z found 555.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.51 – 7.12 (m, 6H), 6.13 (d, J = 19.6 Hz, 1H), 5.95 – 5.74 (m, 3H), 4.48 (dd, J = 12.4, 2.8 Hz, 1H), 4.42 – 4.25 (m, 2H), 3.71 (d, J = 2.8 Hz, 2H), 2.87 (s, 3H), 2.32 (d, J = 6.8 Hz, 2H), 1.70 – 1.63(m, 6H), 1.25 – 1.10 (m, 6H), 1.09 – 0.92(m, 2H). 19 F NMR (376 MHz, DMSO) δ -155.98. Example 80. Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2-amino-6-(methylamino)-9 H- purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 194). [00452] The title compound was prepared according to the procedure of Example 183, Step 1, using Compound 178 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C 22 H 31 FN 6 O 5 , 478.23, m/z found 479.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.80 – 5.60 (m, 3H), 4.46 – 4.42 (m, 1H), 4.35 – 4.27 (m, 2H), 2.87 (s, 3H), 2.33 (d, J = 6.8 Hz, 2H), 2.04 (s, 3H), 1.70 – 1.60 (m, 6H), 1.24 – 1.10 (m, 6H), 1.03 – 0.94 (m, 2H). 19 F NMR (376 MHz, DMSO) δ -156.14. Example 81. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3-( 2- cyclohexylacetoxy)-4-fluoro-4-methyltetrahydrofuran-2-yl)met hyl propionate (Compound 196). [00453] The title compound was prepared according to the procedure of Example 183, Step 1, using Compound 180 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C23H33FN6O5, 492.25, m/z found 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 6.05 – 5.80 (m, 3H), 4.48 – 4.43 (m, 1H), 4.39 – 4.26 (m, 2H), 2.87 (s, 3H), 2.39 – 2.30 (m, 4H), 1.75 – 1.58 (m, 6H), 1.28 – 1.10 (m, 6H), 1.06 – 0.93 (m, 5H). 19 F NMR (376 MHz, DMSO) δ -156.23. Example 82. Synthesis of [(2R,3R,4R,5R)-5-[2-amino-6-(methylamino) purin-9-yl]-4-fluoro-4- methyl-3-[(2-phenylacetyl)oxy]oxolan-2-yl]methyl 3-methylbutanoate (Compound 206) and [(2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-[6-(methylamino )-2-(2-phenylacetamido)purin-9- yl]oxolan-2-yl]methyl 3-methylbutanoate(Compound 316) [0 0454] The title compounds 206 and 316 were prepared according to the procedure of Example 65, Step 1, using 174 and 22-phenylacetyl chloride. [00455] For compound 206: MS (ESI): mass calcd. for C25H31FN6O5, 514.23, m/z found 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.87 (s, 1H), 7.40 – 7.25 (m, 6H), 6.13 (d, J = 19.6 Hz, 1H), 5.92-5.90 (m, 3H), 4.44 (t, J = 7.2 Hz, 1H), 4.35 – 4.29 (m, 2H), 3.83(d, J = 2.0 Hz, 2H), 2.86 (s, 3H), 2.18 (dd, J = 7.2, 2.8 Hz, 2H), 1.96-1.92 (m, 1H), 1.12 (d, J = 22.8 Hz, 3H), 0.88 (dd, J = 6.8, 3.2 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -156.22. [00456] For compound 316: MS (ESI): mass calcd. for C25H31FN6O5, 514.23, m/z found 515.2 [M+H] + . 1 H NMR (400 MHz) δ 10.25 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.33-7.21 (m, 5H), 6.13 (d, J = 20.0 Hz, 1H), 5.66 (d, J = 6.8 Hz, 1H), 4.78-4.70 (m, 1H), 4.47(dd, J = 12.4, 2.0 Hz, 1H), 4.33-4.30 (m, 1H), 4.04 (t, J = 7.6 Hz, 1H), 3.83 (s, 2H), 2.94 (s, 3H), 2.20 (d, J = 7.2 Hz, 2H), 1.97-1.94 (m, 1H), 1.12 (d, J = 22.8Hz, 3H), 0.89 (dd, J = 6.8, 1.6 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -158.53. Example 83. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 209). [00457] The title compound was prepared according to the procedure of Example 183, Step 1, using Compound 177 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C28H29FN6O5, 548.22, m/z found 549.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.44 – 7.18 (m, 11H), 6.14 (d, J = 19.6 Hz, 1H), 5.91 (s, 3H), 4.49 – 4.25(m, 1H), 4.40 – 4.29 (m, 2H), 3.83 (d, J = 2.0 Hz, 2H), 3.68 (d, J = 4.8 Hz, 2H), 2.87 (s, 3H), 1.12 (d, J = 22.8 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -155.94. Example 84. Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2-amino-6-(methylamino)-9 H- purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl 2-phenylacetate (Compound 210). [00458] The title compound was prepared according to the procedure of Example 183, using 178 and 2-phenylacetyl chloride. MS (ESI): m/z calcd. for C 22 H 25 FN 6 O 5 472.19, found 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.40 – 7.23 (m, 6H), 6.13 (d, J = 19.6 Hz, 1H), 5.91 (s, 3H), 4.48 – 4.41 (m, 1H), 4.35 – 4.27 (m, 2H), 3.83 (d, J = 1.6 Hz, 2H), 2.87 (s, 3H), 2.01 (s, 3H), 1.12 (d, J = 22.8 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -156.10. Example 85. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-f luoro-4- methyl-3-(2-phenylacetoxy)tetrahydrofuran-2-yl)methyl propionate (Compound 212). [00459] The title compound was prepared according to the procedure of Example 183, using 180 and 2-phenylacetyl chloride. MS (ESI): m/z calcd. for C23H27FN6O5486.20, found 487.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.40 – 7.23 (m, 6H), 6.13 (d, J = 19.2 Hz, 1H), 5.92 (s, 3H), 4.51 – 4.40 (m, 1H), 4.36 – 4.28 (m, 2H), 3.83 (d, J = 2.8 Hz, 2H), 2.87 (s, 3H), 2.36 – 2.24 (m, 2H), 1.12 (d, J = 23.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -156.17. Example 86. Synthesis of ((2R,3R,4R,5R)-3-acetoxy-5-(2-amino-6-(methylamino)-9H-purin -9-yl)- 4-fl r 4 m th lt tr h dr f r n 2 l m th l 3 m th lb t n t C m nd 214 [00460] The title compound was prepared according to the procedure of Example 183, using 174 and acetyl chloride. MS (ESI): m/z calcd. for C 19 H 27 FN 6 O 5 438.20, found 439.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.2 Hz, 1H), 6.04 – 5.65 (m, 3H), 4.46 (dd, J = 12.0, 2.8 Hz, 1H), 4.39 – 4.27 (m, 2H), 2.87 (s, 3H), 2.25 – 2.19 (m, 2H), 2.15 (s, 3H), 2.03 – 1.92 (m, 1H), 1.15 (d, J = 23.2 Hz, 3H), 0.90 (dd, J = 6.4, 2.4 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -156.44. Example 87. Synthesis of ((2R,3R,4R,5R)-3-acetoxy-5-(2-amino-6-(methylamino)-9H-purin -9-yl)- 4-fluoro-4-methyltetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 215). [00461] The title compound was prepared according to the procedure of Example 183, using 175 and acetyl chloride. MS (ESI): m/z calcd. for C22H31FN6O5478.23, found 479.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.38 (s, 1H), 6.12 (d, J = 19.6 Hz, 1H), 6.04 – 5.68 (m, 3H), 4.49 – 4.41 (m, 1H), 4.37 – 4.26 (m, 2H), 2.87 (s, 3H), 2.21 (d, J = 6.8 Hz, 2H), 2.15 (s, 3H), 1.70 – 1.55 (m, 6H), 1.25 – 1.04 (m, 6H), 0.98 – 0.85 (m, 2H). 19 F NMR (377 MHz, DMSO) δ -156.39. Example 88. Synthesis of ((2R,3R,4R,5R)-3-acetoxy-5-(2-amino-6-(methylamino)-9H-purin -9-yl)- 4-fluoro-4-methyltetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 217). [00462] The title compound was prepared according to the procedure of Example 183, using 177 and acetyl chloride. MS (ESI): m/z calcd. for C22H25FN6O5472.19, found 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.41 – 7.22 (m, 6H), 6.13 (d, J = 19.6 Hz, 1H), 6.04 – 5.71 (m, 3H), 4.49 (dd, J = 12.4, 2.8 Hz, 1H), 4.42 – 4.27 (m, 2H), 3.71 (d, J = 2.4 Hz, 2H), 2.87 (s, 3H), 2.14 (s, 3H), 1.15 (d, J = 22.8 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -156.12. Example 89. Synthesis of ((2R,3R,4R,5R)-3-acetoxy-5-(2-amino-6-(methylamino)-9H-purin -9-yl)- 4-fluoro-4-meth ltetrah drofuran-2- l)meth l acetate (Compound 218). [00463] To a solution of 3.3 (500 mg, 1.6 mmol) in DMA (1 mL) was added HCl/dioxane (0.8 mL, 4 M). The mixture solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and Acetyl chloride (0.91 mL, 12.8 mmol) was added at once. The reaction was stirred at 0 ℃ for 1 hour. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to obtain 218 (24.5 mg, 3.83% yield) as a white solid. MS (ESI): m/z calcd. for C16H21FN6O5, 396.16, found 397.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.93 – 5.80 (m, 3H), 4.50– 4.37 (m, 1H), 4.38 – 4.26 (m, 2H), 2.87 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H), 1.15 (d, J = 22.8 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -156.30. Example 90. Synthesis of [(2R,3R,4R,5R)-3-(acetyloxy)-5-[2-amino-6-(methylamino)purin -9-yl]-4- fluoro-4-methyloxolan-2-yl]methyl 2-methylpropanoate (Compound 219) and [(2R,3R,4R,5R)-3- (acetyloxy)-5-[2-acetamido-6-(methylamino)purin-9-yl]-4-fluo ro-4-methyloxolan-2-yl]methyl 2- methylpropanoate (Compound 323). [00464] The title compound 219&323 was prepared according to the procedure of Example 65, Step 1, using 179 and acetyl chloride. [00465] For compound 219: MS (ESI): mass calcd. for C18H25FN6O5, 424.19, m/z found 425.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.40 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.90-5.86 (m, 3H), 4.45-4.44 (m, 1H), 4.37-4.31 (m, 2H), 2.87 (s, 3H), 2.58-2.52 (m, 1H), 2.15 (s, 3H), 1.20 – 1.07 (m, 9H). 19 F NMR (376 MHz, DMSO) δ -156.51. [00466] For compound 323: MS (ESI): mass calcd. for C20H27FN6O6, 466.20, m/z found 467.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 6.23 (d, J = 19.6 Hz, 1H), 6.11- 6.08 (m, 1H), 4.47 – 4.37 (m, 2H), 4.36 – 4.29 (m, 1H), 2.94 (s, 3H), 2.55-2.51 (m, 1H), 2.20 (s, 3H), 2.14 (s, 3H), 1.17 (d, J = 23.2 Hz, 3H), 1.08 (dd, J = 7.2, 1.2 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ - 155.42. Example 91. Synthesis of ((2R,3R,4R,5R)-3-acetoxy-5-(2-amino-6-(methylamino)-9H-purin -9-yl)- 4-fluoro-4-methyltetrahydrofuran-2-yl)methyl propionate (Compound 220).
[00467] The title compound was prepared according to the procedure of Example 183, using 180 and acetyl chloride. MS (ESI): m/z calcd. for C 17 H 23 FN 6 O 5 410.17, found 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.2 Hz, 1H), 6.05 – 5.69 (m, 3H), 4.51 – 4.43 (m, 1H), 4.38 – 4.28 (m, 2H), 2.87 (s, 3H), 2.39 – 2.31 (m, 2H), 2.15 (s, 3H), 1.15 (d, J = 22.8 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -156.39. Example 92. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-f luoro-3- (isobutyryloxy)-4-methyltetrahydrofuran-2-yl)methyl 3-methylbutanoate (Compound 222). [00468] The title compound was prepared according to the procedure of Example 183, using 174 and 2-methylpropanoyl chloride. MS (ESI): m/z calcd. for C21H31FN6O5466.23, found 467.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.2 Hz, 1H), 6.05 – 5.70 (m, 3H), 4.49 – 4.39 (m, 1H), 4.37 – 4.28 (m, 2H), 2.87 (s, 3H), 2.72 – 2.64 (m, 1H), 2.22 (dd, J = 6.8, 1.2 Hz, 2H), 2.03 – 1.92 (m, 1H), 1.18 – 1.09 (m, 9H), 0.89 (dd, J = 6.8, 2.4 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -156.75. Example 93: Synthesis of (2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-2-{[(2- cyclohexylacetyl)oxy]methyl}-4-fluoro-4-methyloxolan-3-yl 2-methylpropanoate (Compound 223) and [(2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-[6-(methylamino )-2-(2- methylpropanamido)purin-9-yl]oxolan-2-yl]methyl 2-cyclohexylacetate (Compound 335).
[00469] The title compounds 223 and 335 were prepared according to the procedure of Example 65, Step 1, using 175 and 2-methylpropanoyl chloride. [00470] For compound 223: MS (ESI): mass calcd. for C24H35FN6O5, 506.27, m/z found 507.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.94-5.80 (m, 3H), 4.45-4.44 (m, 1H), 4.33-4.30 (m, 2H), 2.87 (s, 3H), 2.68-2.64 (m, 1H), 2.19 (dd, J = 6.8, 2.0 Hz, 2H), 1.76 – 1.58 (m, 6H), 1.21 – 1.07 (m, 12H), 0.97 – 0.88 (m, 2H). 19 F NMR (376 MHz, DMSO) δ -156.70. [00471] For compound 335: MS (ESI): mass calcd. for C24H35FN6O5, 506.27, m/z found 507.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.64 (d, J =6.8 Hz, 1H), 4.80-4.78 (m, 1H), 4.44 (dd, J = 12.4, 2.0 Hz, 1H), 4.3-4.30 (m, 1H), 4.04 (t, J = 8.0 Hz, 1H), 2.94-2.90 (m, 4H), 2.17 (d, J = 6.8 Hz, 2H), 1.62 (d, J = 12.0 Hz, 6H), 1.23 – 1.06 (m, 12H), 0.95 – 0.86(m, 2H). 19 F NMR (376 MHz, DMSO) δ -158.73. Example 94. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl isobutyrate (Compound 225). [00472] The title compound was prepared according to the procedure of Example 183, using 177 and isobutyryl chloride. MS (ESI): m/z calcd. for C 24 H 29 FN 6 O 5 500.22, found 501.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.38 (s, 1H), 7.38 – 7.17 (m, 5H), 6.16 (d, J = 19.6 Hz, 1H), 5.95 (s, 3H), 4.66 – 4.23 (m, 3H), 3.82 – 3.66 (m, 2H), 2.90 (s, 3H), 2.75 – 2.63 (m, 1H), 1.30 – 1.08 (m, 9H). 19 F NMR (377 MHz, DMSO) δ -156.45. Example 95. Synthesis of (2R,3R,4R,5R)-2-[(acetyloxy)methyl]-5-[2-amino-6-(methylamin o)purin- 9-yl]-4-fluoro-4-methyloxolan-3-yl 2-methylpropanoate (Compound 226). [00473] The title compound 226 was prepared according to the procedure of Example 65, Step 1, using 178 and isobutyryl chloride. For compound 226: MS (ESI): mass calcd. for C18H25FN6O5, 424.19, m/z found 425.1 [M+H] +. 1H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.94-5.90 (m, 3H), 4.44-4.40 (m, 1H), 4.38 – 4.25 (m, 2H), 2.87 (s, 3H), 2.68-2.63 (m, 1H), 2.02 (s, 3H), 1.18 – 1.09 (m, 9H). 19 F NMR (376 MHz, DMSO) δ -156.59. Example 96. Synthesis of ([(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluo ro-4- methyl-3-[(2-methylpropanoyl)oxy]oxolan-2-yl]methyl propanoate (Compound 228) and [(2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-[6-(methylamino )-2-(2-methylpropanamido)purin- 9-yl]oxolan-2-yl]methyl propanoate (Compound 319). [00474] The title compounds 228& 319 were prepared according to the procedure of Example 65, Step 1, using 180 and isobutyryl chloride. [00475] For compound 228: MS (ESI): mass calcd. for C19H27FN6O5, 438.20, m/z found 439.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.95-5.80 (m, 3H), 4.45-4.43 (m, 1H), 4.34-4.30 (m, 2H), 2.87 (s, 3H), 2.72-2.65 (m, 1H), 2.34-2.31 (m, 2H), 1.15-1.11 (m, 9H), 1.03 (t, J = 7.6 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -156.67. [00476] For compound 319: MS (ESI): mass calcd. for C 19 H 27 FN 6 O 5 , 438.20, m/z found 439.2 [M+H] + .1H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.63 (d, J = 6.8 Hz, 1H), 4.85-4.80 (m, 1H), 4.39-4.35 (m, 2H), 4.06 (t, J = 7.6 Hz, 1H), 2.94 (s, 3H), 2.51- 2.49 (m, 1H), 2.33-2.28 (m, 2H), 1.16 – 1.06 (m, 9H), 1.00 (t, J = 7.6 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -158.71. Example 97. Synthesis of [(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluor o-4- methyl-3-(propanoyloxy)oxolan-2-yl]methyl 3-methylbutanoate (Compound 230), [(2R,3R,4R,5R)- 4-fluoro-3-hydroxy-4-methyl-5-[6-(methylamino)-2-propanamido purin-9-yl]oxolan-2-yl]methyl 3- methylbutanoate (Compound 310), and [(2R,3R,4R,5R)-4-fluoro-4-methyl-5-[6-(methylamino)-2- propanamidopurin-9-yl]-3-(propanoyloxy)oxolan-2-yl]methyl 3-methylbutanoate (Compound 311).
[00477] The title compounds 230, 310, and 311 were prepared according to the procedure of Example 65, Step 1, using 174 and propanoyl chloride. [00478] For compound 230: MS (ESI): mass calcd. for C20H29FN6O5, 452.22, m/z found 453.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.94-5.90 (m, 3H), 4.46 (dd, J = 12.0, 2.4Hz, 1H), 4.40 – 4.26 (m, 2H), 2.87(s, 3H), 2.45 (d, J = 7.2 Hz, 2H), 2.25 – 2.17 (m, 2H), 1.98-1.94 (m, 1H), 1.14 (d, J = 22.8 Hz, 3H), 1.08 (t, J = 7.6 Hz, 3H), 0.90 (dd, J = 6.8, 2.8 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -156.52. [00479] For compound 310: MS (ESI): mass calcd. for C20H29FN6O5, 452.22, m/z found 453.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.66 (d, J = 7.2 Hz, 1H), 4.79-4.76 (m, 1H), 4.48 (dd, J = 12.4, 2.0 Hz, 1H), 4.35-4.32 (m, 1H), 4.05 (t, J = 8.0 Hz, 1H), 2.93 (s, 3H), 2.52-2.50 (m, 2H), 2.18 (d, J = 6.8 Hz, 2H), 1.96-1.93 (m, 1H), 1.13 (d, J = 22.8 Hz, 3H), 1.06 (t, J = 7.6 Hz, 3H), 0.88 (dd, J = 6.8, 1.6 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -158.47. [00480] For compound 311: MS (ESI): mass calcd. for C23H33FN6O6, 508.24, m/z found 509.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 6.23 (d, J = 20.0 Hz, 1H), 6.08 (d, J = 15.6 Hz, 1H), 4.42-4.37 (m, 2H), 4.35 – 4.27 (m, 1H), 2.94 (s, 3H), 2.54-2.51 (m, 2H), 2.45-2.42 (m, 2H), 2.19 (d, J = 7.2 Hz, 2H), 1.96-1.90 (m, 1H), 1.18 (d, J = 23.6 Hz, 3H), 1.06-1.03 (m, 6H), 0.89 (dd, J = 6.8, 2.0 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -155.59. Example 98. Synthesis of [(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluor o-4- methyl-3-(propanoyloxy)oxolan-2-yl]methyl cyclohexanecarboxylate (Compound 231) and [(2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-[6-(methylamino )-2-propanamidopurin-9- yl] l 2 l th l l h b l t C d 327 [00481] The title compounds 231 and 327 were prepared according to the procedure of Example 65, Step 1, using 175 and propanoyl chloride. [00482] For compound 231: MS (ESI): mass calcd. for C23H33FN6O5, 492.25, m/z found 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.93-5.80 (m, 3H), 4.45 (d, J = 8.0 Hz, 1H), 4.33-4.25 (m, 2H), 2.87 (s, 3H), 2.44 (d, J = 7.6 Hz, 2H), 2.24 – 2.17 (m, 2H), 1.74 – 1.58 (m, 6H), 1.21 – 1.03 (m, 9H), 0.97 – 0.86 (m, 2H). 19 F NMR (376 MHz, DMSO) δ -156.46. [00483] For compound 327: MS (ESI): mass calcd. for C23H33FN6O5, 492.25, m/z found 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 6.12 (d, J = 19.8 Hz, 1H), 5.65 (d, J = 6.8 Hz, 1H), 4.78-4.75 (m, 1H), 4.47 (dd, J = 12.4, 2.0 Hz, 1H), 4.33 (dd, J = 12.4, 7.2 Hz, 1H), 4.04 (t, J = 7.8 Hz, 1H), 2.93 (s, 3H), 2.18 (d, J = 6.8 Hz, 2H), 1.62-1.60 (m, 6H), 1.22 – 1.02 (m, 9H), 0.98 – 0.85 (m, 2H). 19 F NMR (376 MHz, DMSO) δ -158.51. Example 99. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl propionate (Compound 233). [00484] The title compound was prepared according to the procedure of Example 183, using 177 and propionyl chloride. MS (ESI): m/z calcd. for C23H27FN6O5486.20, found 487.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.49 – 7.33 (m, 1H), 7.33 – 7.21 (m, 5H), 6.13 (d, J = 19.6 Hz, 1H), 5.93 (s, 3H), 4.49 (dd, J = 12.0, 2.8 Hz, 1H), 4.38 (dd, J = 12.0, 6.0 Hz, 1H), 4.35 – 4.27 (m, 1H), 3.77 – 3.64 (m, 2H), 2.87 (s, 3H), 2.45 (q, J = 7.2 Hz, 2H), 1.20 – 1.04 (m, 6H). 19 F NMR (377 MHz, DMSO) δ - 156.22. Example 100. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-((propionyloxy)methyl)tetrahydrofuran-3-yl propionate (Compound 236). [00485] The title compound was prepared according to the procedure of Example 183, using 180 and propionyl chloride. MS (ESI): m/z calcd. for C 18 H 25 FN 6 O 5 424.19, found 425.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.38 (s, 1H) 613 (d J = 196 Hz 1H) 594 (s 3H) 447 (d, J = 9.2 Hz, 1H), 4.38 – 4.28 (m, 2H), 2.88 (s, 3H), 2.45 (q, J = 7.6 Hz, 2H), 2.39 – 2.30 (m, 2H), 1.20 – 1.00 (m, 9H). 19 F NMR (377 MHz, DMSO) δ -156.47. Example 101. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-f luoro-3- hydroxy-4-methyltetrahydrofuran-2-yl)methyl (2-(octadecyloxy)ethyl) hydrogen phosphate (Compound 254). [00486] The title compound was prepared according to the procedure of Example 6, Step 3, utilizing alcohol 3.2. MS (ESI): mass calcd. for C32H58FN6O7P, 688.41, m/z found 687.4 [M-H]-. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (s, 1H), 6.14 (d, J = 18 Hz, 1H), 4.26-4.4 (m, 3H), 4.2 (m, 1H), 4.01 (m, 2H), 3.62 (m, 2H), 3.4 (m, 2H), 3.0-3.3 (m, 3H), 1.53 (m, 2H), 1.2-1.35 (br m, 30H), 1.19 (d, J = 22 Hz, 3H), 0.92 (t, J = 7 Hz, 3H). Example 102. Synthesis of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano- 3,4-dihydroxyoxolan-2-yl]methyl (2S)-3-methyl-2-(3-methylbutanamido)butanoate (Compound 255). [00487] The title compound 255 was prepared according to the procedure of Example 65, Step 1, using 11 and 3-methylbutanoyl chloride. For compound 231: MS (ESI): mass calcd. for C22H30FN6O6, 474.22, m/z found 475.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 8.0 Hz, 1H), 7.92 (br, s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.36-6.34 (m, 1H), 5.40-5.35 (m, 1H), 4.68-4.64 (m, 1H), 4.35 – 4.18 (m, 4H), 3.91-3.87 (m, 1H), 2.06 – 1.97 (m, 4H), 0.91 – 0.87 (m, 6H), 0.85 – 0.81 (m, 6H). Example 103. Synthesis of [({[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-y l}-5-cyano- 3,4-dihydroxyoxolan-2-yl]methoxy}({[(2,2- dimethylpropanoyl)oxy]methoxy})phosphoryl)oxy]methyl 2,2-dimethylpropanoate (Compound 256).
Step 1. Synthesis of N'-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)-N,N- dimethylformimidamide (256.1). [00488] To a solution of 6.3 (5.00 g, 17.2 mmol) in dry DMF (60 mL) was added DMF-DMA (2.46 g, 20.6 mmol). The reaction mixture was stirred at 70 °C for 2 h under nitrogen. The reaction mixture was diluted with EA (80 mL) and washed with water (150 mL × 2), followed by brine (150 mL × 2), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was slurried in MeOH (30 mL) for 1 h and filtered. The filter cake was washed with MeOH (5.0 mL), then dried in vacuo to give 256.1 (4.45 g, 74% yield) as a white solid. MS (ESI): m/z calcd. for C 15 H 18 N 6 O 4 346.14, found 347.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.15 (s, 1H), 6.99 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.12 (d, J = 6.4 Hz, 1H), 5.22 (d, J = 5.2 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.67 (dd, J = 6.4, 5.6 Hz, 1H), 4.08 (dd, J = 8.4, 4.4 Hz, 1H), 3.99 (q, J = 5.2 Hz, 1H), 3.68 – 3.61 (m, 1H), 3.56 – 3.48 (m, 1H), 3.25 (s, 3H), 3.19 (s 3H). Step 2. Synthesis of ((oxo-l5-phosphanetriyl)tris(oxy))tris(methylene) tris(2,2-dimethylpropanoate) (256.4). [00489] To a solution of 256.3 (5.00 g, 35.7 mmol) in dry ACN (30 mL) was sequentially added 256.2 (21.5 g, 0.143 mol) and sodium iodide (16.1 g, 0.107 mol). The reaction mixture was stirred at 80 °C for 72 h under nitrogen. TLC showed complete consumption of 256.3. The reaction mixture was diluted with Et2O (150 mL) and washed with water (80 mL × 2), followed by Sat. aq. Na2S2O3 (80 mL × 2), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 20% EA in PE) to give 256.4 (8.65 g, 55% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.66 (d, J = 13.6 Hz, 6H), 1.24 (s, 27H). 31 P NMR (162 MHz, CDCl3) δ -5.22. Step 3. Synthesis of ((hydroxyphosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (256.5). [00490] 256.3 (8.65 g, 20 mmol) was dissolved in piperidine (50 mL) and stirred at 20 °C for 16 h under nitrogen. TLC showed complete consumption of 256.3. The reaction mixture was concentrated until constant weight. The residue was dissolved in water (180 mL) and treated with Dowex W50 × 2 H + form resin (150 g). The suspension was stirred at 20 °C for 1 h and filtered. The filtrate was concentrated to remove the solvent. The residue was lyophilized to give 256.4 (7.46 g, crude) as a white wax. 1 H NMR (400 MHz, CDCl3) δ 5.57 (d, J = 12.4 Hz, 6H), 1.22 (s, 18H). 31 P NMR (162 MHz, CDCl3) δ -4.08. Step 4. Synthesis of [({[(2R,3S,4R,5R)-5-cyano-5-(4- {[(dimethylamino)methylidene]amino}pyrrolo[2,1-f][1,2,4]tria zin-7-yl)-3,4-dihydroxyoxolan-2- yl]methoxy}({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl )oxy]methyl 2,2- dimethylpropanoate (256.6). [00491] To a solution of 256.1 (500 mg, 1.44 mmol) in dry THF (20 mL) was added a solution of triethylammonium bis(POM)phosphate in THF (prepared from 265.5 (565 mg, 1.73 mmol), THF (5.0 mL) and TEA (190 mg, 1.88 mmol)). The resulting mixture was cooled to 0 °C in an ice-batch and DIPEA (746 mg, 5.77 mmol) was added, followed by BOP-Cl (735 mg, 2.89 mmol) and 3-nitro-l,2,4- triazole (329 mg, 2.89 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with DCM (150 mL) and washed with Sat. aq. NaHCO3 (25 mL × 2), followed by brine (25 mL). The aqueous phase was extracted with DCM (25 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% MeOH in DCM) to give 256.6 (71.1 mg, 7.5% yield) as a white solid. MS (ESI): m/z calcd. for C27H39N6O11P 654.24, found 655.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.14 (s, 1H), 6.92 (d, J = 4.8 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.37 (d, J = 6.0 Hz, 1H), 5.57 (s, 2H), 5.54 (s, 2H), 5.44 (d, J = 6.0 Hz, 1H), 4.73 – 4.69 (m, 1H), 4.32 – 4.23 (m, 2H), 4.20 – 4.14 (m, 1H), 3.96 (dd, J = 11.2, 5.6 Hz, 1H), 3.25 (s, 3H), 3.18 (s, 3H), 1.14 (d, J = 5.6 Hz, 18H). 31 P NMR (162 MHz, DMSO) δ -3.93. Step 5. Synthesis of [({[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-y l}-5-cyano-3,4- dihydroxyoxolan-2-yl]methoxy}({[(2,2-dimethylpropanoyl)oxy]m ethoxy})phosphoryl)oxy]methyl 2,2-dimethylpropanoate (Compound 256). [00492] A solution of 256.6 (71.1 mg, 0.109 mmol) in dry THF (1.0 mL) was added aq. HCl (0.5 mL, 1 M). The reaction mixture was radiated at 60 °C in microwave reactor for 10 min under nitrogen. The organic solvent was removed with flowing nitrogen. The residue was purified by Prep-HPLC to afford the title compound 256 (30.6 mg, 47% yield) as a white solid. MS (ESI): m/z calcd. for C 24 H 34 N 5 O 11 P 599.20, found 600.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 5.56 (dd, J = 14.0, 1.2 Hz, 4H), 5.43 (d, J = 5.6 Hz, 1H), 4.68 (t, J = 5.6 Hz, 1H), 4.31 – 4.21 (m, 2H), 4.19 – 4.12 (m, 1H), 3.96 – 3.90 (m, 1H), 1.14 (d, J = 5.2 Hz, 18H). 31 P NMR (162 MHz, DMSO) δ -3.93. Example 104. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(tetrahydro-2H-pyran-4-yl)acetate (Compound 257). Step 1. Synthesis of 2-(tetrahydro-2H-pyran-4-yl)acetyl chloride (257.2). [00493] To a solution of 257.1 (500 mg, 3.47 mmol) in dry DCM (7.0 mL) was added oxalyl chloride (660 mg, 5.20 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to dryness to give 257.2 (510 mg, crude) as a yellow oil, which was used directly in next step. Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(tetrahydro-2H-pyran-4-yl)acetate (257). [00494] To a solution 6.3 (100 mg, 0.343 mmol) in DMPU (1.0 mL) was added HCl/1,4-dioxane (0.1 mL, 4 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then 257.2 (510 mg, crude) was added dropwise into the flask vessel. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was purified by prep-HPLC to afford the title compound 257 (22.39 mg, 16% yield) as a white solid. MS (ESI): m/z calcd. for C 19 H 23 N 5 O 6 417.16, found 418.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.92 (d, J = 4.8 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 5.6 Hz, 1H), 4.69 (t, J = 5.6 Hz, 1H), 4.32 (dd, J = 11.6, 2.4 Hz, 1H), 4.25 – 4.14 (m, 2H), 3.94 (dd, J = 11.2, 6.0 Hz, 1H), 3.76 (dd, J = 11.2, 2.8 Hz, 2H), 3.23 (t, J = 11.6 Hz, 2H), 2.19 (dd, J = 6.8, 2.4 Hz, 2H), 1.89 – 1.77 (m, 1H), 1.51 (d, J = 11.6 Hz, 2H), 1.22 – 1.10 (m, 2H). Example 105. Synthesis of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano- 3,4-dihydroxyoxolan-2-yl]methyl 2-cyclopropylacetate (Compound 258). Step 1. Synthesis of 2-cyclopropylacetyl chloride (258.2). [00495] To a solution of 2-cyclopropylacetic acid (258.1, 500 mg, 5.0 mmol) in DCM (3 mL) was added oxalyl chloride (0.48 mL, 5.64 mmol), followed by a few drops of DMF at 0 ℃. The resulting solution was stirred at 20 ℃ for 1 h The mixture was concentrated in vacuo. and the resulting acid chloride was used for next step without further purification. Step 2. Synthesis of [(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}- 5-cyano-3,4- dihydroxyoxolan-2-yl]methyl 2-cyclopropylacetate (258). [00496] The compound 258 was prepared according to the procedure of Example 1., Step 4, using 6.3 and 258.2. MS (ESI): mass calcd. for C 17 H 19 N 5 O 5 , 373.14, m/z found 374.2 [M+H] + .1H NMR (400 MHz, DMSO) δ 7.92 (br, s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6.4 Hz, 1H), 5.38 (d, J = 5.6 Hz, 1H), 4.68 (t, J = 5.6 Hz, 1H), 4.34 (dd, J = 12.0, 2.8 Hz, 1H), 4.26 – 4.20 (m, 1H), 4.16 (dd, J = 12.0, 5.6 Hz, 1H), 3.95-3.91 (m, 1H), 2.25 – 2.18 (m, 2H), 0.95 – 0.84 (m, 1H), 0.4- 0.40 (m, 2H), 0.13 – 0.06 (m, 2H). Example 106. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclopentylacetate (Compound 259). [00497] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and 2-cyclopentylacetyl chloride. MS (ESI): mass calcd. for C19H23N5O5, 401.17, m/z found 402.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 6.0 Hz, 1H), 4.69 (t, J = 5.6 Hz, 1H), 4.31 (dd, J = 12.0, 2.8 Hz, 1H), 4.22 (dd, J = 10.4, 4.4 Hz, 1H), 4.15 (dd, J = 12.0, 5.6 Hz, 1H), 3.94 (dd, J = 11.2, 6.0 Hz, 1H), 2.27 (dd, J = 7.6, 2.0 Hz, 2H), 2.06 (dt, J = 15.6, 8.0 Hz, 1H), 1.75 – 1.65 (m, 2H), 1.60 – 1.42 (m, 4H), 1.12 – 1.01 (m, 2H). Example 107. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(2,3-dihydro-1H-inden-2-yl)acetate (Compound 260). [00498] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and 2-(2,3-dihydro-1H-inden-2-yl)acetyl chloride (prepared according to J. Am. Chem. Soc. (2019), 141(9), 3849-3853). MS (ESI): mass calcd. for C23H23N5O5, 449.17, m/z found 450.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (br s, 3H), 7.19 – 7.08 (m, 4H), 6.90 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.40 (d, J = 5.2 Hz, 1H), 4.71 (t, J = 5.2 Hz, 1H), 4.34 (dd, J = 11.2, 2.0 Hz, 1H), 4.27 – 4.17 (m, 2H), 3.99 – 3.93 (d, J = 4.0 Hz, 1H), 3.05 – 2.96 (m, 2H), 2.69 (dt, J = 14.8, 7.6 Hz, 1H), 2.60 – 2.52 (m, 2H), 2.47 (d, J = 1.8 Hz, 2H). Example 108. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cycloheptylacetate (Compound 261). Step 1: Synthesis of cycloheptanecarbonyl chloride (261.2). [00499] To a solution of 261.1 (500 mg, 3.2 mmol) in SOCl2 (1.33 g, 11.2 mmol) was stirred at 90 o C for 1.5 hours. The crude (530 mg, 93.8% yield) was used in the next step without any purification. Step 2: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cycloheptylacetate (261). [00500] To a solution of 6.3 (100 mg, 0.34 mmol) in DMPU (1 mL) was added 0.3 mL 4 M HCl dioxane dropwise at 0 o C, the mixture was then stirred for 30 minutes. Then added 261.2 (299 mg, 1.71 mmol) dropwise into the mixture and stirred for 3 hours. After completion, the mixture was diluted with water (2 mL) and purified by prep-HPLC to afford 261 as a white solid (90 mg, 60.4%). MS (ESI): m/z calcd. for C21H27N5O5, 429.20, found 430.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.8 Hz, 1H), 6.33 (d, J = 5.6 Hz, 1H), 5.38 (s, 1H), 4.69 (d, J = 4.8 Hz, 1H), 4.30 (dd, J = 11.6, 2.4 Hz, 1H), 4.25 – 4.12 (m, 2H), 3.94 (t, J = 5.6 Hz, 1H), 2.26 – 2.12 (m, 2H), 1.93 – 1.78 (m, 1H), 1.65 – 1.27 (m, 10H), 1.23 – 1.06 (m, 2H). Example 109. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)meth l 2 (44 difl l h l) t t (C nd 262). Step 1. Synthesis of 2-(4,4-difluorocyclohexyl)acetyl chloride (262.2). [00501] To a solution of 262.1 (400 mg, 2.25 mmol) in dry DCM (4.5 mL) was added oxalyl chloride (427 mg, 3.37 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to dryness to give 262.2 (431 mg, crude) as a yellow oil, which was used directly in next step. Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(4,4-difluorocyclohexyl)acetate (262). [00502] To a solution of 6.3 (100 mg, 0.343 mmol) in DMPU (1.0 mL) was added HCl/1,4-dioxane (0.1 mL, 4 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and 262.2 (431 mg, crude) was added dropwise into the flask vessel. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was purified by prep-HPLC to afford the title compound 262 (22.70 mg, 14% yield) as a white solid. MS (ESI): m/z calcd. for C20H23F2N5O5451.17, found 452.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 6.0 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.32 (dd, J = 11.2, 2.4 Hz, 1H), 4.25 – 4.15 (m, 2H), 3.94 (dd, J = 11.2, 6.0 Hz, 1H), 2.30 – 2.19 (m, 2H), 1.99 – 1.87 (m, 2H), 1.84 – 1.65 (m, 5H), 1.23 – 1.11 (m, 2H). 19 F NMR (377 MHz, DMSO) δ -89.81 (d, J = 231.9 Hz, 1F), -99.51 (d, J = 234.1 Hz, 1F). Example 110. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-((3R,5R,7R)-adamantan-1-yl)acetate (Compound 263). [00503] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and 2-(adamantan-1-yl)acetyl chloride. MS (ESI): m/z calcd. for C24H29N5O5467.22, found 468.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.91 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.30 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H), 4.72 (t, J = 5.6 Hz, 1H), 4.29 – 4.13 (m, 3H), 3.95 (dd, J = 10.8, 5.6 Hz, 1H), 2.00 (d, J = 2.4 Hz, 2H), 1.86 (s, 3H), 1.65 – 1.47 (m, 12H). Example 111. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)pentanamide (Compound 264). Step 1. Synthesis of N-(7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methy l)-4-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)pentanamide (264.1). [00504] To a mixture of 81.1 (100 mg, 0.22 mmol) and DMAP (41 mg, 0.33 mmol) in DCM (1 mL) was added pentanoyl chloride (35 mg, 0.29 mmol) dropwise at 0 o C. The mixture was then stirred at 20 o C for 1 hour. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a residue. The residue was purified by flash column chromatography to afford 264.1 (111 mg, 92.4% yield) as a white solid. MS (ESI): m/z calcd. for C26H39N5O5Si, 529.27, found 530.40 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.52 (s, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 5.40 (d, J = 6.2 Hz, 1H), 4.95 (dd, J = 6.2, 2.4 Hz, 1H), 4.57 – 4.52 (m, 1H), 3.80 (d, J = 4.4 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 1.74 (s, 3H), 1.73 – 1.65 (m, 2H), 1.49 – 1.39 (m, 5H), 1.00 (t, J = 7.2 Hz, 3H), 0.84 – 0.80 (m, 9H), 0.02 (d, J = 16.8 Hz, 6H). Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)pentanamide (264). [00505] To a solution of 264.1 (80.0 mg, 0.15 mmol) in THF (2.0 mL) was added 6 M HCl (2.0 mL) dropwise at 0℃, the mixture was then stirred at 20℃ for 2 hours. After completion, the reaction mixture was purified by prep-HPLC to afford 264 (16 mg, 27.9% yield) as a white solid. MS (ESI): m/z calcd. for C17H21N5O5, 375.15, found 376.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.39 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 4.61 (d, J = 4.8 Hz, 1H), 4.11 – 4.05 (m, 1H), 3.96 – 3.93 (m, 1H), 3.65 (dd, J = 12.0, 3.2 Hz, 1H), 3.51 (dd, J = 12.4, 4.4 Hz, 1H), 2.72 (t, J = 7.2 Hz, 2H), 1.66 – 1.55 (m, 2H), 1.41 – 1.30 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H). Example 112. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrah drofuran-2- l)meth l 2-c clobut lacetate (Com ound 265) Step 1. Synthesis of 2-cyclobutylacetyl chloride (265.2). [00506] To a solution of cyclobutylacetic acid (250 mg, 2.20 mmol) in dry DCM (4.5 mL) was added oxalyl chloride (418 mg, 3.30 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to dryness to give 265.2 (270 mg, crude) as a yellow oil, which was used directly in next step. Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclobutylacetate (Compound 265). [00507] To a solution of 6.3 (100 mg, 0.343 mmol) in DMPU (1.0 mL) was added HCl/1,4-dioxane (0.1 mL, 4 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and 265.2 (270 mg, crude) was added dropwise into the flask vessel. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was purified by prep- to afford the title compound 265 (34.75 mg, 26% yield) as a white solid. MS (ESI): m/z calcd. for C18H21N5O5387.15, found 388.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.35 (s, 1H), 5.38 (s, 1H), 4.73 – 4.65 (m, 1H), 4.30 (dd, J = 12.0, 2.8 Hz, 1H), 4.23 – 4.09 (m, 2H), 3.97 – 3.89 (m, 1H), 2.58 – 2.51 (m, 1H), 2.42 – 2.35 (m, 2H), 2.06 – 1.94 (m, 2H), 1.86 – 1.70 (m, 2H), 1.67– 1.54 (m, 2H). Example 113. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-((1r,4R)-4-aminocyclohexyl)acetate (Compound 266). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-((1r,4R)-4-((tert- butoxycarbonyl)amino)cyclohexyl)acetate (266.2). [00508] To a solution of (3aR,4R,6R,6aR)-4-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl} -6- (hydroxymethyl)-2,2-dimethyl-dihydro-3aH-furo[3,4-d][1,3]dio xole-4-carbonitrile(6.3, 200 mg, 0.603 mol) in THF (20 mL) was added (4-{[tert-butyl(formyl)-$l^{3}-oxidanyl]amino}cyclohexyl)ace tic acid (202.71 mg, 0.784 mol), EDCI (347.13 mg, 1.810 mol) and DMAP (221.23 mg, 1.810 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was washed with EtOAc (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by to afford 266.2 (250 mg, 65% yield) as a white solid. MS (ESI): m/z calcd. for C28H38N6O7570.23, found 571.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.96 (br, s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.40 (d, J = 6.4 Hz, 1H), 4.92 (dd, J = 6.4, 2.8 Hz, 1H), 4.57 (dd, J = 7.6, 4.8 Hz, 1H), 4.19 (dd, J = 12.0, 4.4 Hz, 1H), 4.08 (dd, J = 12.0, 5.6 Hz, 1H), 3.11-3.09 (m, 1H), 2.08 (dd, J = 15.6, 6.8 Hz, 1H), 1.98 (dd, J = 15.6, 7.2 Hz, 1H), 1.70 (d, J = 10.8 Hz, 2H), 1.64 (s, 3H), 1.59 (d, J = 12.0 Hz, 2H), 1.42-1.40 (m, 1H), 1.37 (s, 12H), 1.08-1.05 (m, 2H), 0.98 – 0.84 (m, 2H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-((1r4R)-4-aminocyclohexyl)acetate (Compound 266). [00509] To a solution of [(3aR,4R,6R,6aR)-6-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl }-6-cyano-2,2- dimethyl-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]methyl 2-(4-{[(tert- butoxy)carbonyl]amino}cyclohexyl)acetate (266.2, 80 mg, 0.140 mmol) in THF(2 mL) and water (1 mL) was added HCl in dioxane(4M, 2 mL), the mixture was stirred at 25 °C for 4 h. The reaction concentrated in vacuo. The crude product was purified by to afford 266 (45.5 mg, 73% yield) as a white solid. MS (ESI): m/z calcd. for C20H26N6O5430.20, found 431.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.85 (br, s, 3H), 6.94 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.47 -6.45 (m, 1H), 5.51-5.47 (m, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.31 (dd, J = 11.6, 2.4 Hz, 1H), 4.25 – 4.08 (m, 2H), 3.93-3.90 (m, 1H), 2.82-2.80 (m, 1H), 2.20-2.18 (m, 2H), 1.87 (d, J = 10.0 Hz, 2H), 1.70 (d, J =12.8 Hz, 2H), 1.65 – 1.49 (m, 1H), 1.25- 1.20 (m, 2H), 1.00-0.90 (m, 2H). Example 114. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (267). Step 1. Synthesis of tert-butyl 4-(2-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazi n-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)me thoxy)-2-oxoethyl)piperidine-1- carboxylate (Compound 267.1). [00510] The compound 267.1 was prepared according to the procedure of Example 266, Step 1, using 6.3 and 2-(1-(tert-butoxycarbonyl) piperidin-4-yl) acetic acid. MS (ESI): mass calcd. for C 27 H 36 N 6 O 7 , 556.26, m/z found 557.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.96 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.8 Hz, 1H), 5.41 (d, J = 6.4 Hz, 1H), 4.94 (dd, J = 6.4, 2.8 Hz, 1H), 4.64 – 4.49 (m, 1H), 4.22 (dd, J = 12.0, 4.0 Hz, 1H), 4.10 (dd, J = 12.0, 6.4 Hz, 1H), 3.85 (d, J = 11.2 Hz, 2H), 2.63-2.60 (m, 2H), 2.16 (dd, J = 15.6, 7.2 Hz, 1H), 2.11 – 2.02 (m, 1H), 1.68-1.65 (m, 1H), 1.64 (s, 3H), 1.52 (d, J = 10.8 Hz, 2H), 1.40 (s, 12H), 1.06 – 0.89 (m, 2H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 267). [00511] The title compound 267 was prepared according to the procedure of Example 266, Step 2, using 267.1. MS (ESI): mass calcd. for C19H24N6O5, 416.18, m/z found 417.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 -7.90 (br, s, 3H), 6.93 (d, J = 4.8 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.49 -6.40 (m, 1H), 5.50-5.40 (m, 1H), 4.70 (d, J = 4.8 Hz,1H), 4.32 (dd, J = 11.2, 2.0 Hz, 1H), 4.27 – 4.15 (m, 2H), 3.93 (t, J = 5.2 Hz, 1H), 3.10-3.05 (m, 2H), 2.72-2.68 (m, 2H), 2.26 (d, J = 7.2 Hz, 2H), 1.87-1.80 (m,1H), 1.70 (d, J = 12.0 Hz, 2H), 1.25-1.20 (m, 2H). Example 115. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-(methylsulfonyl)piperidin-4-yl)acetate (Compound 268).
Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-(methylsulfonyl)piperidin-4-yl)acetate (268.1). [00512] To a mixture of 6.4 (300 mg, 0.90 mmol), (1-methanesulfonylpiperidin-4-yl)acetic acid (200 mg, 0.90 mmol) and EDCI (520 mg, 2.71 mmol) in THF was added DMAP (331 mmol, 2.71 mmol) slowly at 0 °C, the mixture was then stirred for 16 hours. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a residue. The residue was purified by prep- HPLC to afford 268.1 (302 mg, 61.3% yield) as a white solid. MS (ESI): m/z calcd. for C23H30N6O7S, 534.19, found 535.30 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.97 (s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H), 4.95 (dd, J = 6.4, 2.8 Hz, 1H), 4.60 – 4.55 (m, 1H), 4.23 (dd, J = 12.0, 4.0 Hz, 1H), 4.10 (dd, J = 12.0, 5.6 Hz, 1H), 3.47 (d, J = 11.6 Hz, 2H), 2.82 (s, 3H), 2.61 (dd, J = 16.8, 7.6 Hz, 2H), 2.22 (dd, J = 15.6, 6.8 Hz, 1H), 2.16 – 2.06 (m, 1H), 1.65 (d, J = 10.4 Hz, 6H), 1.38 (s, 3H), 1.22 – 1.09 (m, 2H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-(methylsulfonyl)piperidin-4-yl)acetate (268). [00513] To a solution of 268.1 (200 mg, 0.37 mmol) in THF (2.0 mL) was added 6 M HCl (2.0 mL) dropwise at 0 °C, the mixture was then stirred at 20 °C for 2 hours. The mixture was quenched with water (2 mL) and dried with a stream of nitrogen to remove the solvent away. The residue was purified by prep-HPLC to afford 268 (130 mg, 69.5% yield) as a white solid. MS (ESI): m/z calcd. for C20H26N6O7S, 494.16, found 495.20 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.28 – 7.87 (m, 3H), 6.96 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.8 Hz, 1H), 6.33 (s, 1H), 5.41 (s, 1H), 4.69 (d, J = 4.8 Hz, 1H), 4.33 (dd, J = 11.6, 2.4 Hz, 1H), 4.26 – 4.15 (m, 2H), 3.98 – 3.90 (m, 1H), 3.50 (s, 2H), 2.83 (s, 3H), 2.65 (dt, J = 12.0, 2.0 Hz, 2H), 2.28 (dd, J = 6.8, 2.4 Hz, 2H), 1.80 – 1.66 (m, 3H), 1.27 – 1.12 (m, 2H). Example 116. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexyl-2-methylpropanoate (Compound 269).
Step 1: Synthesis of methyl 2-cyclohexyl-2-methylpropanoate (269.3). [00514] A solution of LDA (5.40 mL, 2M) in THF (30 mL) was added methyl 269.2 (1.00 g, 9.80 mmol) at 0 ℃ under N2, then the reaction was stirred at 0 ℃ for 30 minutes. Then the mixtures was added 269.1 (1.4 mL, 10.7 mmol) at 0 ℃, and the reaction was stirred at 20 ℃ for 16 hours. The reaction was quenched by HCl (50 mL, 1M) and extracted with MTBE (50 mL x 3). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (EA/PE from 0% to 0%) to obtain 269.3 as a yellow oil (500 mg, 26.5% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 3.65 (s, 3H), 1.80 – 1.71 (m, 2H), 1.68 – 1.62 (m, 1H), 1.58 – 1.52 (m, 3H), 1.29 – 1.23 (m, 2H), 1.09 (s, 6H), 1.04 – 0.95 (m, 2H), 0.90 – 0.85 (m, 1H). Step 2: Synthesis of 2-cyclohexyl-2-methylpropanoic acid (269.4). [00515] To a solution of 269.3 (500 mg, 2.7 mmol) in DMSO (5 mL) was added NaOH (5 mL, 4 M), then the reaction was stirred at 80 ℃ for 16 hours. The mixture was poured into ice-water (50 mL) and acidified with aq. HCl (50 mL, 1 M, pH = 2~3) and a white solid was formed in the aqueous layer, then filtered to obtain 269.4 as a white solid (120 mg, 24.7% yield). 1 H NMR (400 MHz, CDCl3) δ 1.79 – 1.75 (m, 2H), 1.71 – 1.55 (m, 4H), 1.34 – 1.19 (m, 2H), 1.12 (s, 6H), 1.09 – 0.96 (m, 2H). Step 3: Synthesis of 2-cyclohexyl-2-methylpropanoyl chloride (269.5). [00516] To a round bottom flask equipped with a gas bubbler was added 269.4 (120 mg, 0.70 mmol) and DCM (1 mL). Oxalyl chloride (0.12 mL, 1.41 mmol) was added followed by a few drops of DMF at 20 ℃. The resulting solution was stirred at 20 ℃ until gas evolution ceased (~1 h). The mixture was concentrated 3 times from DCM to obtain 269.5 (100 mg, crude) and the resulting acid chloride was used without further purification for the coupling above. Step 4: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexyl-2-methylpropanoate (269.5). [00517] The title compound was prepared according to the procedure of Example 5, Step 4, using 6.3 and 269.5. MS (ESI): mass calcd. for C 22 H 29 N 5 O 5 , 443.22, m/z found 444.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.35 (d, J = 5.6 Hz, 1H), 5.38 (s, 1H), 4.71 (d, J = 4.4 Hz, 1H), 4.31 – 4.12 (m, 3H), 3.97 (s, 1H), 1.67 – 1.51 (m, 3H), 1.48 – 1.37 (m, 3H), 1.14 – 0.96 (m, 9H), 0.93 080 (m 2H) Example 117. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(4-(trifluoromethyl)cyclohexyl)acetate (Compound 270) and (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4-hydroxy-2-((2-(4- (trifluoromethyl)cyclohexyl)acetoxy)methyl)tetrahydrofuran-3 -yl 2-(4- (trifluoromethyl)cyclohexyl)acetate (Compound 271). Step 1. Synthesis of ethyl 2-(4-(trifluoromethyl)cyclohexylidene)acetate (270.2). [00518] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (810 mg, 3.61 mmol) in dry THF (10 mL) was added sodium hydride (150 mg, 60%, 3.76 mmol). The reaction mixture was stirred at 20 °C for 1 h, then a solution of 270.1 (500 mg, 3.01 mmol) in dry THF (5.0 mL) was added dropwise to the solution. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% EA in PE) to give 270.2 (561 mg, 79% yield) as a colorless oil. MS (ESI): m/z calcd. for C11H15F3O2236.10, found 237.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 5.68 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.94 (d, J = 14.4 Hz, 1H), 2.39 (d, J = 13.6 Hz, 1H), 2.32 – 2.15 (m, 2H), 2.13 – 2.05 (m, 2H), 1.92 (td, J = 14.0, 4.4 Hz, 1H), 1.53 – 1.40 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). 19 F NMR (377 MHz,) δ -194.12. Step 2. Synthesis of ethyl 2-(4-(trifluoromethyl)cyclohexyl)acetate (270.3). [00519] To a solution of 270.2 (561 mg, 2.37 mmol) in EtOH (10 mL) was added Pd/C (56 mg, 10% w.t%). The reaction mixture was degassed with H 2 for three times and stirred at 40 °C for 16 h under H 2 . TLC detected complete consumption of 270.2. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give 270.3 (514 mg, 91% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.18 – 4.09 (m, 2H), 2.36 – 2.18 (m, 2H), 2.12 – 1.53 (m, 8H), 1.41 – 1.29 (m, 1H), 1.28 – 1.23 (m, 3H), 1.07 – 0.95 (m, 1H). 19 F NMR (377 MHz, CDCl3) δ -73.82. Step 3. Synthesis of 2-(4-(trifluoromethyl)cyclohexyl)acetic acid (270.4). [00520] To a solution of 270.3 (514 mg, 2.16 mmol) in EtOH (8.0 mL) was added a solution of sodium hydroxide (173 mg, 4.31 mmol) in H2O (4.0 mL). The reaction mixture was stirred at 40 °C for 2 h under nitrogen. TLC showed complete consumption of 270.3. The reaction mixture was diluted with water (10 mL). The aqueous solution was acidified with HCl (1 M) and extracted with EA (5.0 mL × 3). The combined organic phase was washed with b i (50 L) d i d h d N SO , filtered. The filtrate was concentrated to dryness give 270.4 (462 mg, 97% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.92 (br, 1H), 2.33 (dd, J = 52.4, 7.6 Hz, 2H), 2.25 – 1.52 (m, 8H), 1.42 – 1.25 (m, 1H), 1.10 – 0.98 (m, 1H). 19 F NMR (377 MHz,) δ -194.49. Step 4. Synthesis of 2-(4-(trifluoromethyl)cyclohexyl)acetyl chloride (270.5). [00521] To a solution of 270.4 (462 mg, 2.20 mmol) in dry DCM (10 mL) was added oxalyl chloride (418 mg, 3.30 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to dryness to give 270.5 (481 mg, crude), which was used directly in next step. Step 5. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(4-(trifluoromethyl)cyclohexyl)acetate (270) and (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4-hydroxy-2-((2-(4- (trifluoromethyl)cyclohexyl)acetoxy)methyl)tetrahydrofuran-3 -yl 2-(4- (trifluoromethyl)cyclohexyl)acetate (271). [00522] To a solution of 6.3 (100 mg, 0.343 mmol) in DMPU (1.0 mL) was added HCl/1,4-dioxane (0.1 mL, 4 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and 270.5 (481 mg, crude) was added dropwise into the flask vessel. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was purified by prep-HPLC to afford the title compound 270 (60.50 mg, 36% yield) and 271 (49.18 mg, 21% yield) such as a white solid. [00523] Compound 270: MS (ESI): m/z calcd. for C21H24F3N5O5483.17, found 484.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (dd, J = 4.4, 1.6 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 6.0 Hz, 1H), 4.69 (q, J = 5.2 Hz, 1H), 4.35 – 4.25 (m, 1H), 4.25 – 4.13 (m, 2H), 3.98 – 3.89 (m, 1H), 2.35 – 2.09 (m, 3H), 2.08 – 1.37 (m, 7H), 1.26 – 1.13 (m, 1H), 1.04 – 0.90 (m, 1H). 19 F NMR (377 MHz, DMSO) δ -70.74, -72.30. [00524] Compound 271: MS (ESI): m/z calcd. for C30H35F6N5O6675.25, found 676.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.93 (dd, J = 4.4, 1.6 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.66 – 6.59 (m, 1H), 5.17 – 5.04 (m, 2H), 4.46 (dd, J = 8.4, 4.0 Hz, 1H), 4.33 – 4.21 (m, 2H), 2.43 (d, J = 7.2 Hz, 1H), 2.33 – 2.27 (m, 2H), 2.23 – 1.98 (m, 3H), 1.90 – 1.36 (m, 13H), 1.31 – 1.24 (m, 1H), 1.21 – 0.85 (m, 6H). 19 F NMR (377 MHz, DMSO) δ -70.83, -72.35. Example 118. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3,4 - dihydroxy-4-methyltetrahydrofuran-2-yl)methyl isobutyrate((2R,3S,4R,5R)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydrox ytetrahydrofuran-2-yl)methyl 2-(4,4- dim th l l h l t t C d 272 Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(4,4-dimethylcyclohexyl)acetate (272.1). [00525] The compound 272.1 was prepared according to the procedure of Example 266, Step 1, using 6.3 and 2-(4,4-dimethylcyclohexyl) acetic acid. MS (ESI): mass calcd. for C25H33N5O5, 483.25, m/z found 484.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.94 (br, s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.69 – 4.48 (m, 1H), 4.21 (dd, J = 12.0, 4.0 Hz, 1H), 4.09 (dd, J = 12.0, 5.6 Hz, 1H), 2.06-2.00 (m, 2H), 1.64 (s, 3H), 1.37-1.34 (m, 6H), 1.29 – 1.20 (m, 2H), 1.13 – 0.96 (m, 4H), 0.83 (d, J = 14.8 Hz, 6H). Step 2. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3,4 -dihydroxy-4- methyltetrahydrofuran-2-yl)methyl isobutyrate((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-(4,4- dimethylcyclohexyl)acetate (272). [00526] To a solution of [(3aR,4R,6R,6aR)-6-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl }-6-cyano-2,2- dimethyl-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]methyl 2-(4,4-dimethylcyclohexyl)acetate (272.1, 100 mg, 0.206 mmol) in THF(3 mL) was added HCl (12M, 1 mL) at 0 °C, the mixture was stirred at 25 °C for 3 h. The reaction was concentrated in vacuo. The crude product was purified by prep-HPLC to afford 272 (83.32 mg, 91% yield) as a white solid. MS (ESI): mass calcd. for C22H29N5O5, 443.22, m/z found 444.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92-7.90 (br, s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.8 Hz, 1H), 6.31 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 4.68 (t, J= 5.2 Hz, 1H), 4.30 (dd, J = 11.2, 2.4 Hz, 1H), 4.25 – 4.19 (m, 1H), 4.16 (dd, J = 11.2, 5.6 Hz, 1H), 3.93-3.90 (m, 1H), 2.19 (dd, J = 7.2, 2.0 Hz, 2H), 1.53-1.48 (m, 3H), 1.27-1.20 (m, 2H), 1.18 – 1.05 (m, 4H), 0.84 (d, J = 10.8 Hz, 6H). Example 119. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-methylcyclohexyl)acetate (Compound 273). Step 1: Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-methylcyclohexyl)acetate (273.1). [00527] To a solution of 6.4 (300 mg, 0.91 mol) in THF (10 mL) was added (1- methylcyclohexyl)acetic acid (183.90 mg, 1.18 mol), EDCI (520.75 mg, 2.72 mol) and DMAP (331.87 mg, 2.72 mmol), then the mixture was stirred at 25 ℃ for 16 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x3). The organic phase was washed with brine water (50 mL x3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by flash column chromatography (EA/PE from 0% to 15%) to obtain 273.1 as a white solid (450 mg, 52.9% yield). MS (ESI): mass calcd. for C24H31N5O5, 469.23, m/z found 470.1 [M+H] + . Step 2: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-methylcyclohexyl)acetate (273). [00528] To a solution of 273.1 (100 mg, 0.213 mol) in THF (1 mL) was added HCl (1 mL, 12M) at 0℃, the mixture was stirred at 0 ℃ for 1.5 h, and then the reaction was stirred at 20 ℃ for 0.5 h. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to obtain 273 (34.0 mg, 37.0% yield) as a white solid. MS (ESI): m/z calcd. for C21H27N5O5, 429.20, found 430.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (br s, 1H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 6.0 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.34 – 4.11 (m, 3H), 3.94 (d, J = 5.6 Hz, 1H), 2.19 (d, J = 2.4 Hz, 2H), 1.40 – 1.30 (m, 8H), 1.25 – 1.18 (m, 2H), 0.91 (s, 3H). Example 120. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4] triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-(4-phenyltetrahydro-2H-pyran-4-yl)acetate (Compound 274). Step 1. Synthesis of ethyl 2-cyano-2-(tetrahydro-4H-pyran-4-ylidene) acetate (274.2). [00529] To a mixture of oxan-4-one (274.1, 5 g, 0.049 mol) and ethyl cyanoacetate (5.64 g, 0.049 mol) was added acetic acid (0.30 g, 0.0045 mmol) and piperidine (0.425 g, 0.0045 mol) at 0 °C, then acetic acid (0.30 g, 0.0045 mmol) and piperidine (0.425 g, 0.0045 mol) was added to the above solution at 25 °C, the resulting mixture was stirred at 25 °C for 0.5 h. The reaction was quenched by NaHCO3 (sat. aqueous, 10 mL) and extracted with EtOAc (10 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo to obtain 274.2 as a light-yellow solid (10 g, 92% yield). 1 H NMR (400 MHz, CDCl3) δ 4.43 – 4.24 (m, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.19 (t, J = 5.6 Hz, 2H), 2.80 (t, J = 5.2 Hz, 2H), 1.38 (t, J = 3.2 Hz, 2H, 3H). Step 2. Synthesis of ethyl 2-cyano-2-(4-phenyltetrahydro-2H-pyran-4-yl) acetate (274.3). [00530] To a solution of ethyl 2-cyano-2-(oxan-4-ylidene) acetate (274.2, 3 g, 0.015 mol) in dry THF (30 ml) and the mixture was added PhMgBr (1M in THF, 30.8 mL) dropwise at 0 °C, the solution was heated to 60 °C for 6 h. The reaction was quenched by NH4Cl (sat. aqueous, 10 mL) and extracted with EA (10 mL x 3). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (EA/PE from 2% to 20%) to obtain 107.3 as a light-yellow solid (1.5 g, 48% yield). 1 H NMR (400 MHz, CDCl3) δ 7.44 -7.30 (m, 5H), 3.94-3.90 (m, 2H), 3.85-3.82 (m, 2H), 3.65 (s, 1H), 3.59 – 3.41 (m, 2H), 2.69 – 2.43 (m, 2H), 2.21-2.09 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). Step 3. Synthesis of 2-(4-phenyltetrahydro-2H-pyran-4-yl) acetic acid (274.4). [00531] To a solution of ethyl 2-cyano-2-(4-phenyloxan-4-yl) acetate (274.3, 250 mg, 0.914 mmol) in ethylene glycol (5 mL) was added KOH (102.65 mg, 1.83 mmol), the resulting mixture was stirred at 160 °C for 16 h. and concentrated in vacuo. The reaction was washed with ethyl ether (5 mL x 3) and dried in vacuum. The crude product was purified by prep-HPLC to afford 274.4 (160 mg, 75% yield) as a white solid. 1 H NMR (400 MHz, MeOD) δ 7.44 – 7.31 (m, 4H), 7.22 (t, J = 7.2 Hz, 1H), 3.81-3.79 (m, 2H), 3.59-3.57 (m, 2H), 2.63 (s, 2H), 2.40 – 2.24 (m, 2H), 2.18 – 2.03 (m, 2H). Step 4. Synthesis of((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(4-phenyltetrahydro-2H-pyran-4-yl)acetate (274.5). [00532] To a solution of (3aR,4R,6R,6aR)-4-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl} -6- (hydroxymethyl)-2,2-dimethyl-dihy ( 200 mg, 0.603 mmol) in THF (15 mL) was added (4-phenyloxan-4- yl)acetic acid (274.4, 132.79 mg, 0.603 mmol), EDCI (347.13 mg, 1.810 mmol) and DMAP (221.23 mg, 1.810 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was washed with EA (5 mL x 3) and dried in vacuum. The crude product was purified by prep-HPLC to afford 274.5 (200 mg, 59% yield) as a white solid. MS (ESI): m/z calcd. for C 28 H 31 N 5 O 6 533.23, found 534.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.96 (br, s, 3H), 7.31 – 7.22 (m, 4H), 7.21 – 7.13 (m, 1H), 6.92 (d, J = 4.4 Hz, 1H), 6.77 (d, J = 4.8 Hz, 1H), 5.24 (d, J = 6.4 Hz, 1H), 4.58 (dd, J = 6.4, 2.8 Hz, 1H), 4.34-4.30 (m, 1H), 3.95 (dd, J = 12.0, 4.0 Hz, 1H), 3.82 (dd, J = 12.0, 5.6 Hz, 1H), 3.62-3.60 (m, 2H), 3.49 – 3.36 (m, 2H), 2.54-2.50 (m, 2H), 2.07-2.05 (m, 2H), 1.94 – 1.79 (m, 2H), 1.62 (s, 3H), 1.36 (s, 3H). Step 5. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(4-phenyltetrahydro-2H-pyran-4-yl)acetate (274). [00533] To a solution of [(3aR,4R,6R,6aR)-6-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl }-6-cyano-2,2- dimethyl-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]methyl 2-(4-phenyloxan-4-yl)acetate (274.5, 150 mg, 0.281 mmol) in THF (3 mL) was added HCl (12 M, 1 mL) at 0 o C, the mixture was stirred at 25 °C for 4 h. The reaction was dried in vacuum. The crude product was purified by prep-HPLC to afford the title compound 274 (112.15 mg, 81% yield) as a white solid. MS (ESI): m/z calcd. for C 25 H 27 N 5 O 6 493.20, found 494.3 [M+H]. 1 H NMR (400 MHz, DMSO) δ 7.93-7.90 (br, s, 3H), 7.30 – 7.21 (m, 4H), 7.16 (t, J = 6.8 Hz, 1H), 6.94 (d, J = 4.4 Hz, 1H), 6.75 (d, J = 4.4 Hz, 1H), 6.27 -6.20(m,1H), 5.28-5.20 (m, 1H), 4.63-4.60 (m, 1H), 4.08 – 4.00 (m, 2H), 3.89 (dd, J = 12.4, 6.0 Hz, 1H), 3.72 (t, J = 5.6 Hz, 1H), 3.69 – 3.60 (m, 2H), 3.40-3.35 (m, 2H), 2.63 (s, 2H), 2.15 – 2.03 (m, 2H), 2.02 – 1.88 (m, 2H). Example 121. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (R)-2-cyclohexylpropanoate (Compound 275). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (R)-2-cyclohexylpropanoate (275.1). [00534] The title compound was prepared according to the procedure of Example 273, Step 1, using 6.4 and (R)-2-cyclohexylpropanoic acid. MS (ESI): mass calcd. for C 24 H 31 N 5 O 5 , 469.23, m/z found 470.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.96 (br s, 3H), 6.91 (d, J = 4.8 Hz, 1H), 6.84 (d, J = 4.8 Hz, 1H), 5.43 (d, J = 6.4 Hz, 1H), 4.92 (dd, J = 6.4, 3.2 Hz, 1H), 4.55 (d, J = 3.2 Hz, 1H), 4.22 (dd, J = 12.0, 4.4 Hz, 1H), 4.11 (dd, J = 12.0, 6.0 Hz, 1H), 2.16 (t, J = 7.2 Hz, 1H), 1.67 – 1.51 (m, 7H), 1.47 – 1.30 (m, 5H), 1.18 – 0.99 (m, 3H), 0.94 (d, J = 7.2 Hz, 3H), 0.90 – 0.80 (m, 2H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (R)-2-cyclohexylpropanoate (275). [00535] The title compound was prepared according to the procedure of Example 273, Step 2, using 275.1. MS (ESI): mass calcd. for C21H27N5O5, 429.20, m/z found 430.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 5.6 Hz, 1H), 4.69 (t, J = 5.2 Hz, 1H), 4.35 – 4.10 (m, 3H), 3.96 (d, J = 5.2 Hz, 1H), 2.19 (t, J = 7.2 Hz, 1H), 1.60 (d, J = 17.6 Hz, 4H), 1.44 (dd, J = 24.4, 10.8 Hz, 2H), 1.20 – 1.02 (m, 3H), 0.98 (d, J = 7.2Hz, 3H), 0.94 – 0.79 (m, 2H). Example 122. Synthesis ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7- l)tetrah drofuran-2- l)meth l isobut rate (Com ound 276) [00536] The title compound was prepared according to the procedure of Example 288, Step 1, using Compound 264 and 2-methylpropanoyl chloride. MS (ESI): mass calcd. for C21H27N5O6, 445.20, m/z found 446.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.39 (s, 1H), 7.27 (d, J = 4.4 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 5.43 (d, J = 6.0 Hz, 1H), 4.68 (t, J = 5.6 Hz,1H), 4.33 – 4.23 (m, 2H), 4.17 (dd, J = 11.6, 4.4 Hz, 1H), 3.95 (dd, J = 11.2, 6.0 Hz, 1H), 2.70 (m, 2H), 2.53 (s, 1H), 1.66 – 1.53 (m, 2H), 1.40 – 1.28 (m, 2H), 1.03 (dd, J = 7.2, 3.6 Hz, 6H), 0.90 (t, J = 7.6 Hz, 3H). Example 123. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 277). [00537] The title compound was prepared according to the procedure of Example 5, Step 4, using 264 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C25H27N5O6, 493.20, m/z found 494.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.39 (s, 1H), 7.32 – 7.20 (m, 6H), 7.02 (d, J = 4.8 Hz, 1H), 6.43 (d, J = 6.0 Hz, 1H), 5.47 (d, J = 5.6 Hz, 1H), 4.64 (t, J = 5.2 Hz, 1H), 4.37 – 4.33 (m, 1H), 4.31 – 4.25 (m, 1H), 4.23 – 4.18 (m, 1H), 3.94 (dd, J = 11.2, 6.0 Hz, 1H), 2.72 (t, J = 7.2 Hz, 2H), 1.66 – 1.56 (m, 2H), 1.40 – 1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). Example 124. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-((1r,4R)-4-methylcyclohexyl)acetate (Compound 278). Step 1. Synthesis of (1r,4r)-4-methylcyclohexane-1-carbonyl chloride (278.2). [00538] A solution of 4-methylcyclohexane-1-carboxylic acid (500 mg, 3.52 mmol) in SOCl2 (2.5 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated to dryness to give 278.2 (533 mg, crude) as a yellow oil, which was used directly in next step. Step 2. Synthesis of 2-diazo-1-((1r,4r)-4-methylcyclohexyl)ethan-1-one (278.3). [00539] To a solution of 278.2 (533 mg, crude) in THF (10 mL) and ACN (10 mL) was added TMSCHN2 (7.0 mL, 14.0 mmol, 2 M in hexane) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to remove the solvent. The residue was diluted with EA (10 mL) and washed with water (5.0 mL × 2), followed by brine (5.0 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 10% EA in PE) to give 278.3 (354 mg, 60% yield) as a yellow oil. MS (ESI): mass calcd. for C9H14N2O, 166.11, m/z found 167.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 5.25 (s, 1H), 2.15 (s, 1H), 1.88 – 1.73 (m, 4H), 1.48 – 1.28 (m, 3H), 0.99 – 0.86 (m, 5H). Step 3. Synthesis of 2-((1r,4r)-4-methylcyclohexyl)acetic acid (278.4). [00540] To a solution of 278.3 (354 mg, 2.13 mmol) in 1,4-dioxane (60 mL) and water (12 mL) was added silver benzoate (48.8 mg, 0.21 mmol) and TEA (860 mg, 8.52 mmol) under nitrogen. The reaction mixture was sonicated at 20 °C for 1 h while protected from light and then stirred at 20 °C for another 16 h in the dark. TLC showed complete consumption of 278.3. The reaction mixture was filtered, and the filtrate was concentrated to remove solvent. The residue was diluted with water (10 mL) and adjusted pH to 2-3 with HCl (1 M), extracted with EA (5.0 mL × 3). The combined organic phase was washed with brine (5.0 mL) and dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness to give 278.4 (342 mg, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 2.06 (d, J = 6.8 Hz, 2H), 1.73 – 1.47 (m, 5H), 1.31 – 1.20 (m, 1H), 0.99 – 0.82 (m, 7H). Step 4. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-((1r,4R)-4-methylcyclohexyl)acetate (278.5). [00541] A solution of 278.4 (150 mg, 0.96 mmol), EDCI (552 mg, 2.9 mmol) and DMAP (352 mg, 2.9 mmol) in dry THF (15 mL) was stirred at 20 °C for 30 min and then 6.4 (255 mg, 0.77 mmol) was added. The reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched with water (15 mL) and extracted with EA (5.0 mL × 2). The combined organic phase was washed with brine (5.0 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 25% EA in PE) to give 278.5 (309 mg, 69% yield) as a white solid. MS (ESI): mass calcd. for C24H31N5O5, 469.23, m/z found 470.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.61 – 4.54 (m, 1H), 4.20 (dd, J = 12.0, 4.0 Hz, 1H), 4.09 (dd, J = 12.0, 5.6 Hz, 1H), 2.10 – 1.93 (m, 2H), 1.64 (s, 3H), 1.61 – 1.50 (m, 4H), 1.42 – 1.31 (m, 4H), 1.22 – 1.18 (m, 1H), 0.92 – 0.71 (m, 7H). Step 5. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-((1r,4R)-4-methylcyclohexyl)acetate (278). [00542] To a solution of 278.5 (120 mg, 0.26 mmol) in dry THF (1.2 mL) was added Conc. HCl (0.6 mL) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 30 min. LC-MS showed complete consumption of 278.5. The organic solvent was removed with flowing nitrogen and the residue was diluted with ACN. The solution was purified by prep-HPLC to afford the title compound (61.23 mg, 55% yield) as a white solid. MS (ESI): mass calcd. for C21H27N5O5, 429.20, m/z found 430.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 6.0 Hz, 1H), 4.69 (t, J = 5.6 Hz, 1H), 4.30 (dd, J = 12.0, 2.4 Hz, 1H), 4.24 – 4.12 (m, 2H), 3.94 (dd, J = 11.2, 5.6 Hz, 1H), 2.19 – 2.08 (m, 2H), 1.65 – 1.47 (m, 5H), 1.28 – 1.15 (m, 1H), 0.97 – 0.77 (m, 7H). Example 125. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(spiro[4.5]decan-8-yl)acetate (Compound 279). Step 1. Synthesis of ethyl 2-(spiro[4.5]decan-8-ylidene)acetate (279.2). [00543] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (884 mg, 3.94 mmol) in dry THF (5.0 mL) was added sodium hydride (158 mg, 60%, 3.94 mmol) in an ice bath. The reaction mixture was stirred at 20 °C for 1 h and then a solution of 279.1 (500 mg, 3.28 mmol) in dry THF (1.0 mL) was added dropwise. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (5.0 mL × 3). The combined organic phase was washed with brine (5.0 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% EA in PE) to give 279.2 (610 mg, 84% yield) as a colorless oil. MS (ESI): m/z calcd. for C 14 H 22 O 2 222.16, found 223.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 5.61 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.87 – 2.81 (m, 2H), 2.23 – 2.17 (m, 2H), 1.66 – 1.58 (m, 4H), 1.54 (s, 2H), 1.51 – 1.41 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H). Step 2. Synthesis of ethyl 2-(spiro[4.5]decan-8-yl)acetate (279.3). [00544] To a solution of 279.2 (610 mg, 2.74 mmol) in EtOH (10 mL) was added Pd/C (61.0 mg, 10% w.t%). The reaction mixture was degassed with H2 for three times and stirred at 20 °C for 16 h under H2. TLC detected complete consumption of 279.2. The reaction mixture was filtered, the filtrate was concentrated to dryness to give 279.3 (613 mg, 99% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.2 Hz, 2H), 2.18 (d, J = 7.2 Hz, 1H), 1.79 – 1.68 (m, 1H), 1.63 – 1.54 (m, 3H), 1.48 – 1.41 (m, 1H), 1.40 – 1.22 (m, 5H), 1.15 – 1.03. (m, 1H). Step 3. Synthesis of 2-(spiro[4.5]decan 8 yl)acetic acid (2794) [00545] To a solution of 279.3 (613 mg, 2.73 mmol) in EtOH (6.0 mL) was added a solution of sodium hydroxide (219 mg, 5.47 mmol) in water (6.0 mL). The reaction mixture was stirred at 80 °C for 2 h under nitrogen. TLC showed complete consumption of 279.3. The reaction mixture was concentrated to remove the organic solvent. The residue was diluted with water (10 mL) and extracted with EA (5.0 mL). The aqueous phase was acidified with HCl (1 M) and extracted with EA (5.0 mL × 2). The combined organic phase was washed with brine (5.0 mL) and then concentrated to give 279.4 (562 mg, crude) as a white solid. 1 H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 2.08 (d, J = 6.8 Hz, 2H), 1.65 – 1.47 (m, 7H), 1.44 – 1.27 (m, 6H), 1.26 – 1.15 (m, 2H), 1.09 – 0.97 (m, 2H). Step 4. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(spiro[4.5]decan-8-yl)acetate (279.5). [00546] A solution of 279.4 (200 mg, 1.0 mmol), EDCI (586 mg, 3.1 mmol) and DMAP (373 mg, 3.1 mmol) in dry THF (20 mL) was stirred at 20 °C for 30 min and then 6.4 (321 mg, 0.97 mmol) was added. The reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched with water (15 mL) and extracted with EA (5.0 mL × 2). The combined organic phase was washed with brine (5.0 mL), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 25% EA in PE) to give 279.5 (450 mg, 87% yield) as a colorless oil. MS (ESI): m/z calcd. for C27H35N5O5509.26, found 510.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.91 (br s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.61 – 4.54 (m, 1H), 4.21 (dd, J = 12.0, 4.0 Hz, 1H), 4.09 (dd, J = 12.0, 5.6 Hz, 1H), 2.12 – 1.99 (m, 2H), 1.64 (s, 3H), 1.56 – 1.47 (m, 4H), 1.45 – 1.22 (m, 12H), 1.16 – 1.05 (m, 2H), 1.01 – 0.87 (m, 2H). Step 5. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(spiro[4.5]decan-8-yl)acetate (279). [00547] To a solution of 279.5 (100 mg, 0.20 mmol) in dry THF (1.0 mL) was added Conc. HCl (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 30 min. LC-MS showed complete consumption of 279.5. The organic solvent was removed with flowing nitrogen and the residue was diluted with ACN. The solution was purified by prep-HPLC to afford the title compound (33.12 mg, 36% yield) as a white solid. MS (ESI): m/z calcd. for C 24 H 31 N 5 O 5 469.23, found 470.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 4.68 (t, J = 5.2 Hz, 1H), 4.30 (dd, J = 11.6, 2.4 Hz, 1H), 4.24 – 4.13 (m, 2H), 3.93 (dd, J = 11.2, 6.0 Hz, 1H), 2.20 – 2.12 (m, 2H), 1.63 – 1.44 (m, 7H), 1.40 – 1.25 (m, 6H), 1.21 – 1.11 (m, 2H), 1.06 – 0.94 (m, 2H). Example 126. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetate (Compound 280).
Step 1. Synthesis of ethyl 2-(tetrahydro-4H-thiopyran-4-ylidene)acetate (280.2). [00548] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (2.12 g, 9.40 mmol) and 280.1 (1.00 g, 8.6 mmol) in dry DMF (10 mL) was added potassium carbonate (1.78 g, 12.9 mmol). The reaction mixture was stirred at 80 °C for 16 h under nitrogen. The reaction mixture was diluted with water (50 mL) and extracted with EA (15 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% EA in PE) to give 280.2 (1.39 g, 87% yield) as a white solid. MS (ESI): mass calcd. for C9H14O2S, 186.07, m/z found 187.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 5.67 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.22 – 3.17 (m, 2H), 2.80 – 2.73 (m, 4H), 2.56 – 2.51 (m, 2H), 1.28 (t, J = 7.2 Hz, 4H). Step 2. Synthesis of ethyl 2-(tetrahydro-2H-thiopyran-4-yl)acetate (280.3). [00549] To a solution of 280.2 (1.00 g, 5.37 mmol) and nickel (II) chloride hexahydrate (1.28 g, 5.37 mmol) in dry THF (10 mL) was added sodium borohydride (1.02 g, 26.8 mmol) in four potions at 0 °C. The reaction mixture was stirred at 0 °C for 6 h and at 20 °C for 10 h. TLC showed about half consumption of 280.2. The reaction mixture was quenched with EA (10 mL) and Sat. aq. NH4Cl (20 mL). Filtered, the aqueous phase was extracted with EA (10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 5% EA in PE) to give 280.3 (329 mg, 33% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.13 (q, J = 7.2 Hz, 2H), 2.75 – 2.66 (m, 2H), 2.63 – 2.55 (m, 2H), 2.21 (d, J = 7.2 Hz, 2H), 2.06 – 1.97 (m, 2H), 1.90 – 1.78 (m, 1H), 1.46 – 1.35 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H). Step 3. Synthesis of ethyl 2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetate (2804). [00550] To a solution of 280.3 (329 mg, 1.75 mmol) in dry DCM (10 mL) was added m-CPBA (754 mg, 4.37 mmol) portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 6 h and at 20 °C for another 4 h. TLC showed complete consumption of 280.3. The mixture was diluted with DCM (10 mL) and washed with Sat. aq. Na2S2O3 (10 mL), followed by Sat.aq. NaHCO3 (10 mL), water (10 mL) and brine (5.0 mL). The organic phase was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was concentrated to dryness to give 280.4 (693 mg, crude) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 4.06 (q, J = 7.2 Hz, 2H), 3.15 (td, J = 13.2, 3.2 Hz, 2H), 3.03 – 2.94 (m, 2H), 2.34 – 2.23 (m, 2H), 2.09 – 1.92 (m, 3H), 1.73 –1.57 (m, 2H), 1.18 (t, J = 7.2Hz, 3H). Step 4. Synthesis of 2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetic acid (280.5). [00551] To a solution of 280.4 (693 mg, 3.15 mmol) in EtOH (6.0 mL) was added a solution of sodium hydroxide (251 mg, 6.29 mmol) in water (6.0 mL). The reaction mixture was stirred at 80 °C for 2 h under nitrogen. TLC showed complete consumption of 280.4. The reaction mixture was concentrated to remove the organic solvent. The residue was diluted with water (10 mL) and extracted with EA (5.0 mL). The aqueous phase was acidified with HCl (1 M) and extracted with EA (5.0 mL × 5). The combined organic phase washed with brine (5.0 mL) and then concentrated to give 280.5 (501 mg, crude) as a yellow oil. Step 5. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)acetate (280.6). [00552] A solution of 280.5 (155 mg, 0.81 mmol), EDCI (464 mg, 2.42 mmol) and DMAP (296 mg, 2.42 mmol) in dry THF (12 mL) was stirred at 20 °C for 30 min and then 6.4 (240 mg, 0.73 mmol) was added. the reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched with water (15 mL) and extracted with EA (5.0 mL × 2). The combined organic phase was washed with brine (5.0 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 50% EA in PE) to give 280.6 (208 mg, crude with DMAP) as a colorless oil. MS (ESI): mass calcd. for C 22 H 27 N 5 O 7 S, 505.16, m/z found 506.3 [M+H] + . Step 6. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetate (280). [00553] To a solution of 280.6 (208 mg, 0.41 mmol) in dry THF (2.0 mL) was added Conc. HCl (1.0 mL) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 30 min. The organic solvent was removed with flowing nitrogen and the residue was diluted with ACN. The solution was purified by prep-HPLC to afford the title compound (64.73 mg, 33% yield) as a white solid. MS (ESI): mass calcd. for C19H23N5O7S, 465.13, m/z found 466.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6.4 Hz, 1H), 5.39 (d, J = 5.6 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.33 (dd, J = 11.4, 2.0 Hz, 1H), 4.25 – 4.14 (m, 2H), 3.94 (dd, J = 11.2, 5.6 Hz, 1H), 3.12 (td, J = 13.6, 3.2 Hz, 2H), 3.00 – 2.91 (m, 2H), 2.39 – 2.27 (m, 2H), 2.06 – 1.91 (m, 3H), 1.70 – 1.58 (m, 2H). Example 127: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (S)-2-cyclohexylpropanoate (Compound 281). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (S)-2-cyclohexylpropanoate (281.1), [00554] The compound 281.1 was prepared according to the procedure of Example 266, Step 1, using 6.3 and (S)-2-cyclohexylpropanoic acid. MS (ESI): mass calcd. for C24H31N5O5, 469.23, m/z found 470.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92-7.90 (br, s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.39 – 4.13 (m, 3H), 4.08 – 3.83 (m, 1H), 2.24-2.17 (m, 1H), 1.64 – 1.36 (m, 6H), 1.20 – 1.00 (m, 3H), 0.98 (d, J = 7.2 Hz, 3H), 0.95 – 0.83 (m, 2H). Step 2: Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (S)-2-cyclohexylpropanoate (Compound 281). [00555] The title compound 281 was prepared according to the procedure of Example 272, Step 2, using 281.1. MS (ESI): mass calcd. for C21H27N5O5, 429.20, m/z found 430.2 [M+H] + .1H NMR (400 MHz, DMSO) δ 7.92-7.90 (br, s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H), 4.71 (t, J= 5.6 Hz, 1H), 4.39 – 4.13 (m, 3H), 4.08 – 3.83 (m, 1H), 2.24- 2.17 (m, 1H), 1.64 – 1.36 (m, 6H),1.20 – 1.00 (m, 3H), 0.98 (d, J = 7.2 Hz, 3H), 0.95 – 0.83 (m,2H). Example 128. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl propionate (Compound 282). [00556] The title compound was prepared according to the procedure of Example 5, Step 4, using 264 and propionyl chloride. MS (ESI): mass calcd. for C20H25N5O6, 431.18, m/z found 432.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.39 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 6.44 (d, J = 6.0 Hz, 1H), 5.45 (d, J = 6.0 Hz, 1H), 4.67 (t, J = 5.2 Hz, 1H), 4.38 – 4.31 (m, 1H), 4.29 – 4.24 (m, 1H), 4.19 – 4.13 (m, 1H), 3.94 (dd, J = 11.6, 6.0 Hz, 1H), 2.71 (t, J = 7.6 Hz, 2H), 2.34 – 2.27 (m, 2H), 1.67 – 1.54 (m, 2H), 1.40 – 1.30 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Example 129. Synthesis ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl 3-methylbutanoate (Compound 283). [00557] The title compound was prepared according to the procedure of Example 288, Step 1, using Compound 264 and 3-methylbutanoyl chloride. MS (ESI): mass calcd. for C22H29N5O6, 459.21, m/z found 460.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.39 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.05 (d, J = 4.8 Hz, 1H), 6.43 (d, J = 6.0 Hz, 1H), 5.44 (d, J = 6.0 Hz, 1H), 4.70 – 4.65 (m, 1H), 4.35 – 4.23 (m, 2H), 4.17 (dd, J = 12.0, 5.2 Hz, 1H), 3.94 (dd, J = 11.6, 6.4 Hz, 1H), 2.75 – 2.67 (m, 2H), 2.20 – 2.08 (m, 2H), 1.91 (m, 1H), 1.66 – 1.54 (m, 2H), 1.40 – 1.28 (m, 2H), 0.95 – 0.81 (m, 9H). Example 130. Synthesis ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 284). [00558] The title compound was prepared according to the procedure of Example 288, Step 1, using Compound 264 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C25H33N5O6, 499.24, m/z found 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.39 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.05 (d, J = 4.8 Hz, 1H), 6.55 (s, 1H), 5.55 (s, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.34 – 4.22 (m, 2H), 4.16 (dd, J = 12.0, 5.2 Hz, 1H), 3.99 – 3.90 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.19 – 2.05 (m, 2H), 1.65 – 1.53 (m, 8H), 1.42 – 1.29 (m, 2H), 1.21 – 1.04 (m, 3H), 0.94 – 0.80 (m, 5H). Example 131. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 285). [00559] The title compound was prepared according to the procedure of Example 103, Step 1, using Compound 85 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C27H29N5O6, 519.21, m/z found 520.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.34 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 3.2 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 6.45 (s, 1H), 5.47 (s, 1H), 4.70 (s, 1H), 4.35 – 4.24 (m, 2H), 4.17 (dd, J = 12.0, 5.2 Hz, 1H), 3.97 (t, J = 5.6 Hz, 1H), 2.20 – 2.04 (m,2H), 1.60 (d, J = 11.2 Hz, 6H), 1.24 – 0.99 (m, 3H), 0.96 – 0.79 (m, 2H). Example 132. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate. Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetate (286.1). [00560] To a mixture of 6.4 (300 mg, 0.90 mmol), (1-{[(tert-butoxy)carbonyl]amino}cyclohexyl)acetic acid (233 mg, 0.90 mmol) and EDCI (520 mg, 2.71 mmol) in THF was added DMAP (331 mg, 2.71 mmol) at 0 o C slowly. The mixture was then stirred at 20 o C for about 5 hours. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a residue. The residue was purified by prep-HPLC to afford 286.1 (410 mg, 78.5% yield) as a white solid. MS (ESI): m/z calcd. for C28H38N6O7, 570.28, found 571.35 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.96 (s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.24 (s, 1H), 5.43 (d, J = 6.4 Hz, 1H), 4.96 (dd, J = 6.4, 3.2 Hz, 1H), 4.54 (dd, J = 8.4, 5.2 Hz, 1H), 4.18 (dd, J = 12.0, 4.4 Hz, 1H), 4.07 (dd, J = 12.0, 6.0 Hz, 1H), 1.95 (d, J = 10.0 Hz, 2H), 1.64 (s, 3H), 1.55 – 1.00 (m, 22H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (286). [00561] To a solution of 286.1 (200 mg, 0.37 mmol) in THF (2.0 mL) was added 6 M HCl (2.0 mL) dropwise at 0 °C, the mixture was then stirred at 20 °C for 2 hours. The mixture was quenched with water (2 mL) and dried with a stream of nitrogen to remove the solvent away. The residue was purified by prep-HPLC to afford 286 (113 mg, 74.6% yield) as a white solid. MS (ESI): m/z calcd. for C20H26N6O5, 430.20, found 431.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 5H), 6.93 (d, J = 4.4 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 6.35 (d, J = 4.8 Hz, 1H), 5.46 (s, 1H), 4.74 (s, 1H), 4.41 – 4.32 (m, 1H), 4.30 – 4.20 (m, 2H), 3.97 (t, J = 5.2 Hz, 1H), 2.68 (s, 2H), 1.71 – 1.20 (m, 10H). Example 133. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-methoxycyclohexyl)acetate (Compound 287). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-methoxycyclohexyl)acetate (287.1). [00562] To a mixture of 6.4 (200 mg, 0.60 mmol) and (1-methoxycyclohexyl)acetic acid (103.9 mg, 0.60 mmol) and EDCI (347 mg, 1.81 mmol) in THF (4 mL) was added DMAP (221 mg, 1.81 mmol) at 0 °C slowly. The mixture was then stirred at 20 °C for about 5 hours. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a residue. The residue was purified by prep-HPLC to afford 287.1 (220 mg, 74.3% yield) as a white solid. MS (ESI): m/z calcd. for C 24 H 31 N 5 O 6 , 485.23, found 486.30 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.96 (s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.55 (dd, J = 7.6, 5.2 Hz, 1H), 4.14 (ddd, J = 18.0, 12.0, 5.2 Hz, 2H), 3.04 (s, 3H), 2.37 (s, 2H), 1.65 (d, J = 11.2 Hz, 5H), 1.47 – 1.28 (m, 10H), 1.14 (d, J = 9.6 Hz, 1H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-methoxycyclohexyl)acetate (287). [00563] To a solution of 287.1 (150 mg, 0.3 mmol) in THF (1.5 mL) was added 6 M HCl (1.5 mL) dropwise at 0 °C, the mixture was then stirred at 20 °C for 2 hours. LCMS (ENB214167-097-M2) showed that the starting material was consumed completely. The mixture was quenched with water (2 mL) and dried with a stream of nitrogen to remove the solvent away. The residue was purified by prep- HPLC to afford 287 (113 mg, 74.8% yield) as a white solid. MS (ESI): m/z calcd. for C21H27N5O6, 445.20, found 446.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.30 (d, J = 6.4 Hz, 1H), 5.38 (d, J = 5.6 Hz, 1H), 4.71 (t, J = 5.2 Hz, 1H), 4.31 – 4.18 (m, 2H), 4.18 – 4.08 (m, 1H), 3.96 (q, J = 5.2 Hz, 1H), 3.06 (s, 3H), 2.43 (s, 2H), 1.74 – 1.61 (m, 2H), 1.48 – 1.31 (m, 7H), 1.20 – 1.09 (m, 1H). Example 134. Synthesis ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin [00564] To a solution of 264 (80.0 mg, 0.21 mmol) in DMPU (0.5 mL) was added HCl/dioxane (0.1 mL, 4 M). The mixture solution was stirred at 0 °C for 15 minutes. Then acetyl chloride (50.2 mg, 0.64 mmol) was added at 0 °C. The resulting mixture was stirred at 20 °C for another 2 hours. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to afford the title compound (19.5 mg, 21.5% yield) as a white solid. MS (ESI): m/z calcd. for C19H23N5O6417.16, found 418.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.40 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.05 (d, J = 4.8 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 5.44 (d, J = 6.0 Hz, 1H), 4.71 – 4.61 (m, 1H), 4.35 – 4.23 (m, 2H), 4.15 (dd, J = 12.0, 5.6 Hz, 1H), 3.93 (dd, J = 12.0, 5.2 Hz, 1H), 2.73 – 2.66 (m, 2H), 2.01 (s, 3H), 1.65 – 1.55 (m, 2H), 1.41 – 1.29 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). Example 135. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 1-phenylcyclopropane-1-carboxylate (Compound 289). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 1-phenylcyclopropane-1-carboxylate (289.1). [00565] The title compound was prepared according to the procedure of Example 273, Step 1, using 6.4 and 1-phenylcyclopropane-1-carboxylic acid. MS (ESI): mass calcd. for C25H25N5O5, 475.19, m/z found 476.1 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 1-phenylcyclopropane-1-carboxylate (289). [00566] The title compound was prepared according to the procedure of Example 273, Step 2, using 289.1. MS (ESI): mass calcd. for C22H21N5O5, 435.15, m/z found 436.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (br s, 3H), 7.33 – 7.19 (m, 5H), 6.92 (d, J = 4.4 Hz, 1H), 6.64 (d, J = 4.4 Hz, 1H), 6.21 (d, J = 6.0 Hz, 1H), 5.36 (d, J = 5.2 Hz, 1H), 4.41 (t, J = 5.2 Hz, 1H), 4.30 – 4.23 (m, 1H), 4.20 – 4.10 (m, 2H), 3.87 – 3.80 (m, 1H), 1.50 – 1.41 (m, 2H), 1.23 – 1.12 (m, 2H). Example 136. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate (Compound 290).
Step 1. Synthesis of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -(((tert- butyldiphenylsilyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran- 2-carbonitrile (290.1). [00567] To a solution of 6.3 (1.00 g, 3.4 mmol) and pyridine (540 mg, 6.8 mmol) in dry DMSO (10 mL) was added TBDPSCl (1.03 g, 3.7 mmol) dropwise. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into cold water (25 mL) and white solid precipitated. Filter, the filter cake was collected and dried to obtain 290.1 (1.90 g, 94.1% yield) as a white solid. MS (ESI): m/z calcd. for C 28 H 31 N 5 O 4 Si, 529.21, found 530.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.63 – 7.55 (m, 4H), 7.41 – 7.35 (m, 3H), 7.30 (dd, J = 13.2, 7.2 Hz, 4H), 6.86 – 6.81 (m, 2H), 4.37 (t, J = 5.2 Hz, 1H), 4.34 – 4.27 (m, 1H), 3.93 (dd, J = 11.6, 2.8 Hz, 1H), 3.83 (dd, J = 11.6, 3.6 Hz, 1H), 1.00 – 0.92 (m, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl benzoate (290.2). [00568] A solution of benzoic acid (184 mg, 1.51 mmol), HOBT (612 mg, 4.53 mmol), EDCI (869 mg, 4.53 mmol) and DIPEA (586 mg, 4.53 mmol) in dry DMF (8.0 mL) was stirred at 25 °C for 1 h. Then 290.1 (800 mg, 1.51 mmol) was added into the flask vessel. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (5.0 mL × 2). The combined organic phase was washed with brine (5.0 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (Gradient: 15% EA in PE) to give 290.2 (582 mg, 93% purity, 57% yield) as a white solid. MS (ESI): m/z calcd. for C 35 H 35 N 5 O 5 Si, 633.24, found 634.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.13 (d, J = 7.2 Hz, 2H), 7.91 (br s, 3H), 7.73 – 7.67 (m, 1H), 7.60 – 7.51 (m, 4H), 7.48 – 7.35 (m, 4H), 7.29 (t, J = 7.2 Hz, 2H), 7.21 (t, J = 7.6 Hz, 2H), 6.86 (dd, J = 16.0, 4.4 Hz, 2H), 6.73 (d, J = 6.4 Hz, 1H), 5.70 (dd, J = 5.2, 3.2 Hz, 1H), 5.20 (t, J = 6.0 Hz, 1H), 4.55 (dd, J = 6.0, 3.2 Hz, 1H), 3.89 – 4.77 (m, 2H), 0.94 (s, 9H). Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4-hydroxy- 2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate (290). [00569] A mixture of 290.2 (80.0 mg, 0.126 mmol) in THF (1.0 mL) was added TBAF (0.2 mL, 1M) dropwise. The reaction mixture was stirred at 20 °C for 2 h. The reaction was diluted with ACN (2.0 mL) and purified by prep-HPLC to obtain 290 (120 mg 24% yield) as a white solid MS (ESI): m/z calcd. for C19H17N5O5, 395.12, found 396.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.16 – 8.09 (m, 2H), 7.96 (br s, 3H), 7.69 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 6.93 (q, J = 4.8 Hz, 2H), 6.56 (d, J = 6.4 Hz, 1H), 5.53 (dd, J = 5.6, 2.8 Hz, 1H), 5.12 (q, J = 6.0 Hz, 2H), 4.44 (q, J = 3.6 Hz, 1H), 3.73 – 3.51 (m, 2H). Example 137. Synthesis of ((2R,3R,4R,5R)-5-(2-amino-6-(2-cyclohexyl-N-methylacetamido) -9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 291). [00570] To a solution of 3.3 (1.00 g,3.2 mmol) in DMPU (4 mL) was added HCl in dioxane (4 M, 1.6 mL), The solution was stirred at 20 °C for 15 min. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.59 mL, 3.8 mmol) was added at once. The reaction was stirred for 2 hours at 0 ℃. The reaction was diluted with ACN (4.0 mL) and purified by prep-HPLC to obtain 291 (27.8 mg, 1.55% yield) as a white solid. MS (ESI): m/z calcd. for C28H41FN6O5, 560.31, found 561.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 6.82 (s, 2H), 6.14 (d, J = 19.2 Hz, 1H), 5.84 (s, 1H), 4.56 – 4.25 (m, 3H), 4.16 – 4.03 (m, 1H), 2.42 – 2.32 (m, 2H), 2.23 (d, J = 6.8 Hz, 2H), 1.58 (dd, J = 28.8, 10.8 Hz, 13H), 1.25 – 0.73 (m, 15H). 19 F NMR (376 MHz, DMSO) δ -159.44 (s, 1H). Example 138. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 292). [00571] To a solution of 3.3 (1.00 g,3.2 mmol) in DMPU (4 mL) was added HCl in dioxane (4 M, 1.6 mL), The solution was stirred at 20 °C for 15 min. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.59 mL, 3.8 mmol) was added at once. The reaction was stirred for 2 hours at 0 ℃. The reaction was diluted with ACN (4.0 mL) and purified by prep-HPLC to obtain 292 (28.0 mg, 1.52% yield) as a white solid. MS (ESI): m/z calcd. for C28H41FN6O5, 560.31, found 561.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.12 (s, 1H), 7.83 (d, J = 17.6 Hz, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.64 (s, 1H), 4.86 (s, 1H), 4.47 (dd, J = 12.4, 2.0 Hz, 1H), 4.33 (dd, J = 12.4, 7.6 Hz, 1H), 4.03 (t, J = 8.0 Hz, 1H), 2.93 (s, 3H), 2.38 (s, 1H), 2.17 (d, J = 6.8 Hz, 2H), 1.84 – 1.54 (m, 13H), 1.30 – 1.05 (m, 10H), 0.93 (dt, J = 16.4, 10.8 Hz, 4H). 19 F NMR (376 MHz, DMSO) δ -159.44. Example 139. Synthesis of ((2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-propio namido- 9H-purin-9-yl)-3-(propionyloxy)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 293). [00572] To a solution of 3 (50 mg, 0.13 mmol) in NMP (0.5 mL) was added 4 M HCl/dioxane (0.05 mL) dropwise, the mixture was then stirred at 0 °C for 20 minutes. Propanoyl chloride (0.05 mL) was added dropwise to the mixture at 0 °C, the mixture was then stirred at 20 °C for 16 hours. After completion, the mixture was purified by prep-HPLC to afford 293 (20 mg, 30.9% yield) as a white solid. MS (ESI): m/z calcd. for C22H31FN6O6, 494.23, found 495.20 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 6.17 (dd, J = 55.6, 17.6 Hz, 2H), 4.53 – 4.21 (m, 3H), 2.94 (s, 3H), 2.59 – 2.52 (m, 2H), 2.48 – 2.31 (m, 3H), 1.24 – 0.94 (m, 15H). 19 F NMR (377 MHz, DMSO) δ - 155.61. Example 140. Synthesis of (2R,3R,4R,5R)-4-fluoro-5-(2-isobutyramido-6-(methylamino)-9H - purin-9-yl)-2-((isobutyryloxy)methyl)-4-methyltetrahydrofura n-3-yl isobutyrate (Compound 294). [00573] The title compound was prepared according to the procedure of Example 293, using 3 and isobutyryl chloride. MS (ESI): m/z calcd. for C24H35FN6O6522.26, found 523.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 6.24 (d, J = 19.6 Hz, 2H), 4.51 – 4.27 (m, 3H), 2.94 (s, 4H), 2.71 – 2.63 (m, 1H), 2.57 – 2.52 (m, 1H), 1.25 – 1.03 (m, 21H). 19 F NMR (377 MHz, DMSO) δ -156.16. Example 141. Synthesis of (2R,3R,4R,5R)-4-fluoro-2-((isobutyryloxy)methyl)-4-methyl-5- (6- (methylamino)-2-(3-methylbutanamido)-9H-purin-9-yl)tetrahydr ofuran-3-yl 3-methylbutanoate (Compound 295). [00574] The title compound was prepared according to the procedure of Example 293, using 3 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C26H39FN6O6550.29, found 551.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 6.23 (d, J = 19.6 Hz, 2H), 4.56 – 4.25 (m, 3H), 2.95 (s, 3H), 2.57 – 2.51 (m, 1H), 2.32 (dd, J = 17.6, 6.8 Hz, 4H), 2.04 (tt, J = 15.6, 6.8 Hz, 2H), 1.18 (d, J = 23.2 Hz, 3H), 1.07 (d, J = 7.2 Hz, 6H), 0.99 – 0.88 (m, 12H). 19 F NMR (377 MHz, DMSO) δ -155.59. Example 142. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-3-(2-cyclohexylacetoxy)-4-fluoro-4-methyltetrahy drofuran-2-yl)methyl isobutyrate (Compound 296). [00575] To a solution of 3 (100 mg,0.26 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.3 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.2 mL,1.3 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 296 (25.5 mg, 14.7% yield) as a white solid. MS (ESI): m/z calcd. for C 32 H 47 FN 6 O 6 , 630.35, found 631.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 6.23 (d, J = 19.6 Hz, 2H), 4.48 – 4.39 (m, 2H), 4.34 – 4.27 (m, 1H), 2.94 (s, 3H), 2.56 – 2.52 (m, 1H), 2.36 – 2.27 (m, 4H), 1.76 – 1.60 (m, 11H), 1.25 – 0.92 (m, 20H). Example 143. Synthesis of ((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(methylamino )-2-(2- phenylacetamido)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 297). [00576] To a solution of 3 (100 mg,0.26 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.3 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- phenylacetyl chloride (0.17 mL,1.3 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 297 (8.72 mg, 6.65% yield) as a white solid. MS (ESI): m/z calcd. for C 24 H 29 FN 6 O 5 , 500.22, found 501.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.35 – 7.28 (m, 4H), 7.25 – 7.19 (m, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.65 (d, J = 6.0 Hz, 1H), 4.81 (s, 1H), 4.46 (dd, J = 12.4, 2.0 Hz, 1H), 4.32 (dd, J = 12.4, 7.6 Hz, 1H), 4.04 (t, J = 8.0 Hz, 1H), 3.82 (s, 2H), 2.93 (s, 2H), 2.57 – 2.52 (m, 1H), 1.10 (t, J = 15.6 Hz, 10H). 19 F NMR (376 MHz, DMSO) δ -158.63. Example 144. Synthesis of ((2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-(2- phenylacetamido)-9H-purin-9-yl)-3-(2-phenylacetoxy)tetrahydr ofuran-2-yl)methyl isobutyrate (Compound 298). [00577] To a solution of 3 (100 mg,0.26 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.3 mL), the solution was stirred at 20℃ for 15 minutes. The reaction mixture was cooled at 0℃ and 2- phenylacetyl chloride (0.17 mL, 1.3 mmol) was added at once. The reaction was stirred at 20℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 298 (6.75 mg, 4.71% yield) as a white solid. MS (ESI): m/z calcd. for C32H35FN6O6, 618.26, found 619.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.40 – 7.15 (m, 10H), 6.23 (d, J = 19.6 Hz, 2H), 4.46 – 4.29 (m, 3H), 3.89 – 3.71 (m, 4H), 2.92 (s, 3H), 1.23 (s, 1H), 1.13 (d, J = 23.2 Hz, 3H), 1.06 (dd, J = 7.2, 2.0 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -155.52. Example 145. Synthesis of ((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(methylamino )-2-(2- phenylacetamido)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 299). [00578] To a solution of 175 (100 mg,0.22 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.2 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- phenylacetyl chloride (0.21 mL, 1.6 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 299 (9.27 mg, 7.29% yield) as a white solid. MS (ESI): m/z calcd. for C28H35FN6O5, 554.27, found 555.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 7.35 – 7.28 (m, 4H), 7.25 – 7.20 (m, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.64 (d, J = 7.2 Hz, 1H), 4.77 (s, 1H), 4.46 (dd, J = 12.4, 2.0 Hz, 1H), 4.30 (dd, J = 12.4, 7.2 Hz, 1H), 4.02 (t, J = 7.6 Hz, 1H), 3.82 (s, 2H), 2.93 (s, 3H), 2.17 (d, J = 6.8 Hz, 2H), 1.62 (d, J = 12.8 Hz, 6H), 1.15 (dd, J = 29.6, 17.6 Hz, 6H), 0.89 (dd, J = 18.8, 8.8 Hz, 2H). Example 146. Synthesis of (2R,3R,4R,5R)-2-((2-cyclohexylacetoxy)methyl)-4-fluoro-4-met hyl-5-(6- (methylamino)-2-propionamido-9H-purin-9-yl)tetrahydrofuran-3 -yl propionate (Compound 300). [00579] The title compound was prepared according to the procedure of Example 293, using 175 and propionyl chloride. MS (ESI): m/z calcd. for C26H37FN6O6548.28, found 549.35 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 6.23 (d, J = 19.6 Hz, 1H), 6.08 (d, J = 14.8 Hz, 1H), 4.48 – 4.25 (m, 3H), 2.94 (s, 3H), 2.54 (Q, J = 7.6 Hz, 2H), 2.45 (q, J = 7.6 Hz, 2H), 2.17 (d, J = 6.8 Hz, 2H), 1.69 – 1.54 (m, 6H), 1.24 – 1.02 (m, 12H), 0.97 – 0.82 (m, 2H). 19 F NMR (377 MHz, DMSO) δ -155.53. Example 147. Synthesis of (2R,3R,4R,5R)-2-((2-cyclohexylacetoxy)methyl)-4-fluoro-5-(2- isobutyramido-6-(methylamino)-9H-purin-9-yl)-4-methyltetrahy drofuran-3-yl isobutyrate (Compound 301). [00580] The title compound was prepared according to the procedure of Example 293, using 175 and isobutyryl chloride. MS (ESI): m/z calcd. for C28H41FN6O6576.31, found 577.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 6.23 (d, J = 19.6 Hz, 2H), 4.48 – 4.27 (m, 3H), 2.94 (s, 4H), 2.71 – 2.63 (m, 1H), 2.16 (d, J = 6.4 Hz, 2H), 1.71 – 1.51 (m, 6H), 1.26 – 1.03 (m, 18H), 0.96 – 0.83 (m, 2H). 19 F NMR (377 MHz, DMSO) δ -156.04. Example 148. Synthesis of (2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-propion amido- 9H-purin-9-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3- yl propionate (Compound 302). [00581] The title compound was prepared according to the procedure of Example 293, using 177 and propionyl chloride. MS (ESI): m/z calcd. for C26H31FN6O6542.23, found 543.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.35 – 7.19 (m, 5H), 6.24 (d, J = 19.6 Hz, 1H), 6.18 – 5.99 (m, 1H), 4.51 – 4.41 (m, 2H), 4.37 – 4.30 (m, 1H), 3.74 – 3.63 (m, 2H), 2.94 (s, 3H), 2.57 – 2.52 (m, 2H), 2.44 (q, J = 7.2 Hz, 2H), 1.18 (d, J = 23.2 Hz, 3H), 1.10 – 1.00 (m, 6H). 19 F NMR (377 MHz, DMSO) δ -155.41. Example 149. Synthesis of ((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(methylamino )-2-(3- methylbutanamido)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 303).
[00582] The title compound was prepared from Example 185. MS (ESI): m/z calcd. for C25H31FN6O5 514.23, found 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.32 – 7.21 (m, 5H), 6.13 (d, J = 20.0 Hz, 1H), 5.63 (s, 1H), 4.88 (s, 1H), 4.50 – 4.36 (m, 2H), 4.05 (t, J = 8.0 Hz, 1H), 3.68 (s, 2H), 2.94 (s, 3H), 2.43 – 2.34 (m, 2H), 2.12 – 2.01 (m, 1H), 1.13 (d, J = 22.4Hz, 3H), 0.91 (d, J = 6.4 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -158.33. Example 150. Synthesis of (2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-(3- methylbutanamido)-9H-purin-9-yl)-2-((2-phenylacetoxy)methyl) tetrahydrofuran-3-yl 3- methylbutanoate (Compound 304). [00583] The title compound was prepared from Example 185. MS (ESI): m/z calcd. for C30H39FN6O6 598.29, found 599.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 8.16 (s, 1H), 7.85 (s, 1H), 7.32 – 7.21 (m, 5H), 6.44 – 6.16 (m, 2H), 4.53 – 4.43 (m, 2H), 4.35 – 4.29 (m, 1H), 3.67 (s, 2H), 2.94 (s, 3H), 2.35 – 2.27 (m, 4H), 2.07 – 1.96 (m, 2H), 1.17 (d, J = 23.2 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H), 0.90 (d, J = 6.8 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -155.42. Example 151. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 305). [00584] To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20.℃ for 15 minutes. The reaction mixture was cooled at 0.℃ and 2- cyclohexylacetyl chloride (0.36 mL, 2.32 mmol) was added at once. The reaction was stirred at 20.℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 305 (8.40 mg, 6.50% yield) as a white solid. MS (ESI): m/z calcd. for C 28 H 35 FN 6 O 5 , 554.27, found 555.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.36 – 7.17 (m, 5H), 6.13 (d, J = 20.0 Hz, 1H), 5.62 (s, 1H), 4.85 (s, 1H), 4.48 (dd, J = 12.4, 2.0 Hz, 1H), 4.39 (dd, J = 12.4, 7.2 Hz, 1H), 4.05 (t, J = 7.6 Hz, 1H), 3.68 (s, 2H), 2.93 (s, 3H), 2.36 (s, 2H), 1.79 – 1.57 (m, 6H), 1.24 – 1.08 (m, 6H), 0.98 – 0.90 (m, 2H). Example 152. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-3-(2-cyclohexylacetoxy)-4-fluoro-4-methyltetrahy drofuran-2-yl)methyl 2-phenylacetate (Compound 306). [00585] To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20.℃ for 15 minutes. The reaction mixture was cooled at 0.℃ and 2- cyclohexylacetyl chloride (0.36 mL, 2.32 mmol) was added at once. The reaction was stirred at 20.℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 306 (12.0 mg, 7.62% yield) as a white solid. MS (ESI): m/z calcd. for C36H47FN6O6, 678.35, found 679.43 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.40 – 7.09 (m, 5H), 6.23 (d, J = 20.0 Hz, 2H), 4.47 (d, J = 5.2 Hz, 2H), 4.31 (dt, J = 9.6, 5.2 Hz, 1H), 3.67 (s, 2H), 2.94 (s, 3H), 2.28 (d, J = 6.8 Hz, 2H), 1.75 – 1.57 (m, 12H), 0.99 – 0.83 (m, 11H), 1.01 – 0.86 (m, 4H). 19 F NMR (376 MHz, DMSO) δ -155.45. Example 153. Synthesis of ((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(methylamino )-2-(2- phenylacetamido)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 307). [00586] To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- phenylacetyl chloride (0.25 mL, 1.85 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 307 (13.6 mg, 10.3% yield) as a white solid. MS (ESI): m/z calcd. for C28H29FN6O5, 548.22, found 549.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.35 – 7.17 (m, 10H), 6.13 (d, J = 20.0 Hz, 1H), 5.64 (s, 1H), 4.85 (s, 1H), 4.52 – 4.43 (m, 1H), 4.37 (dd, J = 12.4, 7.6 Hz, 1H), 4.04 (t, J = 7.6 Hz, 1H), 3.81 (s, 2H), 3.68 (s, 2H), 2.93 (s, 3H), 1.11 (d, J = 22.8 Hz, 3H). Example 154. Synthesis of (2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-(2- phenylacetamido)-9H-purin-9-yl)-2-((2-phenylacetoxy)methyl)t etrahydrofuran-3-yl 2- phenylacetate (Compound 308). [00587] To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- phenylacetyl chloride (0.25 mL, 1.85 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 308 (22.1 mg, 13.9% yield) as a white solid. MS (ESI): m/z calcd. for C36H35FN6O6, 666.26, found 667.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.33 – 7.17 (m, 15H), 6.24 (m, 2H), 4.49 – 4.39 (m, 2H), 4.34 (dt, J = 9.6, 4.8 Hz, 1H), 3.86 – 3.74 (m, 4H), 3.69 – 3.61 (m, 2H), 2.93 (s, 3H), 1.14 (d, J = 23.2 Hz, 3H). Example 155. Synthesis of (2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-propion amido- 9H-purin-9-yl)-2-((propionyloxy)methyl)tetrahydrofuran-3-yl propionate (Compound 309). [00588] The title compound was prepared according to the procedure of Example 293, using 180 and propionyl chloride. MS (ESI): m/z calcd. for C21H29FN6O6480.21, found 481.10 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 6.23 (d, J = 19.6 Hz, 1H), 6.09 (d, J = 15.2 Hz, 1H), 4.51 – 4.24 (m, 3H), 2.95 (s, 3H), 2.59 – 2.51 (m, 2H), 2.45 (q, J = 7.2 Hz, 2H), 2.32 (q, J = 7.2 Hz, 2H), 1.26 – 0.96 (m, 12H). 19 F NMR (377 MHz, DMSO) δ -155.56. Example 156. Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fl uoro-4- methyl-2-(((3-methylbutanoyl)oxy)methyl)tetrahydrofuran-3-yl 3-methylbutanoate (Compound 312). [00589] The title compound was prepared according to the procedure of Example 183, using 174 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C 22 H 33 FN 6 O 5 480.25, found 481.25 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.39 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 6.04 – 5.76 (m, 3H), 4.50 – 4.40 (m, 1H), 4.40 – 4.26 (m, 2H), 2.87 (s, 3H), 2.33 (dd, J = 7.6, 1.2 Hz, 2H), 2.26 – 2.19 (m, 2H), 2.08 – 1.92 (m, 2H), 1.14 (d, J = 22.8 Hz, 3H), 0.99 – 0.85 (m, 12H). 19 F NMR (377 MHz, DMSO) δ -156.35. Example 157. Synthesis of (2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-(3- methylbutanamido)-9H-purin-9-yl)-2-(((3-methylbutanoyl)oxy)m ethyl)tetrahydrofuran-3-yl 3- methylbutanoate (Com o nd 313) [00590] The title compound was prepared according to the procedure of Example 293, using 174 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C27H41FN6O6564.31, found 565.40 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 6.40 – 6.10 (m, 2H), 4.45 (d, J = 5.2 Hz, 2H), 4.35 – 4.25 (m, 1H), 2.94 (s, 3H), 2.40 – 2.27 (m, 4H), 2.17 (d, J = 7.2 Hz, 2H), 2.10 – 1.89 (m, 3H), 1.18 (d, J = 23.2 Hz, 3H), 0.98 – 0.85 (m, 18H). 19 F NMR (377 MHz, DMSO) δ -155.56. Example 158. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 314). [00591] To a solution of 174 (100 mg,0.25 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.39 mL, 2.52 mmol) was added at once. The reaction was stirred at 20 ℃ for 48 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 314 (7.30 mg, 5.55% yield) as a white solid. MS (ESI): m/z calcd. for C 25 H 37 FN 6 O 5 , 520.28, found 521.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.62 (s, 1H), 4.82 (s, 1H), 4.55 – 4.41 (m, 1H), 4.35 (dd, J = 12.4, 7.6 Hz, 1H), 4.04 (t, J = 8.0 Hz, 1H), 2.93 (s, 3H), 2.38 – 2.33 (m, 2H), 2.18 (d, J = 7.2 Hz, 2H), 1.96 – 1.91 (m, 1H), 1.84 – 1.59 (m, 6H), 1.23– 1.10 (m, 6H), 1.00 – 0.91 (m, 2H), 0.88 (dd, J = 6.8, 1.2Hz, 6H). Example 159. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-3-(2-cyclohexylacetoxy)-4-fluoro-4-methyltetrahy drofuran-2-yl)methyl 3- methylbutanoate (Compound 315). [00592] To a solution of 174 (100 mg,0.25 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.39 mL, 2.52 mmol) was added at once. The reaction was stirred at 20 ℃ for 48 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 315 (35.4 mg, 21.4% yield) as a white solid. MS (ESI): m/z calcd. for C33H49FN6O6, 644.37, found 645.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.16 (s, 1H), 7.85 (s, 1H), 6.22 (d, J = 19.6 Hz, 2H), 4.51 – 4.37 (m, 2H), 4.35 – 4.26 (m, 1H), 2.94 (s, 3H), 2.30 (d, J = 6.8 Hz, 2H), 2.17 (d, J = 7.2 Hz, 2H), 1.95 (dt, J = 14.0, 6.8 Hz, 1H), 1.77 – 1.57 (m, 12H), 1.20 – 1.14 (m, 10H), 1.05 – 0.91 (m, 4H), 0.88 (dd, J = 6.8, 0.8 Hz, 6H). Example 160. Synthesis of ((2R,3R,4R,5R)-5-(2-acetamido-6-(methylamino)-9H-purin-9-yl) -4- fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl propionate (Compound 317). [00593] The title compound was prepared from Example 220. MS (ESI): m/z calcd. for C 17 H 23 FN 6 O 5 410.17, found 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 6.12 (d, J = 19.6 Hz, 1H), 5.70 – 5.60 (m, 1H), 4.91 – 4.70 (br, 1H), 4.49 – 4.43 (m, 1H), 4.39 – 4.32 (m, 1H), 4.07 – 4.01 (m, 1H), 2.93 (s, 3H), 2.35 – 2.29 (m, 2H), 2.19 (s, 3H), 1.13 (d, J = 22.8 Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -158.46. Example 161. Synthesis of ((2R,3R,4R,5R)-5-(2-acetamido-6-(methylamino)-9H-purin-9-yl) -3- acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl propionate (Compound 318). [00594] The title compound was prepared from Example 220. MS (ESI): m/z calcd. for C 19 H 25 FN 6 O 6 452.18, found 453.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 6.23 (d, J = 20.0 Hz, 1H), 6.17 – 5.98 (m, 1H), 4.47 – 4.38 (m, 2H), 4.35 – 4.29 (m, 1H), 2.93 (s, 3H), 2.35 – 2.28 (m, 2H), 2.20 (s, 3H), 2.14 (s, 3H), 1.17 (d, J = 23.2 Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -155.35. Example 162. Synthesis of (2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-(3- methylbutanamido)-9H-purin-9-yl)-2-((propionyloxy)methyl)tet rahydrofuran-3-yl 3- methylbutanoate (Compound 320). [00595] The title compound was prepared according to the procedure of Example 293, using 180 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C25H37FN6O6536.28, found 537.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 6.23 (d, J = 19.6 Hz, 2H), 4.44 (d, J = 4.8 Hz, 2H), 4.36 – 4.27 (m, 1H), 2.94 (s, 3H), 2.39 – 2.25 (m, 6H), 2.11 – 1.96 (m, 2H), 1.18 (d, J = 23.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.95 (dd, J = 6.8, 1.6 Hz, 6H), 0.91 (dd, J = 6.4, 0.4 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -155.51. Example 163. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl propionate (Compound 321). [00596] To a solution of 180 (100 mg,0.27 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.33 mL, 2.17 mmol) was added at once. The reaction was stirred at 20℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 321 (12.0 mg, 8.99% yield) as a white solid. MS (ESI): m/z calcd. for C23H33FN6O5, 492.25, found 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.63 (d, J = 6.4 Hz, 1H), 4.82 (s, 1H), 4.45 (dd, J = 12.4, 2.0 Hz, 1H), 4.36 (dd, J = 12.4, 7.2 Hz, 1H), 4.05 (t, J = 7.6 Hz, 1H), 2.93 (s, 3H), 2.32 (d, J = 7.6 Hz, 2H), 1.81 – 1.59 (m, 7H), 1.32 – 1.07 (m, 7H), 1.03 – 0.92 (m, 5H). Example 164. Synthesis of ((2R,3R,4R,5R)-5-(2-(2-cyclohexylacetamido)-6-(methylamino)- 9H- purin-9-yl)-3-(2-cyclohexylacetoxy)-4-fluoro-4-methyltetrahy drofuran-2-yl)methyl propionate (Compound 322). [00597] To a solution of 180 (100 mg,0.27 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.33 mL, 2.17 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 322 (31.8 mg, 19.0% yield) as a white solid. MS (ESI): m/z calcd. for C31H45FN6O6, 616.34, found 617.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 6.35 – 6.20 (m, 2H), 4.47 – 4.40 (m, 2H), 4.31 (dt, J = 9.6, 5.2 Hz, 1H), 2.94 (s, 3H), 2.35 – 2.26 (m, 5H), 1.80 – 1.58 (m, 12H), 1.30 – 1.09 (m, 10H), 1.02 – 0.92 (m, 7H). 19 F NMR (376 MHz, DMSO) δ -155.52. Example 165. Synthesis of ((2R,3R,4R,5R)-5-(2-acetamido-6-(methylamino)-9H-purin-9-yl) -3- acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl 3-methylbutanoate (Compound 324). [00598] The title compound was prepared from Example 214. MS (ESI): m/z calcd. for C21H29FN6O6 480.21, found 481.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 6.23 (d, J = 20.0 Hz, 1H), 6.17 – 5.99 (m, 1H), 4.48 – 4.38 (m, 2H), 4.34 – 4.28 (m, 1H), 2.94 (s, 3H), 2.22 – 2.13 (m, 8H), 2.00 – 1.92 (m, 1H), 1.17 (d, J = 22.8 Hz, 3H), 0.89 (dd, J = 6.4, 1.2 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -155.37. Example 166. Synthesis of ((2R,3R,4R,5R)-4-fluoro-5-(2-isobutyramido-6-(methylamino)-9 H- purin-9-yl)-3-(isobutyryloxy)-4-methyltetrahydrofuran-2-yl)m ethyl 3-methylbutanoate (Compound 32 [00599] The title compound was prepared from Example 222. MS (ESI): m/z calcd. for C 25 H 37 FN 6 O 6 536.28, found 537.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 6.34 – 5.96 (m, 2H), 4.47 – 4.36 (m, 2H), 4.35 – 4.29 (m, 1H), 2.94 (s, 3H), 2.71 – 2.63 (m, 1H), 2.18 (d, J = 7.2 Hz, 2H), 2.01 – 1.90 (m, 1H), 1.21 – 1.12 (m, 9H), 1.06 (dd, J = 6.8, 4.0 Hz, 6H), 0.88 (dd, J = 6.8, 2.0 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -156.11. Example 167. Synthesis of ((2R,3R,4R,5R)-5-(2-acetamido-6-(methylamino)-9H-purin-9-yl) -3- acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (Compound 326). [00600] The title compound was prepared from Example 215. MS (ESI): m/z calcd. for C24H33FN6O6 520.24, found 521.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 6.23 (d, J = 19.6 Hz, 1H), 6.08 (d, J = 18.4 Hz, 1H), 4.47 – 4.35 (m, 2H), 4.33 – 4.27 (m, 1H), 2.94 (s, 3H), 2.26 – 2.08 (m, 8H), 1.68 – 1.53 (m, 6H), 1.25 – 1.03 (m, 6H), 0.96 – 0.83 (m, 2H). 19 F NMR (377 MHz, DMSO) δ -155.31. Example 168. Synthesis of ((2R,3R,4R,5R)-5-(2-acetamido-6-(methylamino)-9H-purin-9-yl) -4- fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl acetate (Compound 328). [00601] To a solution of 3 (700 mg, 2.24 mmol) in DMA (3 mL) was added HCl/dioxane (1.1 mL, 4 M). The mixture solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and Acetyl chloride (1.27 mL, 17.9 mmol) was added at once. The reaction was stirred at 0 ℃ for 1 hour. The reaction was diluted with ACN (4.0 mL) and purified by prep-HPLC to obtain 328 (12.6 mg, 1.35% yield) as a white solid.MS (ESI): m/z calcd. for C16H21FN6O5, 396.16, found 397.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.13 (s, 1H), 7.83 (d, J = 10.4 Hz, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.65 (d, J = 7.2 Hz, 1H), 4.82 (s, 1H), 4.45 (dd, J = 12.4, 2.0 Hz, 1H), 4.34 (dd, J = 12.4, 7.6 Hz, 1H), 4.05 (t, J = 7.6 Hz, 1H), 2.93 (s, 3H), 2.19 (s, 3H), 2.01 (s, 3H), 1.17 – 1.09 (m, 3H). 19 F NMR (376 MHz, DMSO) δ -158.32 (s, 1H). Example 169. Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2-amino-6-(methylamino)-9 H- purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (Compound 329), ((2R,3R,4R,5R)-4- fluoro-3-hydroxy-4-methyl-5-(6-(methylamino)-2-propionamido- 9H-purin-9-yl)tetrahydrofuran-2- yl)methyl acetate (Compound 330), and (2R,3R,4R,5R)-2-(acetoxymethyl)-4-fluoro-4-methyl-5-(6- (methylamino)-2-propionamido-9H-purin-9-yl)tetrahydrofuran-3 -yl propionate (Compound 331).
[00602] The title compound 329& 330& 331 was prepared according to the procedure of Example 65, Step 1, using 178 and propionyl chloride. [00603] For compound 329: MS (ESI): mass calcd. for C17H23FN6O5, 410.17, m/z found 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.38 (s, 1H), 6.13 (d, J = 19.6 Hz, 1H), 5.97 (d, J = 29.2 Hz, 3H), 4.53 – 4.39 (m, 1H), 4.38 – 4.25 (m, 2H), 2.88 (s, 3H), 2.48 – 2.43 (m, 2H), 2.06 – 2.00 (m, 3H), 1.15 (d, J = 22.8 Hz, 6H), 1.08 (t, J = 7.6 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -156.37. [00604] For compound 330: MS (ESI): mass calcd. for C17H23FN6O5, 410.17, m/z found 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.65 (d, J = 6.4 Hz, 1H), 4.78 (s, 1H), 4.44 (dd, J = 12.4, 2.0 Hz, 1H), 4.35 (dd, J = 12.4, 7.2 Hz, 1H), 4.06 (d, J = 7.6 Hz, 1H), 2.93 (s, 3H), 2.52 (s, 2H), 2.01 (s, 3H), 1.16 – 1.03 (m, 6H). [00605] For compound 331: MS (ESI): mass calcd. for C20H27FN6O6, 466.20, m/z found 467.1 [M+H] + . 19 F NMR (376 MHz, DMSO) δ -155.50. Example 170. Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-4-fluoro-4-methyl-5-(6- (methylamino)-2-(3-methylbutanamido)-9H-purin-9-yl)tetrahydr ofuran-3-yl 3-methylbutanoate (Compound 332). [00606] The title compound was prepared according to the procedure of Example 293, using 178 and 3- methylbutanoyl chloride. MS (ESI): m/z calcd. for C 24 H 35 FN 6 O 6 522.26, found 523.15 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 6.23 (d, J = 19.6 Hz, 2H), 4.49 – 4.38 (m, 2H), 4.36 – 4.28 (m, 1H), 2.94 (s, 3H), 2.40 – 2.26 (m, 4H), 2.11 – 1.96 (m, 5H), 1.18 (d, J = 23.2 Hz, 3H), 0.98 – 0.83 (m, 12H). 19 F NMR (377 MH DMSO) δ 15547 Example 171. Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2-(2-cyclohexylacetamido) -6- (methylamino)-9H-purin-9-yl)-4-fluoro-4-methyltetrahydrofura n-3-yl 2-cyclohexylacetate (Compound 333). [00607] To a solution of 178 (100 mg,0.28 mmol) in NMP (1 mL) was added HCl in dioxane (4 M, 0.5 mL), the solution was stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and 2- cyclohexylacetyl chloride (0.35 mL, 2.25 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 hours. The reaction was diluted with ACN (2 mL) and purified by prep-HPLC to obtain 333 (35.5 mg, 20.6% yield) as a white solid. MS (ESI): m/z calcd. for C30H43FN6O6, 602.32, found 603.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 6.25 – 6.19 (m, 2H), 4.41 (d, J = 5.2 Hz, 2H), 4.33 – 4.28 (m, 1H), 2.94 (s, 3H), 2.38 – 2.26 (m, 4H), 2.00 (s, 3H), 1.74 – 1.60 (m, 11H), 1.32 – 1.05 (m, 10H), 1.05 – 0.87 (m, 4H). 19 F NMR (376 MHz, DMSO) δ -155.48. Example 172. Synthesis of ((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(methylamino )-2-(2- phenylacetamido)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl acetate (Compound 334). [00608] The title compound was prepared from Example 210. MS (ESI): m/z calcd. for C22H25FN6O5 472.19, found 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.35 – 7.28 (m, 4H), 7.25 – 7.20 (m, 1H), 6.12 (d, J = 20.0 Hz, 1H), 5.64 (s, 1H), 4.80 (s, 1H), 4.45 – 4.38 (m, 1H), 4.35 – 4.29 (m, 1H), 4.07 – 4.01 (m, 1H), 3.82 (s, 2H), 2.93 (s, 3H), 2.01 (s, 3H), 1.11 (d, J = 22.4 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -158.02. Example 173. Synthesis of ((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(methylamino )-2-(2- phenylacetamido)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl propionate (Compound 336).
[00609] The title compound was prepared from Example 212. MS (ESI): m/z calcd. for C23H27FN6O5 486.20, found 487.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.35 – 7.20 (m, 5H), 6.12 (d, J = 20.0 Hz, 1H), 5.64 (d, J = 6.0 Hz, 1H), 4.79 (s, 1H), 4.47 – 4.30 (m, 2H), 4.07 – 4.00 (m, 1H), 3.82 (s, 2H), 2.93 (s, 3H), 2.32 (q, J = 7.6 Hz, 2H), 1.11 (d, J = 22.4 Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -158.58. Example 174. Synthesis of ((2R,3R,4R,5R)-4-fluoro-4-methyl-5-(6-(methylamino)-2-(2- phenylacetamido)-9H-purin-9-yl)-3-(2-phenylacetoxy)tetrahydr ofuran-2-yl)methyl propionate (Compound 337). [00610] The title compound was prepared from Example 212. MS (ESI): m/z calcd. for C31H33FN6O6 604.24, found 605.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.36 – 7.18 (m, 10H), 6.23 (d, J = 19.6 Hz, 2H), 4.42 – 4.30 (m, 3H), 3.82 (s, 4H), 2.92 (s, 3H), 2.28 (q, J = 7.6 Hz, 2H), 1.14 (d, J = 23.2 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ - 155.42. Example 175. Synthesis of ((2R,3R,4R,5R)-5-(2-acetamido-6-(methylamino)-9H-purin-9-yl) -3- acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 338). [00 611] The title compound was prepared from Compound 217. MS (ESI): m/z calcd. for C24H27FN6O6 514.20, found 515.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.33 – 7.22 (m, 5H), 6.24 (d, J = 20.0 Hz, 1H), 6.11 (s, 1H), 4.50 – 4.41 (m, 2H), 4.35 – 4.29 (m, 1H), 3.68 (s, 2H), 2.93 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H), 1.17 (d, J = 23.2 Hz, 3H).19F NMR (377 MHz, DMSO) δ -155.20. Example 176. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl L- valinate (Compound 86). Step 1. Synthesis of pentyl (7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)carbamate (86.1). [00612] The title compound 86.1 was prepared according to the procedure of Example 58, Step 1, using 81.1. MS (ESI): mass calcd. for C 21 H 27 N 5 O 6 , 445.20 m/z found 446.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.39 (s, 1H), 7.30 (d, J = 4.4 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 5.35 (d, J = 6.4 Hz, 1H), 5.03 (t, J = 5.6 Hz, 1H), 4.90 (dd, J = 6.4, 2.8 Hz, 1H), 4.36 (dd, J = 8.0, 5.2 Hz, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3.59 – 3.45 (m, 2H), 1.72 – 1.63 (m, 5H), 1.35 (dd, J = 14.0, 10.8 Hz, 7H),0.90 (t, J = 7.2 Hz, 3H). Step 2. Synthesis of ((3aR,4R,6R,6aR)-6-cyano-2,2-dimethyl-6-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl (tert-butoxycarbonyl)-L-valinate (86.2). [00613] The title compound 86.2 was prepared according to the procedure of Example 19, Step 1, using 86.1 and (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C31H44N6O9, 644.32, m/z found 645.5 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.42 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.61 (s, 1H), 4.29 – 4.10 (m, 4H), 3.76 (s, 1H), 1.82 (dd, J = 13.2, 6.8 Hz, 1H), 1.76 – 1.60 (m, 5H), 1.41 – 1.22 (m, 16H), 0.90 (t, J = 7.2 Hz, 3H), 0.77 (dd, J = 13.2, 6.8 Hz, 6H). Step 3. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-2-yl)methyl L- valinate (86). [00614] The title compound 86 was prepared according to the procedure of Example 19, Step 2, using 86.2. MS (ESI): mass calcd. for C23H32N6O7, 504.23 m/z found 505.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 6.45 (s, 1H), 5.46 (s, 1H), 4.69 (s, 1H), 4.33 – 4.25 (m, 3H), 4.18 (t, J = 6.8 Hz, 2H), 3.95 (s, 1H), 3.21 (d, J = 5.2 Hz, 1H), 1.84 – 1.75 (m, 1H), 1.71 – 1.64 (m, 2H), 1.41 – 1.31 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). Example 177. ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl L-valinate (Compound 94). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (tert-butoxycarbonyl)-L-valinate (94.1). [00615] A solution of (tert-butoxycarbonyl)-L-valine (37 mg, 0.17 mmol), EDCI (48 mg, 0.25 mmol), HOBT (34 mg, 0.25 mmol) and DIEA (65 mg, 0.50 mmol) in dry DMF (1.0 mL) was stirred at 20°C for 1 h. Then 97.1 (100 mg, 0.17 mmol) was added into the flask vessel. The reaction mixture was stirred at 20°C for 16 h. The reaction mixture was purified by prep-HPLC (0.1% FA) to give 94.1 (71 mg, 53% yield) as a white solid. MS (ESI): mass calcd. for C39H50FN7O10, 795.36, m/z found 796.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.52 (s, 1H), 7.42 (dd, J = 7.2, 5.2 Hz, 2H), 7.33 – 7.20 (m, 2H), 7.16 – 7.07 (m, 4H), 5.43 (d, J = 6.4 Hz, 1H), 4.96 – 4.77 (m, 2H), 4.67 – 4.60 (m, 1H), 4.30 – 4.11 (m, 2H), 3.76 (t, J = 7.2 Hz, 1H), 3.13 – 3.01 (m, 1H), 2.81 (dd, J = 13.2, 11.2 Hz, 1H), 1.86 – 1.75 (m, 1H), 1.66 (s, 3H), 1.38 (s, 3H), 1.36 – 1.22 (m, 18H), 0.77 (dd, J = 14.4, 6.8 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -116.72 (s, 1F). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl L-valinate (94). [00616] To a solution of 94.1 (71 mg, 0.089 mmol) in THF (0.8 mL) was added conc. HCl (0.4 mL, 12 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The organic solvent was removed with flowing nitrogen. The residue was purified by prep-HPLC (0.1% FA) to give a crude product. The crude product was dissolved with THF and adjusted pH to 8 with Sat. aq. NaHCO3. The organic solvent was removed with flowing nitrogen and the residue was purified by prep-HPLC (0.1% FA) to afford Compound 94 (8.69 mg, 18% yield) as a white solid. MS (ESI): mass calcd. for C 26 H 30 FN 7 O 6 , 555.22, m/z found 556.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.58 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.39 (dd, J = 8.4, 5.6 Hz, 2H), 7.09 – 7.02 (m, 3H), 6.81 (d, J = 4.4 Hz, 1H), 6.36 (s, 1H), 5.39 (s, 1H), 4.97 – 4.89 (m, 1H), 4.64 (d, J = 4.8 Hz, 1H), 4.32 – 4.18 (m, 3H), 3.92 (t, J = 5.2 Hz, 1H), 3.20 – 3.12 (m, 2H), 3.02 (dd, J = 13.6, 11.6 Hz, 2H), 1.82 – 1.71 (m, 1H), 0.79 (dd, J = 20.8, 6.4 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -116.75 (s, 1F). Example 178. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl acetate (Compound 95). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate (95.1). [00617] To a solution of 97.1 (100 mg, 0.17 mmol) in DMPU (1.0 mL) was added HCl/1,4-dioxane (0.1 mL, 4 M) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 30 min and then acetyl chloride (105 mg, 1.33 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 3 h. The reaction mixture was purified by prep-HPLC (0.1% FA) to give 95.1 (58 mg, 54% yield) as a white solid. MS (ESI): mass calcd. for C31H35FN6O8, 638.25, m/z found 639.2 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl acetate (95). [00618] To a solution of 95.1 (58 mg, 0.09 mmol) in THF (0.6 mL) was added conc. HCl (0.3 mL, 12 M) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 h. The organic solvent was removed with flowing nitrogen. The residue was purified by prep-HPLC (0.1% FA) to give a crude product. The crude product was dissolved with THF and adjusted pH to 8 with Sat. aq. NaHCO3. The organic solvent was removed with flowing nitrogen and the residue was purified by prep-HPLC (0.1% FA) to afford Compound 95 (9.32 mg, 21% yield) as a white solid. MS (ESI): m/z calcd. for C23H23FN6O6498.17, found 499.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.56 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.39 (dd, J = 8.4, 5.6 Hz, 2H), 7.18 (s, 1H), 7.10 – 7.03 (m, 3H), 6.80 (d, J = 4.8 Hz, 1H), 6.31 (d, J = 6.0 Hz, 1H), 5.38 (d, J = 6.0 Hz, 1H), 4.97 – 4.89 (m, 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.30 (dd, J = 11.6, 2.4 Hz, 1H), 4.23 – 4.17 (m, 1H), 4.12 (dd, J = 12.0, 6.0 Hz, 1H), 3.91 (dd, J = 11.6, 6.4 Hz, 1H), 3.18 (dd, J = 14.0, 3.6 Hz, 1H), 3.07 – 2.98 (dd, J = 13.6, 11.2 Hz, 1H), 1.99 (s, 3H). 19 F NMR (377 MHz, DMSO) δ -116.75 (s, 1F). Example 179. ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-cyclohexylacetate (Compound 96). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-cyclohexylacetate (96.1). [00619] The title compound was prepared according to the procedure of Example 58, Step 2, using 97.1 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C 37 H 45 FN 6 O 8 , 720.33, m/z found 721.2 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-cyclohexylacetate (96). [00620] The title compound was prepared according to the procedure of Example 178, Step 2, using 96.1. MS (ESI): mass calcd. for C29H33FN6O6, 580.24, m/z found 581.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.55 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.39 (dd, J = 8.4, 5.6 Hz, 2H), 7.17 (s, 1H), 7.09 – 7.02 (m, 3H), 6.79 (d, J = 4.4 Hz, 1H), 6.30 (d, J = 6.0 Hz, 1H), 5.36 (d, J = 6.0 Hz, 1H), 4.97 – 4.90 (m, 1H), 4.66 – 4.61 (m, 1H), 4.29 (dd, J = 11.6, 2.4 Hz, 1H), 4.23 – 4.12 (m, 2H), 3.91 (dd, J = 11.2, 6.4 Hz, 1H), 3.17 (dd, J = 14.0, 3.6 Hz, 1H), 3.03 (dd, J = 13.6, 11.2 Hz, 1H), 2.16 (d, J = 6.4 Hz, 2H), 1.67 – 1.52 (m, 6H), 1.24 – 0.99 (m, 3H), 0.90 (dd, J = 22.8, 12.0 Hz, 2H). 19 F NMR (377 MHz, DMSO) δ -116.77 (s, 1F). Example 180. ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl propionate (Compound 99 Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl propionate (95.1). [00621] The title compound was prepared according to the procedure of Example 178, Step 1, using 97.1 and propionyl chloride. MS (ESI): mass calcd. for C 32 H 37 FN 6 O 8 , 652.27, m/z found 653.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 8.50 (s, 1H), 7.49 – 7.36 (dd, J = 7.6, 6.0 Hz, 1H), 7.32 – 7.05 (m, 5H), 5.41 (d, J = 6.0 Hz, 1H), 4.98 (dd, J = 6.0, 2.4 Hz, 1H), 4.91 – 4.76 (m, 1H), 4.68 – 4.62 (m, 1H), 4.23 (dd, J = 12.0, 4.0 Hz, 1H), 4.10 (dd, J = 12.0, 5.6 Hz, 1H), 3.09 (dd, J = 14.4, 3.2 Hz, 1H), 2.87 – 2.74 (m, 1H), 2.27 – 2.03 (m, 2H), 1.66 (s, 3H), 1.39 (s, 3H), 1.37 – 1.13 (m, 11H), 0.90 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -116.75 (s, 1F). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl propionate (99). [00622] The title compound was prepared according to the procedure of Example 178, Step 2, using 99.1. MS (ESI): mass calcd. for C24H25FN6O6, 512.18, m/z found 513.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.55 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.39 (dd, J = 7.2, 6.0 Hz, 2H), 7.10 – 7.01 (m, 3H), 6.79 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 5.2 Hz, 1H), 5.39 (d, J = 4.4 Hz, 1H), 4.97 – 4.88 (m, 1H), 4.65 (t, J = 4.8 Hz, 1H), 4.35 – 4.28 (m, 1H), 4.23 – 4.18 (m, 1H), 4.13 (dd, J = 12.0, 5.2 Hz, 1H), 3.95 – 3.89 (m, 1H), 3.21 – 3.14 (m, 1H), 3.07 – 2.98 (m, 1H), 2.34 – 2.21 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -116.75 (s, 1F). Example 181. ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl isobutyrate (Compound 100). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (100.1). [00623] The title compound was prepared according to the procedure of Example 178, Step 1, using 97.1 and isobutyryl chloride. MS (ESI): mass calcd. for C 33 H 39 FN 6 O 8 , 666.28, m/z found 667.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 8.52 (s, 1H), 7.42 (dd, J = 8.0, 6.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 4.4 Hz, 1H), 7.15 – 7.06 (m, 3H), 5.40 (d, J = 6.0 Hz, 1H), 4.98 (dd, J = 6.4, 2.8 Hz, 1H), 4.85 (br, 1H), 4.68 – 4.62 (m, 1H), 4.22 (dd, J = 12.0, 4.0 Hz, 1H), 4.10 (dd, J = 12.0, 5.6 Hz, 1H), 3.08 (dd, J = 13.6, 3.6 Hz, 1H), 2.81 (dd, J = 13.2, 10.8 Hz, 1H), 2.43 – 2.34 (m, 1H), 1.66 (s, 3H), 1.39 (s, 3H), 1.34 – 1.21 (m, 9H), 0.96 (dd, J = 18.0, 7.2 Hz, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanami do)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl isobutyrate (100). [00624] The title compound was prepared according to the procedure of Example 178, Step 2, using 100.1. MS (ESI): mass calcd. for C25H27FN6O6, 526.20, m/z found 527.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.58 (d, J = 8.4 Hz, 1H), 8.49 (s, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.39 (dd, J = 8.4, 6.0 Hz, 2H), 7.16 (s, 1H), 7.09 – 7.03 (m, 3H), 6.79 (d, J = 4.4 Hz, 1H), 6.39 (d, J = 4.4 Hz, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.96 – 4.88 (m, 1H), 4.65 (t, J = 5.2 Hz, 1H), 4.29 (dd, J = 12.0, 2.8 Hz, 1H), 4.24 – 4.19 (m, 1H), 4.13 (dd, J = 12.0, 4.8 Hz, 1H), 3.97 – 3.91 (m, 1H), 3.17 (dd, J = 13.6, 3.6 Hz, 1H), 3.06 – 2.98 (m, 1H), 2.48 – 2.42 (m, 1H), 1.00 (dd, J = 11.6, 7.2 Hz, 6H). 19 F NMR (377 MHz, DMSO) δ -116.79 (s, 1F). Example 182. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-valinate (Compound 102).
Step 1. Synthesis of N-(7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)benzamide (102.1). [00625] The compound 102.1 was prepared according to the procedure of Example 58, Step 1, using 85.1. MS (ESI): mass calcd. for C22H21N5O5, 435.15, m/z found 436.1 [M+H] + . Step 2. ((3aR,4R,6R,6aR)-6-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (tert-butoxycarbonyl)-L-valinate (102.2). [00626] The compound 102.2 was prepared according to the procedure of Example 266, Step 1, using 102.1 and (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C32H38N6O8, 634.69, m/z found 635.2 [M+H] + . Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl L-valinate (Compound 102). [00627] The compound 102 was prepared according to the procedure of Example 112, Step 3, using 102.2. MS (ESI): mass calcd. for C24H26N6O6, 494.51, m/z found 495.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 4.8 Hz, 1H), 7.09 (d, J = 4.0Hz, 1H), 6.52 (d, J = 6.0 Hz, 1H), 5.54 (d, J = 5.6 Hz, 1H), 4.74 (t, J = 5.2 Hz, 1H), 4.42 (d, J = 4.4 Hz, 2H), 4.34-4.32 (m, 1H), 4.03 – 3.95 (m, 1H), 3.80 (d, J = 4.0 Hz, 1H), 2.05-2.03 (m, 1H), 0.90 (t, J = 6.8 Hz, 6H). Example 183. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl propionate (Compound 115). Ste p 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl propionate (115.1). [00628] The compound 115.1 was prepared according to the procedure of Example 1, Step 4, using 112.1 and propionyl chloride. MS (ESI): mass calcd. for C 28 H 38 N 6 O 8 , 586.65, m/z found 587.3 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl propionate (Compound 115). [00629] The compound 115 was prepared according to the procedure of Example 66, Step 3, using 112.2. MS (ESI): mass calcd. for C 20 H 26 N 6 O 6 , 446.46, m/z found 447.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.22 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J = 4.8 Hz, 1H), 6.34 (d, J =6.0 Hz, 1H), 5.40 (d, J = 6.0 Hz, 1H), 4.70 – 4.61 (m, 2H), 4.33 (dd, J = 12.0, 2.4 Hz, 1H), 4.24-4.20 (m, 1H), 4.15 (dd, J = 12.0, 5.6 Hz, 1H), 3.93-3.90 (m, 1H), 2.33 – 2.27 (m, 2H), 2.23 – 2.14 (m, 1H), 1.00 (t, J = 7.6 Hz, 3H), 0.96 (dd, J = 6.8, 3.6 Hz, 6H). Example 184. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano- 4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl L-valinate (Compound 128). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (128.1) [00630] To a mixture of (2S)-2-{[tert-butyl(formyl)-$l^{3}-oxidanyl]amino}-3-methylb utanoic acid 85 (55.2 mg, 0.253 mmol), EDCI (72.7 mg, 0.379 mmol) and 1-Hydroxybenzotrizole(51.3 mg, 0.379 mmol) in DMF (1 mL) under nitrogen. The DIEA (98.1 mg, 0.379 mmol) was added in mixture, the reaction mixture was stirred for 30 min and N-{7-[(2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl }benzamide (100 mg, 0.253 mmol) was added dropwise. The reaction mixture stirred at 25 °C for 16 h. The residue was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give the crude product. The crude product was purified by prep-HPLC to afford product 128.1 (41.7 mg, 23.8% yield) as a white solid. MS (ESI): m/z calcd. for C29H34N6O8, 594.6, found 595.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.46 (s, 1H), 8.05 (s, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.18 (s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 6.8 Hz, 1H), 5.20 – 5.16 (m, 1H), 5.08 (t, J = 5.6 Hz, 1H), 4.99 (s, 1H), 4.27 (s, 1H), 4.15 – 4.07 (m, 1H), 3.66 – 3.53 (m, 2H), 1.41 (s, 9H), 0.91 (dd, J = 12.4, 6.8 Hz, 6H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl L-valinate (Compound 128). [00631] To a solution of compound 128.1 (40 mg, 0.0672 mmol) in THF(1 mL), then HCl/1,4-dioxane (0.5 mL, 4M) was added in mixture at 0 ℃. The mixture was stirred at 20 ℃ for 2 h. The residue was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo to give the crude product. The crude product was purified by prep- HPLC to afford product 128 (4.52 mg, 12.8% yield) as a white solid. MS (ESI): m/z calcd. for C24H26N6O6, 494.5, found 495.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.22 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 12.8 Hz, 2H), 6.62 (s, 1H), 5.21 (dd, J = 5.6, 3.6 Hz, 1H), 5.09 (s, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.29 (d, J = 3.6 Hz, 1H), 3.62 - 3.54 (m, 2H), 3.25 (d, J = 5.2 Hz, 1H), 2.09 - 1.98 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). Example 185. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 137). Step 1. Synthesis of tert-butyl ((S)-1-((7-((2R,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)m ethyl)-2- cyano-3,4-dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4 ]triazin-4-yl)amino)-3-(4- fluorophenyl)-1-oxopropan-2-yl)carbamate (137.1). [00632] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)propano ic acid (1.71 g, 0.006 mmol) in THF (20 mL) was added HATU (342 g 0009 mmol) the solution was stirred at 25 o C for 1 h. To the above solution was added 129.1 (1.6 g, 0.003 mmol) and DIEA (2.34 mg, 0.018 mmol), and the mixture was stirred at 25 o C for 16 h. The reaction was washed with EtOAc (10 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with EA in PE from 0% to 50% to obtain 137.1 (0.85 g, 0.001 mol, 33% yield) as a white solid. MS (ESI): m/z calcd. for C42H47FN6O7Si 794.96, found 795.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.45 (s, 1H), 7.55 (dd, J = 18.0, 7.2 Hz, 4H), 7.48 – 7.40 (m, 4H), 7.33-7.07 (m, 4H), 7.18 – 7.03 (m, 4H), 6.41 (d, J = 6.0 Hz, 1H), 5.33 (d, J = 5.6 Hz, 1H), 4.86-4.80 (m, 1H), 4.79 – 4.68 (m, 1H), 4.21-4.18 (m, 2H), 3.86 (d, J = 10.0 Hz, 1H), 3.74 (dd, J = 11.6, 3.6 Hz, 1H),3.10 (d, J = 10.0 Hz, 1H), 2.90 – 2.76 (m, 1H), 1.32 (s, 9H), 0.90 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2-(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl 2-cyclohexylacetate (137.2). [00633] The compound 137.2 was prepared according to the procedure of Example 19, Step 1, using 137.1 and 2-cyclohexylacetic acid. MS (ESI): mass calcd. for C50H59FN6O8Si, 919.14, m/z found 919.4 [M+H] + . Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl 2-cyclohexylacetate (137.3). [00634] The compound 137.3 was prepared according to the procedure of Example 97, Step 1, using 137.2. MS (ESI): mass calcd. for C34H41FN6O8Si, 680.73, m/z found 681.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.29 (s, 1H), 8.46 (s, 1H), 7.50 – 7.37 (m, 2H), 7.24 –7.22 (m, 2H), 7.16 – 7.09 (m, 3H), 6.60 (d, J = 5.6 Hz, 1H), 5.24 – 5.16 (m, 1H), 5.06-5.05 (m, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.85-4.80 (m, 1H), 4.29 (d, J = 3.6 Hz, 1H), 3.58-3.56 (m, 2H), 3.12 (d, J = 10.4 Hz, 1H), 2.81 (t, J = 12.4Hz, 1H), 2.27 (d, J = 6.8 Hz, 2H), 1.81 – 1.72 (m, 3H), 1.64 – 1.58 (m, 3H), 1.32 (s, 9H), 1.17 – 1.10 (m, 3H), 1.03 – 0.91 (m, 2H). Step 4. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanamid o)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2- cyclohexylacetate (Compound 137). [00635] The compound 137 was prepared according to the procedure of Example 19, Step 2, using 137.3. MS (ESI): mass calcd. for C29H33FN6O6, 580.62, m/z found 581.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 7.38 (dd, J = 8.4, 5.6 Hz, 2H), 7.19 (s, 1H), 7.06 (dd, J = 10.0, 7.6 Hz, 3H), 6.87 (d, J = 4.4 Hz, 1H), 6.43 (d, J = 6.6 Hz, 1H), 5.20 – 5.12 (m, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.95–4.92 (m, 2H), 4.29 – 4.20 (m, 1H), 3.64 – 3.45 (m, 2H), 3.22 – 3.15 (m, 1H), 3.09 – 2.97 (m, 1H), 2.25 (d, J = 6.8 Hz, 2H), 1.90 –1.69 (m, 3H), 1.65–1.58 (m, 3H), 1.29 – 1.05 (m, 3H), 0.99 –0.93 (m, 2H). 19F NMR (377 MHz, DMSO) δ -116.77 (s, 1H). Example 186. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2- cyclohexylacetate (Compound 139). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl 2-cyclohexylacetate (139.1). [00636] The compound 139.1 was prepared according to the procedure of Example 19, Step 1, using 129.1 and 2-cyclohexylacetic acid. MS (ESI): mass calcd. for C36H43N5O5Si, 653.86, m/z found 654.3 [M+H] +. 1H NMR (400 MHz, DMSO) δ 7.89-7.80 (m, 3H), 7.53 (d, J = 6.8 Hz, 2H), 7.49 – 7.31 (m, 6H), 7.24 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.63 (d, J = 6.4 Hz, 1H), 5.36 (t, J = 4.8 Hz, 1H), 5.05 (t, J = 6.0 Hz, 1H), 4.36 (d, J = 3.6 Hz, 1H), 3.77-3.75 (m, 2H), 2.26 (d, J = 6.8 Hz, 2H), 1.87 – 1.53 (m, 6H), 1.32 – 0.95 (m, 5H), 0.92 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(((ter t-butyldiphenylsilyl)oxy)methyl)-5- cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (139.2). [00637] The compound 139.2 was prepared according to the procedure of Example 129, Step 1, using 139.1 and (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C 46 H 60 N 6 O 8 Si, 853.11, m/z found 853.4 [M+H] + . Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl 2-cyclohexylacetate (139.3). [00638] The compound 139.3 was prepared according to the procedure of Example 97, Step 1, using 139.2. MS (ESI): mass calcd. for C30H42N6O8, 614.70, m/z found 615.2 [M+H] + . Step 4. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2- cyclohexylacetate (Compound 139). [00639] The compound 139 was prepared according to the procedure of Example 19, Step 2, using 139.3. MS (ESI): mass calcd. for C25H34N6O6, 514.58, m/z found 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.26 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.14 (s, 1H), 6.89 (d, J = 4.8 Hz, 1H), 6.46 (d, J = 6.4 Hz, 1H), 5.17 (dd, J = 5.2, 3.6 Hz, 1H), 5.03 (t, J = 5.6 Hz, 1H), 4.97 (t, J = 6.4 Hz, 1H), 4.66 (t, J = 8.0 Hz, 1H), 4.25-4.24 (m, 1H), 3.68 – 3.46 (m, 2H), 2.26 (d, J = 7.2 Hz, 2H), 2.18-2.15 (m, 1H), 1.90 – 1.53 (m, 7H), 1.22-1.10 (m, 4H), 0.95 (dd, J = 6.8, 4.4 Hz, 6H). Example 187. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-3-yl 2-phenylacetate (Compound 141). Step 1. Synthesis of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -6-(((tert- butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3, 4-d][1,3]dioxole-4-carbonitrile (141.1). [00640] The title compound 141.1 was prepared according to the procedure of Example 6, Step 2, using 290.1. MS (ESI): mass calcd. for C31H35N5O4Si, 569.25 m/z found 570.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.89 (br s, 3H), 7.52 (t, J = 8.4 Hz, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 4H), 6.88 (dd, J = 10.8, 4.4 Hz, 2H), 5.36 (d, J = 6.4 Hz, 1H), 4.91 (dd, J = 6.4, 2.8 Hz, 1H), 4.45 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 4.8 Hz, 2H), 1.64 (s, 3H), 1.36 (s, 3H), 0.92 (s, 9H). Step 2. Synthesis of pentyl (7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl) -4-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2, 1-f][1,2,4]triazin-4-yl)carbamate (141.2). [00641] The title compound 141.2 was prepared according to the procedure of Example 48, Step 2, using 141.1 and pentyl carbonochloridate. MS (ESI): mass calcd. for C37H45N5O6Si, 683.31, m/z found 684.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.35 (s, 1H), 7.54 – 7.48 (m, 4H), 7.45 – 7.40 (m, 2H), 7.36 – 7.32 (m, 4H), 7.30 – 7.28 (m, 1H), 7.08 (d, J = 4.4 Hz, 1H), 5.34 (d, J = 6.0 Hz, 1H), 4.91 (dd, J = 6.2, 2.8 Hz, 1H), 4.50 (d, J = 2.8 Hz, 1H), 4.19 (t, J = 6.8 Hz, 2H), 3.76 (t, J = 8.0 Hz, 2H), 1.72 – 1.60 (m, 5H), 1.40 – 1.34 (m, 7H), 0.92 – 0.88 (m, 12H). Step 3. Synthesis of pentyl (7-((2R,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2 -cyano-3,4- dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4 -yl)carbamate (141.3) [00642] To a solution of pentyl 141.2 (500 mg, 0.73 mmol) in THF (5 mL) was added HCl (2 mL, 12 M) at 0℃, then the reaction was stirred at 20 ℃ for 1 h. The mixture was adjusted to pH 8 with aqueous NaHCO3 and extracted with EtOAc (50 mL×3). The organic phase was washed with brine water (50 mL×3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by flash column chromatography (Petroleum ether/Ethyl acetate from 0% to 30%) to obtain 141.3 as a light yellow solid (250 mg, 50.5% yield). MS (ESI): mass calcd. for C34H41N5O6Si, 643.28 m/z found 644.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.35 (s, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.43 (q, J = 7.2 Hz, 2H), 7.38 – 7.28 (m, 4H), 7.23 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.38 (d, J = 6.4 Hz, 1H), 5.32 (d, J = 5.2 Hz, 1H), 4.82 – 4.64 (m, 1H), 4.18 (t, J = 5.6 Hz, 4H), 3.84 (d, J = 10.0 Hz, 1H), 3.72 (dd, J = 11.6, 3.2 Hz, 1H), 1.72 – 1.62 (m, 2H), 1.40 – 1.32 (m, 4H), 0.94 – 0.99 (m, 12H). Step 4. Synthesis of (2R,3S,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-cya no-4-hydroxy-5- (4-(((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin- 7-yl)tetrahydrofuran-3-yl 2- phenylacetate (141.4). [00643] The title compound 141.4 was prepared according to the procedure of Example 17, Step 2, using 141.3 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C 42 H 47 N 5 O 7 Si, 761.32 m/z found 762.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.33 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.46 – 7.26 (m, 11H), 7.21 (t, J = 7.6 Hz, 3H), 6.99 (d, J = 4.0 Hz, 1H), 6.80 (d, J = 6.4 Hz, 1H), 5.54 – 5.34 (m, 1H), 5.07 (t, J = 6.0 Hz, 1H), 4.42 (d, J = 3.2 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 3.83 – 3.72 (m, 4H), 1.76 – 1.60 (m, 2H), 1.40 – 1.30 (m, 4H), 0.94 – 0.85 (m, 12H). Step 5. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-y l)tetrahydrofuran-3-yl 2-phenylacetate (141). [00644] The title compound 141 was prepared according to the procedure of Example 58, Step 1, using 141.4. MS (ESI): mass calcd. for C26H29N5O7, 523.21 m/z found 524.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.36 (s, 1H), 7.38 – 7.22 (m, 6H), 7.09 (d, J = 4.4 Hz, 1H), 6.64 (d, J = 6.4 Hz, 1H), 5.28 – 5.14 (m, 1H), 5.05 (t, J = 5.6 Hz, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.32 – 4.27 (m, 1H), 4.17 (t, J = 6.8 Hz, 2H), 3.86 – 3.71 (m, 2H), 3.64 – 3.50 (m, 2H), 1.69 – 1.63 (m, 2H), 1.36 – 1.31 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H). Example 188. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano- 4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 143). Step 1. Synthesis of N-(7-((3aR,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methy l)-4-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)benzamide (143.1). [00645] The title compound 143.1 was prepared according to the procedure of Example 51, Step 1, using 141.1 and benzoyl chloride. MS (ESI): mass calcd. for C 38 H 39 N 5 O 5 Si, 673.27 m/z found 674.2 [M+H] + . 1 H NMR (400 MHz, DMSO) 11.40 (s, 1H), 8.20 – 7.90 (m, 3H), 7.71 – 7.32 (m, 15H), 7.15 (s, 2H), 5.37 (d, J = 6.4 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.51 (d, J = 2.8 Hz, 1H), 1.66 (s, 3H), 1.37 (s, 3H), 0.92 (s, 9H). Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl) -2-cyano-3,4- dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4 -yl)benzamide (143.2). [00646] The title compound 143.2 was prepared according to the procedure of Example 187, Step 3, using 143.1. MS (ESI): mass calcd. for C35H35N5O5Si, 633.24, m/z found 634.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 8.46 (s, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.63 – 7.49 (m, 6H), 7.46 – 7.29 (m, 6H), 7.08 (d, J = 4.4 Hz, 2H), 6.39 (d, J = 6.0 Hz, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.71 – 4.76 (m, 1H), 4.26 – 4.12 (m, 2H), 3.88 – 3.85 (m, 1H), 3.77 – 3.73 (m, 1H), 0.92 (s, 9H). Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-2-(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl 2-phenylacetate (143.3). [00647] The title compound 143.3 was prepared according to the procedure of Example 17, Step 2, using 141.2 and 2-phenylacetyl chloride. MS (ESI): mass calcd. for C43H41N5O6Si, 751.28 m/z found 752.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.42 – 8.01 (m, 2H), 7.76 – 6.95 (m, 20H), 6.82 (d, J = 6.8 Hz, 1H), 5.45 – 5.42 (m, 1H), 5.08 (s, 1H), 4.43 (d, J = 3.6 Hz, 1H), 3.78 (d, J = 3.2 Hz, 3H), 1.36 – 1.17 (m, 2H), 0.90 (s, 9H). Step 4. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-phenylacetate (143). [00648] The title compound 143 was prepared according to the procedure of Example 58, Step 1, using 143.3. MS (ESI): mass calcd. for C27H23N5O6, 513.16 m/z found 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 8.33 (s, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.37 – 7.23 (m, 5H), 7.13 – 7.09 (m, 2H), 6.66 (d, J = 6.4 Hz, 1H), 5.27 – 5.17 (m, 1H), 5.11 – 5.06 (m, 1H), 5.00 (t, J = 6.0 Hz, 1H), 4.28 – 4.34 (m, 1H), 3.87 – 3.67 (m, 2H), 3.64 – 3.51 (m, 2H). Example 189. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2-phenylacetate (Compound 144). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl 2-phenylacetate (144.1). [00649] The compound 144.1 was prepared according to the procedure of Example 19, Step 1, using 129.1 and 2-phenylacetic acid. MS (ESI): mass calcd. for C36H37N5O5Si, 647.81, m/z found 648.2. [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(((ter t-butyldiphenylsilyl)oxy)methyl)-5- cyano-4-hydroxytetrahydrofuran-3-yl 2-phenylacetate (144.2). [00650] Compound 144.2 was prepared according to the procedure of Example 129, Step 1, using 139.1 and (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C 46 H 54 N 6 O 8 Si, 847.06, m/z found 847.3 [M+H] + . Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl 2-phenylacetate (144.3). [00651] Compound 144.3 was prepared according to the procedure of Example 97, Step 1, using 144.2. MS (ESI): mass calcd. for C30H36N6O8, 608.65, m/z found 609.2 [M+H] + . Step 4. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2-phenylacetate (Compound 144). [00652] Compound 144 was prepared according to the procedure of Example 19, Step 2, using 144.3. MS (ESI): mass calcd. for C25H28N6O6, 508.54, m/z found 509.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.27 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 7.37 – 7.26 (m, 5H), 7.25 (d, J = 4.8 Hz, 1H), 7.15 (s, 1H), 6.90 (d, J = 4.8 Hz, 1H), 6.54 (d, J = 6.4 Hz, 1H), 5.25 – 5.16 (m, 1H), 5.04 (t, J = 5.6 Hz, 1H), 5.00 (t, J = 6.0 Hz, 1H), 4.66 (t, J = 8.4 Hz, 1H), 4.27-4.25 (m, 1H), 3.76 (d, J =11.2 Hz, 2H), 3.57-3.52 (m, 2H), 2.18-2.15 (m, 1H), 0.95 (dd, J = 6.4, 4.4 Hz, 6H). Example 190. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-methylbutanamido)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl acetate (Compound 339). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl acetate (339.1). [00653] The compound 339.1 was prepared according to the procedure of Example 1, Step 4, using 112.1 and AcCl. MS (ESI): mass calcd. for C27H36N6O8, 572.62, m/z found 573.2 [M+H] + . Step 2. Synthesis of Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2- yl)methyl acetate (Compound 339). [00654] The compound 339 was prepared according to the procedure of Example 112, Step 3, using 112.1. MS (ESI): mass calcd. for C19H26N6O6, 432.44, m/z found 433.1 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.21 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.55 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.13 (s, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 4.73 – 4.61 (m, 2H), 4.32 (dd, J = 12.0, 2.4 Hz, 1H), 4.22-4.20 (m, 1H), 4.14 (dd, J = 12.0, 6.0 Hz, 1H), 3.92-3.90 (m, 1H), 2.18-2.15 (m, 1H), 2.01 (s, 3H), 0.96 (dd, J = 6.8, 3.6 Hz, 6H). Example 191. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran -3-yl 2-phenylacetate (Compound 340). Step 1. Synthesis of (2R,3S,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-cya no-4-hydroxy-5- (4-pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofu ran-3-yl 2-phenylacetate (340.2.) [00655] The title compound was prepared according to the procedure of Example 17, Step 2, using 340.1 and 2-phenylacetyl chloride. MS (ESI): m/z calcd. for C41H45N5O6Si, 731.1, found 732.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.37 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.2 Hz, 3H), 7.37 – 7.27 (m, 7H), 7.23 – 7.19(m, 3H), 7.03 (d, J = 4.8 Hz, 1H), 6.80 (d, J = 6.8 Hz, 1H), 5.46 – 5.37 (m, 1H), 5.07 (t, J = 6.0 Hz, 1H), 4.42 (d, J = 3.2 Hz, 1H), 3.77 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 1.67 – 1.54 (m, 2H), 1.35 (dd, J = 14.8, 7.2 Hz, 2H), 1.23 (s, 2H), 0.93 – 0.85 (m, 12H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran -3-yl 2-phenylacetate (Compound 340). [00656] To a solution of compound 340.2 (40 mg, 0.0547 mmol) in THF (1 mL) was added HF/pyridine (27.1 mg, 0.274 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 20 °C. The residue was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo to give the crude product. The crude product was purified by prep-HPLC to afford product 340 (4.89 mg, 15.9% yield) as a white solid. MS (ESI): m/z calcd. for C 25 H 27 N 5 O 6 , 493.5, found 494.1 [M+H] . 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.42 (s, 1H), 7.36 – 7.24 (m, 6H), 7.13 (d, J = 4.8 Hz, 1H), 6.65 (d, J = 6.4 Hz, 1H), 5.24 – 5.17 (m, 1H), 4.98 (s, 2H), 4.30 (d, J = 4.0 Hz, 1H), 3.82 – 3.72 (m,2H), 3.62 – 3.52 (m, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.66 – 1.54 (m, 2H), 1.42 – 1.30 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H). Example 192. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl L-valinate (Compound 341).
Step 1. Synthesis of N-(7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)pentanamide (341.1). [00657] The title compound 341.1 was prepared according to the procedure of Example 58, Step 1, using 264.1. MS (ESI): mass calcd. for C20H25N5O5, 415.19 m/z found 416.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.43 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 5.35 (d, J = 6.4 Hz, 1H), 5.03 (t, J = 5.6 Hz, 1H), 4.90 (dd, J = 6.4, 2.8 Hz, 1H), 4.36 (dd, J = 8.0, 5.2 Hz, 1H), 3.61 – 3.45 (m, 2H), 2.72 (dd, J = 9.2, 5.2 Hz, 2H), 1.66 – 1.57 (m, 5H), 1.39 – 1.33 (m, 5H), 0.91 (t, J = 7.2 Hz, 3H). Step 2. Synthesis of ((3aR,4R,6R,6aR)-6-cyano-2,2-dimethyl-6-(4-pentanamidopyrrol o[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl) methyl (tert-butoxycarbonyl)-L-valinate (341.2). [00658] The title compound 341.2 was prepared according to the procedure of Example 19, Step 1, using 341.1 and (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C 30 H 42 N 6 O 8 , 614.31, m/z found 615.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.44 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H), 4.93 (dd, J = 6.4, 2.8 Hz, 1H), 4.62 (s, 1H), 4.24 (dd, J = 12.0, 4.0 Hz, 1H), 4.14 (dd, J = 12.0, 6.4 Hz, 1H), 3.82 – 3.69 (m, 1H), 2.72 (t, J = 7.2 Hz, 2H), 1.82 (d, J = 6.8 Hz, 1H), 1.65 (d, J = 6.0 Hz, 3H), 1.60 (dd, J = 15.2, 7.6 Hz, 2H), 1.40 – 1.33 (m, 14H), 0.91 (t, J = 7.2 Hz, 3H), 0.77 (dd, J = 13.6, 6.8 Hz, 6H). Step 3. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-pentanamidopyrrolo [2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl L-valinate (341). [00659] The title compound 341 was prepared according to the procedure of Example 19, Step 2, using 341.2. MS (ESI): mass calcd. for C 22 H 30 N 6 O 6 , 474.22 m/z found 475.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.39 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.47 (d, J = 6.0 Hz, 1H), 5.47 (s, 1H), 4.69 (t, J = 5.2 Hz, 1H), 4.36 – 4.26 (m, 3H), 3.97 – 3.92 (m, 1H), 3.30 (s, 1H), 2.72 (t, J = 7.2 Hz, 2H), 1.88 – 1.79 (m, 1H), 1.67 – 1.55 (m, 2H), 1.40 – 1.30 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H), 0.82 (dd, J = 14.4, 6.8 Hz, 6H). Example 193. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano- 4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 342). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-2-(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl 2-cyclohexylacetate (342.1). [00660] The title compound 342.1 was prepared according to the procedure of Example 17, Step 2, using 143.2 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C 43 H 47 N 5 O 6 Si, 757.33 m/z found 758.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.42 (s, 1H), 8.04 (s, 2H), 7.70 – 7.62 (m, 1H), 7.58 – 7.51 (m, 4H), 7.47 – 7.44 (m, 3H), 7.41 – 7.33 (m, 3H), 7.24 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 4.4 Hz, 1H), 7.04 (s, 1H), 6.75 (d, J = 6.4 Hz, 1H), 5.47 – 5.35 (m, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.42 (d, J = 3.6 Hz, 1H), 3.79 (d, J = 2.8 Hz, 2H), 2.28 (d, J = 6.8 Hz, 2H), 1.85 – 1.70 (m, 3H), 1.68 – 1.56 (m, 3H), 1.28 – 1.20 (m, 5H), 0.92 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-cyclohexylacetate (342). [00661] The title compound 342 was prepared according to the procedure of Example 19, Step 2, using 342.1. MS (ESI): mass calcd. for C27H29N5O6, 519.21, m/z found 520.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 8.37 (s, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.16 – 7.06 (m, 2H), 6.59 (d, J = 6.8 Hz, 1H), 5.25 – 5.16 (m, 1H), 5.07 (t, J = 5.6 Hz, 1H), 4.97 (t, J = 6.0 Hz, 1H), 4.34 – 4.22 (m, 1H), 3.64 – 3.51 (m, 2H), 2.27 (d, J = 6.8 Hz, 2H), 1.82 – 1.72 (m, 3H), 1.69 – 1.56 (m, 3H), 1.32 – 1.07 (m, 3H), 1.05 – 0.90 (m, 2H). Example 194. Synthesis of (2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]triaz in-7-yl)-5- cyano-2-((2- hen lacetox )meth l)tetrah drof ran-3- l L- alinate (Com o nd 343) Step 1. Synthesis of (2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]triaz in-7-yl)-5-cyano- 2-((2-phenylacetoxy)methyl)tetrahydrof ran 3 l (tert b to carbon l) L alinate (343.1). [00662] To a solution of 43.1 (containing DMAP, 80 mg, 0.131 mmol) in DMF (3 mL) was added 2,5- dioxopyrrolidin-1-yl acetate (61.94 mg, 0.394 mmol), the mixture was stirred at 20 o C for 16 h. The reaction was washed with EtOAc (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 343 (40 mg, 42% yield) as a white solid. MS (ESI): m/z calcd. for C32H38N6O9650.69, found 651.2 [M+H] + . Step 2. Synthesis of Synthesis of (2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]triaz in-7- yl)-5-cyano-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (Compound 343). [00663] The compound 343 was prepared according to the procedure of Example 19, Step 2, using 343.1. MS (ESI): mass calcd. for C27H30N6O7, 550.57, m/z found 551.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 22.0 Hz, 2H), 7.94 (s, 1H), 7.49 – 7.13 (m, 5H), 6.94 (d, J = 4.4 Hz, 1H), 6.79 (d, J = 4.8 Hz, 1H), 6.09 (d, J = 6.0 Hz, 1H), 5.45 (dd, J = 5.6, 3.6 Hz, 1H), 4.61-4.58 (m, 1H), 4.40 (dd, J = 12.4, 3.6 Hz, 1H), 4.30 (dd, J = 12.0, 4.8 Hz, 1H), 3.66 (d, J = 4.4 Hz, 2H), 3.21 (d, J = 5.6 Hz, 1H), 2.11 (s, 3H), 1.95 -1.92 (m, 1H), 0.90 (dd, J = 14.4, 6.8 Hz, 6H). Example 195. Synthesis of (2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano- 4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (Compound 344). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-4- hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (344.1). [00664] To a solution of 43.1 (60 mg, 0.098 mmol) in DMA (2 mL)was added HCl in dioxane (4 M, 0.1 mL), The reaction was stirred at 20 o C for 15 min. Then acetyl chloride (387.00 mg, 4.93 mmol) was added to the above solution at 0 o C, The resulting mixture was stirred at 20 o C for 16 h. The crude product was purified by prep-HPLC to afford 344 (30 mg, 42% yield) as a white solid. MS (ESI): m/z calcd. for C32H38N6O9650.69, found 651.2 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-4- hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (Compound 344). [00665] The compound 344 was prepared according to the procedure of Example 19, Step 2, using 344.1. MS (ESI): mass calcd. for C27H30N6O7, 550.57, m/z found 551.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.39 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.29 – 7.23 (m, 3H), 7.20 –7.18 (m, 2H), 7.07 (d, J = 4.8 Hz, 1H), 6.69 (d, J= 6.4 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 5.04 (t, J = 5.6 Hz, 1H), 4.52 – 4.49 (m, 1H), 4.32 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s,2H), 3.25 (d, J = 5.2 Hz, 1H), 2.40 (s, 3H), 2.01 –1.97 (m, 1H), 0.90 (dd, J = 20.0, 6.8 Hz, 6H). Example 196. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl 2-(1-aminocyclohexyl)acetate (Compound 345). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2-(((tert- butyldiphenylsilyl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofu ran-3-yl 2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetate (345.1). [00666] The compound 345.1 was prepared according to the procedure of Example 19, Step 1, using 137.1 and 2-(1-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid. MS (ESI): mass calcd. for C 55 H 68 FN 7 O 10 Si, 1034.27, m/z found 1034.5 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl 2-(1-((tert-butoxycarbonyl)amino)cyclohexyl)acetate (345.2). [00667] Compound 345.2 was prepared according to the procedure of Example 97, Step 1, using 345.1. MS (ESI): mass calcd. for C39H50FN7O10, 795.87, m/z found 796.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 8.48 (s, 1H), 7.45 – 7.40 (m, 2H), 7.27 – 7.22 (m, 2H), 7.17 – 7.10 (m, 3H), 6.58 (d, J = 6.4 Hz, 1H), 6.27 – 6.25(m, 1H), 5.06-5.02 (m, 2H), 4.94 (t, J = 6.0 Hz, 1H), 4.87 – 4.85 (m, 1H), 4.37 – 4.27 (m, 1H), 3.71 – 3.51 (m, 2H), 3.11 – 3.09 (m, 1H), 2.86 – 2.77 (m, 1H), 2.70 – 2.66 (m, 2H), 1.45-1.22 (m, 28H). Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4-fluorophenyl)propanamid o)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2-(1- aminocyclohexyl)acetate (Compound 345). [00668] Compound 345 was prepared according to the procedure of Example 19, Step 2, using 345.2. MS (ESI): mass calcd. for C29H34FN7O6 59563 / f d 5962 [M+H] + 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.38 (dd, J = 8.4, 5.6 Hz, 2H), 7.18 (s, 1H), 7.06 (dd, J = 10.4, 7.2 Hz, 3H), 6.87 (d, J = 4.4 Hz, 1H), 5.33 – 5.22 (m, 1H), 4.97 – 4.95 (m, 1H), 4.90 (d, J = 5.6 Hz, 1H), 4.28-4.27 (m, 1H), 3.56 –3.50 (m, 2H), 3.23 – 3.16 (m, 1H), 3.06 – 2.98 (m, 1H), 2.42 (d, J = 12.8 Hz, 2H), 1.59 – 1.30 (m, 10H). 19 F NMR (376 MHz, DMSO) δ -116.76 (s, 1F). Example 197. Synthesis of (2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3 -yl L-valinate (Compound 346). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-4- hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (346.1). [00669] The compound 346.1 was prepared according to the procedure of Example 195, Step 1, using 43.1 and butyryl chloride. MS (ESI): mass calcd. for C34H42N6O9, 678.74, m/z found 679.3 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-4- hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (Compound 346). [00670] Compound 346 was prepared according to the procedure of Example 19, Step 2, using 346.1. MS (ESI): mass calcd. for C29H34N6O7, 578.63, m/z found 579.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.40 (s, 1H), 7.32 – 7.18 (m, 6H), 7.07 (d, J = 4.8 Hz, 1H), 6.69 (d, J = 6.0 Hz, 1H), 5.20 – 5.09 (m, 1H), 5.05 (t, J = 4.8 Hz, 1H), 4.50 (dd, J = 8.0, 4.4 Hz, 1H), 4.32 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s, 2H), 3.25 (d, J = 5.2 Hz, 1H), 2.71 (t, J = 7.2 Hz, 2H), 2.07 – 1.97 (m, 1H), 1.65-1.60 (m, 2H), 0.94 (dd, J = 14.0, 6.8 Hz, 6H), 0.86 (t, J = 6.0 Hz, 3H). Example 198. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2, 1- f][124]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofu ran-3-yl L-valinate (Compound 347). Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2, 1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydro furan-3-yl (tert-butoxycarbonyl)-L- valinate (347.1). [00671] Compound 347.1 was prepared according to the procedure of Example 195, Step 1, using 43.1 and isobutyryl chloride. MS (ESI): mass calcd. for C 34 H 42 N 6 O 9 , 678.74, m/z found 679.3 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2, 1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydro furan-3-yl L-valinate (Compound 347). [00672] Compound 347 was prepared according to the procedure of Example 19, Step 2, using 347.1. MS (ESI): mass calcd. for C29H34N6O7, 578.63, m/z found 579.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.41 (s, 1H), 7.28 – 7.18 (m, 6H), 7.08 (d, J = 4.8 Hz, 1H), 6.70 –6.68 (m, 1H), 5.19 – 5.12 (m, 1H), 5.04 (d, J = 5.6 Hz, 1H), 4.51 (dd, J = 8.0, 4.0 Hz, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s, 2H), 3.28 (d, J = 5.2 Hz, 1H), 3.11 –3.07 (m, 1H), 2.09 – 1.98 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H), 0.95 – 0.85 (m, 6H). Example 199. Synthesis of (2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano- 2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-y l L-valinate (Compound 348). Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-2-((2- cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (348.1). [00673] To a solution 27.1 (200 mg, 0.325 mmol) in DMA (1.0 mL) was added HCl solution in 1-4 dioxane (0.2 mL, 4 M) and the mixture was stirred at 20 ℃ for 15 minutes. Then the reaction mixture was cooled at 0 ℃ and acetyl chloride (0.46 mL, 6.5 mmol) was added at once. The reaction was stirred at 20 ℃ for 12 h. The reaction was diluted with ACN (1 mL) and purified by prep-HPLC (column: Gemini - C18150 × 21.2 mm, 5 µm; mobile phase: ACN - H2O (0.1% FA); gradient: 40% – 70%) to obtain 348.1 (40 mg, 17.8% yield) as a white solid.. MS (ESI): mass calcd. for C32H44N6O9, 656.30 m/z found 657.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.40 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 2H), 6.76 (d, J = 6.4 Hz, 1H), 5.13 (t, J = 5.2 Hz, 1H), 5.10 – 5.03 (m, 1H), 4.46 (d, J = 3.6 Hz, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.18 (dd, J = 12.4, 4.8 Hz, 1H), 4.06 (dd, J = 8.0, 6.0 Hz, 1H), 2.40 (s, 3H), 2.26 – 2.16 (m, 1H), 2.15 – 2.06 (m, 2H), 1.56 (s, 6H), 1.40 (s, 9H), 1.11 (d, J = 10.4 Hz, 3H), 0.94 – 0.80 (m, 8H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-2-((2- cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L-valinate (348). [00674] To a solution of 348.1 (40 mg, 0.061 mmol) in THF (1.0 mL) was added HCl in dioxane (2.0 mL, 4 M) at 0 ℃, then the reaction was stirred at 20 ℃ for 2 h. After completion, the mixture was concentrated in vacuo to afford a residue, the residue was purified by prep-HPLC (mobile phase: ACN— H2O (0.1% FA), 20%-45%) to afford 348 (14.61 mg, 38.9% yield) as a white solid. MS (ESI): mass calcd. for C27H36N6O7, 556.26, m/z found 557.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.40 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.72 (d, J = 6.0 Hz, 1H), 5.17 – 5.12 (m, 1H), 5.10 – 5.06 (m, 1H), 4.49 (d, J = 4.0 Hz, 1H), 4.31 – 4.26 (m, 1H), 4.24 – 4.19 (m, 1H), 3.24 (d, J = 5.2 Hz, 1H), 2.40 (s, 3H), 2.16 – 2.09 (m, 2H), 2.03 – 1.96 (m, 1H), 1.60 – 1.50 (m, 6H), 1.18 – 1.05 (m, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.87 – 0.82 (m, 5H). Example 200. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5- (4-isobutyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydro furan-3-yl L-valinate (Compound 349). Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5-(4- isobutyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofur an-3-yl (tert-butoxycarbonyl)-L- valinate (349.1). [00675] The title compound 349.1 was prepared according to the procedure of Example 199, Step 1, using 27.1 and isobutyryl chloride. MS (ESI): mass calcd. for C 34 H 48 N 6 O 9 , 684.35 m/z found 685.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.41 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.17 – 7.04 (m, 2H), 6.77 (d, J = 6.4 Hz, 1H), 5.18 – 5.12 (m, 1H), 5.11 – 5.07 (m, 1H), 4.53 – 4.41 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.18 (dd, J = 12.4, 4.8 Hz, 1H), 4.07 (dd, J = 8.0, 5.6 Hz, 1H), 3.12 (dt, J = 13.6, 6.8 Hz, 1H), 2.27 – 2.16 (m, 1H), 2.15 – 2.06 (m, 2H), 1.62 – 1.50 (m, 6H), 1.41 – 1.36 (m, 9H), 1.17 – 1.04 (m, 9H), 0.95 – 0.77 (m, 8H).. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5-(4- isobutyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofur an-3-yl L-valinate (349). [00676] The title compound 349 was prepared according to the procedure of Example 199, Step 2, using 349.1. MS (ESI): mass calcd. for C 29 H 40 N 6 O 7 , 584.30, m/z found 585.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.41 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.72 (d, J = 6.0 Hz, 1H), 5.18 – 5.12 (m, 1H), 5.11 – 5.07 (m, 1H), 4.50 (q, J = 4.0 Hz, 1H), 4.28 (dd, J = 12.4, 3.6 Hz, 1H), 4.21 (dd, J = 12.4, 4.8 Hz, 1H), 3.24 (d, J = 5.2 Hz, 1H), 3.16 – 3.08(m, 1H), 2.18 – 2.10 (m, 2H), 2.03 – 1.95 (m, 1H), 1.61 – 1.50 (m, 6H), 1.18 – 1.05(m, 9H), 0.96 – 0.80 (m, 8H). Example 201. Synthesis of (2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-2-((2-c clohex lacetox )meth l)-4-h drox tetrah drofuran-3- l L-valinate (Com ound 35 Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-2-((2- cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (350.1). [00677] The title compound 350.1 was prepared according to the procedure of Example 199, Step 1, using 27.1 and butyryl chloride. MS (ESI): mass calcd. for C34H48N6O9, 684.35 m/z found 685.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.40 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.11 (t, J = 7.6 Hz, 2H), 6.76 (d, J = 6.4 Hz, 1H), 5.13 (t, J = 5.2 Hz, 1H), 5.10 – 5.04 (m, 1H), 4.46 (d, J = 4.0 Hz, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.22 – 4.14 (m, 1H), 4.12 – 4.04 (m, 1H), 2.70 (t, J = 7.2 Hz, 2H), 2.26 – 2.06 (m, 3H), 1.69 – 1.52 (m, 8H), 1.40 (s, 9H), 1.15 – 0.81 (m, 14H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-2-((2- cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L-valinate (350). [00678] The title compound 350 was prepared according to the procedure of Example 199, Step 2, using 350.1. MS (ESI): mass calcd. for C29H40N6O7, 584.30, m/z found 585.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.40 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.75 – 6.70 (m, 1H), 5.16 – 5.11 (m, 1H), 5.10 – 5.06 (m, 1H), 4.51 – 4.47 (m, 1H), 4.31 – 4.16 (m, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.73 – 2.66 (m, 2H), 2.19 – 2.07 (m, 2H), 2.04 – 1.95 (m, 1H), 1.69 – 1.51 (m, 8H), 1.19 – 0.99 (m, 3H), 0.97 – 0.90 (m, 6H), 0.88 – 0.82 (m, 5H). Example 202. Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5- ((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl (2S,2'S)-bis(2-amino-3-methylbutanoate) (Compound 351). Step 1. Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl (2S,2'S)-bis(2-amino-3-methylbutanoate) (Compound 351). [00679] The compound 351 was prepared according to the procedure of Example 19, Step 2, using 351.1. MS (ESI): mass calcd. for C30H37N7O7, 607.67, m/z found 608.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 24.0 Hz, 2H), 7.95 (s, 1H), 7.25 - 7.20 (m, 5H), 6.95 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.13 (d, J = 6.0 Hz, 1H), 5.46 (dd, J = 5.6, 4.0 Hz, 1H), 4.57 - 4.55(m, 1H), 4.42 (dd, J = 12.4, 3.2 Hz, 1H), 4.31 (dd, J = 12.4, 4.8 Hz, 1H), 3.67 (d, J = 2.8 Hz, 2H), 3.30 (d, J = 5.2 Hz, 1H), 3.27 (d, J = 4.8 Hz, 1H), 2.04 - 2.00 (m, 1H), 1.93 -1.90 (m, 1H), 0.90 (dd, J = 13.2, 6.8 Hz, 6H), 0.85 (d, J = 6.8 Hz, 6H). Example 203. Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (Compound 352). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-((S)-2-((tert-butoxycarbonyl)amino)-3- (4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetate (Compound 352.1). [00680] The compound 352.1 was prepared according to the procedure of Example 185, Step 1, using 286.1 and (S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)propano ic acid. MS (ESI): mass calcd. for C42H54FN7O10, 835.93, m/z found 836.2 [M+H] + . Step 2. Synthesis of Synthesis of ((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (Compound 352). [00681] The compound 352 was prepared according to the procedure of Example 49, Step 2, using 352.1. MS (ESI): mass calcd. for C29H34FN7O6, 595.63, m/z found 596.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.57 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.39 (dd, J = 8.4, 5.6 Hz, 2H), 7.17 (s, 1H), 7.09 – 7.03 (m, 3H), 6.81 (d, J = 4.4 Hz, 1H), 6.33 – 6.30 (m, 1H), 5.50 – 5.45 (m, 1H), 4.93 (dd, J = 13.2, 5.6 Hz, 1H), 4.66 (d, J = 4.4 Hz, 1H), 4.30 (d, J = 10.8 Hz, 1H), 4.24 – 4.16 (m, 2H), 3.94 – 3.90 (m, 1H), 3.17 (d, J = 10.4 Hz, 1H), 3.01 (d, J = 13.6 Hz, 1H), 2.40 (s, 2H), 1.43 – 1.31 (m, 10H). 19 F NMR (376 MHz, DMSO) δ -116.76 (s, 1F). Example 204. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-4-hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 353). Ste p 1. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (353.1). [00682] Compound 353.1 was prepared according to the procedure of Example 195, Step 1, using 39.1 and AcCl. MS (ESI): mass calcd. for C 27 H 36 N 6 O 9 , 588.62, m/z found 589.2 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 353). [00683] Compound 353 was prepared according to the procedure of Example 19, Step 2, using 347.1. MS (ESI): mass calcd. for C22H28N6O7, 488.50, m/z found 489.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.40 (s, 1H), 7.32 (d, J = 4.4 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.71 (d, J = 6.0 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 5.05 (t, J = 6.0 Hz, 1H), 4.53 – 4.50 (m, 1H), 4.29 – 4.24 (m, 2H), 3.09 (d, J = 5.2 Hz, 1H), 2.41 –2.38 (m, 5H), 1.78 – 1.73 (m, 1H), 1.09 (t, J = 7.2 Hz, 3H), 0.77 (dd, J = 22.4, 6.8 Hz, 6H). Example 205. Synthesis of ((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (Compound 354). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin -7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetate (354.1). [00684] Compound 354.1 was prepared according to the procedure of Example 195, Step 1, using 286.1 and butyryl chloride. MS (ESI): mass calcd. for C32H44N6O8, 640.74, m/z found 641.2 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (Compound 354). [00685] Compound 354 was prepared according to the procedure of Example 49, Step 2, using 354.1. MS (ESI): mass calcd. for C24H32N6O6, 500.56, m/z found 501.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.46 (d, J = 6.0 Hz, 1H), 5.49–5.48 (m, 1H), 4.71 (t, J = 4.4 Hz, 1H), 4.38 – 4.28 (m, 2H), 4.23 (dd, J = 11.6, 5.6 Hz, 1H), 3.96 (t, J = 5.6 Hz, 1H), 2.70 (t, J = 7.2 Hz, 2H), 2.55 (s, 2H), 1.68 – 1.61 (m, 2H), 1.54 –1.31 (m, 10H), 0.94 (t, J = 7.2 Hz, 3H). Example 206. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy )methyl)tetrahydrofuran-3-yl L- valinate (Compound 355). Step 1. Synthesis of (2R,3R,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-phenylacetoxy)methyl)-4 -((trimethylsilyl)oxy)tetrahydrofuran- 3-yl (tert-butoxycarbonyl)-L-valinate (355.1). [00686] To a solution of 43.1 (80 mg, 0.131 mmol) in DCM (5 mL) was added TMSCl (42.83 mg, 0.394 mmol) at 0 oC and stirred at 20 oC for 2 h. To the above solution was added [(chlorocarbonyl)oxy]methyl acetate (60.13 mg, 0.394 mmol) at 0 o C and stirred at 0 o C for 2 h. The reaction was washed with DCM (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 355.1 (25 mg, 21% yield) as a white solid. MS (ESI): m/z calcd. for C37H48N6O12Si 796.91, found 797.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 8.29 (s, 1H), 7.30 – 7.21 (m, 6H), 7.14 (d, J = 8.4 Hz, 1H), 6.99 –6.95 (m, 1H), 5.79 (s, 2H), 5.26 (d, J = 5.2 Hz, 1H), 5.16 (t, J = 5.2 Hz, 1H), 4.60 – 4.48 (m, 1H), 4.40 (dd, J = 12.4, 3.2 Hz, 1H), 4.30 (dd, J = 12.0, 5.2 Hz, 1H), 4.04 (dd, J = 8.0, 6.0 Hz, 1H), 3.69 (s, 2H), 2.20 – 2.12 (m, 1H), 2.11 (s, 3H), 1.38 (s, 9H), 0.88 (t, J = 6.8 Hz, 6H), 0.00 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy )methyl)tetrahydrofuran-3-yl L- valinate (Compound 355). [00687] The compound 355 was prepared according to the procedure of Example 19, Step 2, using 355.1. MS (ESI): mass calcd. for C29H32N6O10, 624.61, m/z found 625.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.24 –7.18 (m, 6H), 7.02 (d, J = 4.4 Hz, 1H), 6.69 (d, J = 6.0 Hz, 1H), 5.81 (s, 2H), 5.15 (t, J = 4.8 Hz, 1H), 5.04 – 5.02 (m, 1H), 4.50 – 4.49 (m, 1H), 4.33 (dd, J = 12.4, 3.2 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s, 2H), 3.25 (d, J = 5.2 Hz, 1H), 2.12 (s, 3H), 2.06 – 1.97 (m, 1H), 0.89 (dd, J = 26.4, 6.4 Hz, 6H). Example 207. (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((2- cyclohexylacetoxy)methyl)tetrahydrofuran-3,4-diyl (2S,2'S)-bis(2-amino-3-methylbutanoate) (Compound 356.1). Step 1. Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((2- cyclohexylacetoxy)methyl)tetrahydrofuran-3,4-diyl (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)-3- methylbutanoate) (356.1). [00688] To a solution of compound 10 (6.0 g,14.4 mmol) in THF (200 mL) was added (tert- butoxycarbonyl)-L-valine (3.14 g, 14.4 mmol), EDCI (8.28 g, 43.2 mmol) and DMAP (5.28 g, 43.2 mmol), the mixture was stirred at 25 ℃ for 16 h. The organic phase was washed with brine water (100 mL x3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. the residue was purified by prep-HPLC [Gradient: 70% - 95% ACN in water (0.1% FA)] to obtain 356.1 (3.0 g, 26% yield) as a white solid. MS (ESI): mass calcd. for C 40 H 59 N 7 O 11 , 813.43 m/z found 814.7 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.95 (br s, 3H), 7.22 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 6.04 (d, J = 6.0 Hz, 1H), 5.46 (dd, J = 5.2, 3.2 Hz, 1H), 4.52 (d, J = 3.2 Hz, 1H), 4.44 – 4.33 (m, 1H), 4.30 – 4.23 (m, 1H), 4.12 – 4.07 (m, 1H), 4.06 – 3.98 (m, 1H), 2.35 – 2.25 (m, 1H), 2.20 – 2.05 (m, 3H), 1.56 (s, 6H), 1.39 (d, J = 5.2 Hz, 16H), 1.25 – 0.99 (m, 5H), 0.98 – 0.75 (m, 14H).. Step 2. Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((2- cyclohexylacetoxy)methyl)tetrahydrofuran-3,4-diyl (2S,2'S)-bis(2-amino-3-methylbutanoate) (356). [00689] The title compound 356 was prepared according to the procedure of Example 199, Step 2, using 356.1. MS (ESI): mass calcd. for C 30 H 43 N 7 O 7 , 613.32, m/z found 614.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.11 – 7.90 (m, 3H), 6.95 (d, J = 4.8 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.18 (d, J = 6.0 Hz, 1H), 5.51 – 5.40 (m, 1H), 4.57 (dd, J = 7.6, 4.0 Hz, 1H), 4.40 – 4.35 (m, 1H), 4.32 – 4.25 (m, 1H), 3.38 (d, J = 4.8 Hz, 1H), 3.34 (d, J = 4.8 Hz, 1H), 2.21 – 1.92 (m, 4H), 1.65 – 1.50 (m, 6H), 1.20 – 1.00 (m, 3H), 0.98 – 0.80 (m, 14H). Example 208. Synthesis of ((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5- cy Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (357.1). [00690] The title compound 357.1 was prepared according to the procedure of Example 199, Step 1, using 39.1 and butyryl chloride. MS (ESI): mass calcd. for C29H40N6O9, 616.29 m/z found 617.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.40 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.71 (d, J = 6.4 Hz, 1H), 5.12 (d, J = 5.2 Hz, 1H), 5.05 (d, J = 6.0 Hz, 1H), 4.56 – 4.50 (m, 1H), 4.32 – 4.24 (m, 2H), 3.88 – 3.80 (m, 1H), 2.70 (t, J = 7.2 Hz, 2H), 2.41 (q, J = 7.6 Hz, 2H), 1.99 – 1.83 (m, 1H), 1.67 – 1.59 (m, 2H), 1.36 (s, 8H), 1.20 (s, 1H), 1.08 (t, J = 7.6 Hz, 3H), 0.94 (t, J = 7.6 Hz, 3H), 0.80 – 0.74 (m, 6H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (357). [00691] The title compound 357 was prepared according to the procedure of Example 199, Step 2, using 357.1. MS (ESI): mass calcd. for C24H32N6O7, 516.23 m/z found 517.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.40 (s, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.71 (d, J = 6.4 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.53 (q, J = 4.4 Hz, 1H), 4.33 – 4.24 (m, 2H), 3.09 (d, J = 5.2 Hz, 1H), 2.70 (t, J = 7.2 Hz, 2H), 2.44 – 2.38 (m, 2H), 1.78 – 1.73 (m, 1H), 1.69 – 1.60 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H). Example 209. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methy l)-4-hydroxytetrahydrofuran-3-yl L- valinate (Compound 358). Step 1. Synthesis of (2R,3R,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methy l)-4- ((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (358.1). [00692] To a solution of 27.1 (80.0 mg, 0.13 mmol) and pyridine (0.13 mL, 1.56 mmol) in DCM (1.0 mL) was added TMSCl (42.4 mg, 0.39 mmol) at 0 ℃, the mixture was stirred at 20 ℃ for 1 h. And then the reaction was added [(chlorocarbonyl)oxy]methyl acetate (29.8 mg, 0.195 mmol) at 0 ℃, the mixture was stirred at 0 ℃ for 1 h. Then the reaction was diluted with water (50 mL) and extracted with DCM (50 mL x3). The organic phase was washed with brine water (50 mL x3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was diluted with ACN (2 mL) and purified by prep-HPLC (mobile phase: ACN-H2O (0.1% FA), 50% - 80%) to obtain 358.1 (25.0 mg, 22.8% yield) as a white solid. MS (ESI) l d f C H N O Si 80236 /z found 803.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 8.32 (s, 1H), 7.27 (s, 1H), 7.17 – 7.11 (m, 1H), 7.05 (s, 1H), 5.79 (s, 2H), 5.28 (d, J = 5.2 Hz, 1H), 5.16 (t, J = 5.2 Hz, 1H), 4.49 (dd, J = 8.8, 5.2 Hz, 1H), 4.34 (dd, J = 12.0, 3.2 Hz, 1H), 4.26 (dd, J = 12.4, 5.2 Hz, 1H), 4.04 (dd, J = 8.4, 6.0 Hz, 1H), 2.22 – 2.15 (m, 2H), 2.11 (s, 3H), 1.60 (d, J = 13.2 Hz, 6H), 1.38 (s, 9H), 1.26 – 0.81 (m, 12H), 0.00 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methy l)-4-hydroxytetrahydrofuran-3-yl L- valinate (358). [00693] The title compound 358 was prepared according to the procedure of Example 199, Step 2, using 358.1. MS (ESI): mass calcd. for C29H38N6O10, 630.26 m/z found 631.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.28 – 7.25 (m, 1H), 7.08 – 7.02 (m, 1H), 6.70 (d, J = 6.4 Hz, 1H), 5.80 (s, 2H), 5.17 – 5.13 (m, 1H), 5.11 – 5.07 (m, 1H), 4.51 – 4.46 (m, 1H), 4.31 – 4.26 (m, 1H), 4.24 – 4.19 (m, 1H), 3.25 (d, J = 5.2 Hz, 1H), 2.17 – 2.09 (m, 5H), 2.04 – 1.97 (m, 1H), 1.65 – 1.50 (m, 7H), 1.20 – 1.05 (m, 3H), 0.95 – 0.84 (m, 7H). Example 210. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (Compound 359). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetate (359.1). [00694] To a solution of 286.1 (250 mg, 0.438 mmol) and pyridine (416 mg, 5.26 mmol) in DCM (1.0 mL) was added acetyl chloride (68.8 mg, 0.88 mmol) at 0 ℃, then the reaction was stirred at 0 ℃ for 2 h. After completion, the mixture was concentrated in vacuo to afford a residue, the residue was purified by prep-HPLC (mobile phase: ACN-H2O(0.1% FA), 40% - 70%) to afford 359.1 (180 mg, 63.7% yield) as a white solid. MS (ESI): mass calcd. for C30H40N6O8, 612.29 m/z found 613.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.43 (s, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.26 (s, 1H), 5.41 (d, J = 6.2 Hz, 1H), 4.96 (dd, J = 6.4, 2.8 Hz, 1H), 4.62 (s, 1H), 4.21 – 4.15 (m, 1H), 4.10 – 4.05 (m, 1H), 2.48 (s, 2H), 2.39 (s, 3H), 1.96 – 1.88 (m, 2H), 1.65 (s, 3H), 1.43 – 1.15 (m, 20H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-aminocyclohexyl)acetate (359). [00695] To a solution of 359.1 (100 mg, 0.163 mmol) in THF (1.0 mL) was added HCl (0.8 mL, 4 M) at 0℃, then the reaction was stirred at 0 ℃ for 0.5 h. After completion, the mixture was concentrated in vacuo to afford a residue, the residue was purified by Prep-HPLC [Gradient: 5 - 35% ACN in water (0.1% FA)] to obtain 359 (39.5 mg, 49.0% yield) as a white solid. MS (ESI): mass calcd. for C 22 H 28 N 6 O 6 , 472.21 m/z found 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.41 – 8.38 (m, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.60 – 6.40 (m, 1H), 4.71 (d, J = 4.8 Hz, 1H), 4.35 – 4.25 (m, 2H), 4.23 – 4.18 (m, 1H), 3.96 (t, J = 5.6 Hz, 1H), 2.44 (s, 2H), 2.39 (s, 3H), 1.53 – 1.29 (m, 10H). Example 211. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)- 5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)tetrahydrofuran-3-yl L- valinate (Compound 360). Step 1. Synthesis of (2R,3R,4R,5R)-5-cyano-2-((2-phenylacetoxy)methyl)-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-4- ((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (360.1). [00696] The compound 360.1 was prepared according to the procedure of Example 206, Step 1, using 43.1 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C40H54N6O12Si, 838.99, m/z found 839.3 [M+H] + . Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)- 5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)tetrahydrofuran-3-yl L- valinate (Compound 360). [00697] The compound 360 was prepared according to the procedure of Example 19, Step 2, using 360.1. MS (ESI): mass calcd. for C32H38N6O10, 666.69, m/z found 667.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 7.33 –7.17 (m, 6H), 7.06 (d, J = 4.4 Hz, 1H), 6.76 (d, J = 6.4 Hz, 1H), 5.85 (s, 2H), 5.25 – 5.15 (m, 1H), 5.05 (t, J =6.0 Hz, 1H), 4.53 (d, J = 4.0 Hz, 1H), 4.34 – 4.24 (m, 2H), 3.66 (s, 2H), 3.50 – 3.47 (m, 1H) 2.10 – 2.09 (m, 1H), 1.18 (s, 9H), 0.93 (dd, J = 16.0, 6.8 Hz, 6H). Example 212. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5- (4-((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (Compound 361).
Step 1. Synthesis of (2R,3R,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-4- ((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (358.1). [00698] The title compound 361.1 was prepared according to the procedure of Example 209, Step 1, using 27.1 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C 40 H 60 N 6 O 12 Si, 844.40 m/z found 845.3 [M+H] +. 1H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 8.41 (s, 1H), 7.36 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 5.84 (s, 2H), 5.25 (s, 1H), 5.15 (t, J = 5.2 Hz, 1H), 4.50 (d, J = 4.0 Hz, 1H), 4.34 (d, J = 9.6 Hz, 1H), 4.25 (dd, J = 12.4, 5.2 Hz, 1H), 4.06 – 4.01 (m, 1H), 2.18 – 2.08 (m, 3H), 1.59 (d, J = 12.0 Hz, 6H), 1.38 (s, 9H), 1.17 (s, 11H), 0.94 – 0.83 (m, 9H), 0.02 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)tetrahydrofuran-3-yl L- valinate (361). [00699] The title compound 361 was prepared according to the procedure of Example 209, Step 2, using 361.1. MS (ESI): mass calcd. for C 32 H 44 N 6 O 10 , 672.31 m/z found 673.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.26 (s, 1H), 7.06 (d, J = 4.8 Hz, 1H), 6.70 (d, J = 6.0 Hz, 1H), 5.83 (s, 2H), 5.18 – 5.12 (m, 1H), 5.10 – 5.06 (m, 1H), 4.53 – 4.45 (m, 1H), 4.30 – 4.26 (m, 1H), 4.24 – 4.19 (m, 1H), 3.25 (d, J = 5.2 Hz, 1H), 2.20 – 2.06 (m, 2H), 2.03 – 1.96 (m, 1H), 1.62 – 1.50 (m, 6H), 1.17 (s, 9H), 1.12 – 0.98 (m, 3H), 0.96 – 0.80 (m, 8H). Example 213. Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-3-(propionyloxy)tetrahydrofuran-2-yl) methyl L-valinate (Compound 362). Ste p 1. Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-3-(propionyloxy)tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl)-L- valinate (362.1). [00700] Compound 362.1 was prepared according to the procedure of Example 195, Step 1, using 39.1 and isobutyryl chloride. MS (ESI): mass calcd. for C29H40N6O9, 616.67, m/z found 617.2 [M+H] + . Step 2. Synthesis of Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4- isobutyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-(propionyl oxy)tetrahydrofuran-2-yl)methyl L- valinate (Compound 362). [00701] Compound 362 was prepared according to the procedure of Example 19, Step 2, using 362.1. MS (ESI): mass calcd. for C24H32N6O7, 516.56, m/z found 517.1 [M+H] + . 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.41 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.71 (d, J = 6.4 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.58 – 4.50 (m, 1H), 4.33 – 4.25 (m, 2H), 3.12 – 3.08 (m, 2H), 2.44 – 2.38 (m, 2H), 1.77 – 1.75 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H), 1.08 (t, J = 7.6 Hz, 3H), 0.77 (dd, J = 16.0, 9.2 Hz, 6H). Example 214. Synthesis of ((2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo [2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-(1- aminocyclohexyl)acetate (Compound 363). Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-((tert-butoxycarbonyl)amino)cyclohexyl)acetate (363.1). [00702] Compound 363.1 was prepared according to the procedure of Example 17, Step 1, using 363.1. MS (ESI): mass calcd. for C25H34N6O7, 530.58, m/z found 531.2 [M+H] + . Step 2. Synthesis of (2R,3R,4R,5R)-5-cyano-2-((2-phenylacetoxy)methyl)-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-4- ((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (360.1). [00703] Compound 363.2 was prepared according to the procedure of Example 206, Step 1, using 363.1 and ((chlorocarbonyl)oxy)methyl acetate. MS (ESI): mass calcd. for C35H54N6O11Si2, 791.02, m/z found 791.3 [M+H] +. Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo [2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-(1- aminocyclohexyl)acetate (Compound 363). [00704] Compound 363 was prepared according to the procedure of Example 19, Step 2, using 363.2. MS (ESI): mass calcd. for C24H30N6O9, 546.54, m/z found 547.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.23 (s, 1H), 7.16 (d, J = 4.4 Hz, 1H), 6.99 (d, J = 4.8 Hz, 1H), 6.43-6.40 (m, 1H), 5.78 (s, 2H), 4.72 (d, J = 4.4 Hz, 1H), 4.36 – 4.24 (m, 2H), 4.20 (dd, J = 11.6, 5.8 Hz, 1H), 3.96 (t, J = 5.8 Hz, 1H), 2.44 (s, 2H), 2.11 (s, 3H), 1.61 – 1.22 (m, 10H). Example 215. Synthesis of ((2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo [2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-3-(propionyloxy)tet rahydrofuran-2-yl)methyl L-valinate (Compound 364). Step 1. Synthesis of ((2R,3R,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo [2,1- f][1,2,4]triazin-7-yl)-5-cyano-3-(propionyloxy)-4-((trimethy lsilyl)oxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (364.1). [00705] The title compound 364.1 was prepared according to the procedure of Example 209, Step 1, using 39.1 and ((chlorocarbonyl)oxy)methyl acetate. MS (ESI): mass calcd. for C32H46N6O12Si, 734.29 m/z found 735.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.55 – 10.65 (m, 1H), 8.32 (s, 1H), 7.27 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 5.79 (s, 2H), 5.27 (d, J = 4.4 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 4.54 (d, J = 4.0 Hz, 1H), 4.36 (s, 2H), 3.90 (t, J = 6.8 Hz, 1H), 2.45 – 2.35 (m, 2H), 2.11 (s, 3H), 2.02 – 1.94 (m, 1H), 1.37 (s, 9H), 1.07 (t, J = 7.6 Hz, 3H), 0.81 (d, J = 6.8 Hz, 6H), -0.01 (d, J = 4.4 Hz, 9H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo [2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-3-(propionyloxy)tet rahydrofuran-2-yl)methyl L-valinate (364). [00706] The title compound 364 was prepared according to the procedure of Example 209, Step 2, using 364.1. MS (ESI): mass calcd. for C24H30N6O10, 562.20 m/z found 563.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.30 – 7.26 (m, 1H), 7.07 (d, J = 4.4 Hz, 1H), 6.70 (d, J = 6.4 Hz, 1H), 5.80 (s, 2H), 5.16 (t, J = 5.2 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.55 – 4.50 (m, 1H), 4.34 – 4.24 (m, 2H), 3.14 (d, J = 5.2 Hz, 1H), 2.41 (q, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.82 – 1.72 (m, 1H), 1.08 (t, J = 7.6 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H). Example 216. Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-3- (propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (Compound 365). Step 1. Synthesis of ((2R,3R,4R,5R)-5-cyano-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-3-(propionyloxy)-4- ((trimethylsilyl)oxy)tetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-valinate (365.1). [00707] The title compound 365.1 was prepared according to the procedure of Example 209, Step 1, using 39.1 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C 35 H 52 N 6 O 12 Si, 776.34 m/z found 777.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.36 (s, 1H), 7.31 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 5.83 (s, 2H), 5.25 (d, J = 4.8 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 4.54 (dd, J = 9.2, 4.8 Hz, 1H), 4.38 – 4.34 (m, 2H), 3.98 – 3.83 (m, 1H), 2.45 – 2.31 (m, 2H), 2.03 – 1.90 (m, 1H), 1.40 – 1.25 (m, 9H), 1.17 (s, 9H), 1.06 (t, J = 7.6 Hz, 3H), 0.81 (d, J = 6.8 Hz, 6H), 0.00 (s, 9H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-3- (propionyloxy)tetrahydrofuran-2-yl)methyl L-valinate (365). [00708] The title compound 365 was prepared according to the procedure of Example 209, Step 2, using 365.1. MS (ESI): mass calcd. for C27H36N6O10, 604.25 m/z found 605.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.27 (d, J = 44 H 1H) 707 (d J = 48 H 1H) 670 (d J = 6.4 Hz, 1H), 5.83 (s, 2H), 5.15 (t, J = 5.2 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.55 – 4.49 (m, 1H), 4.34 – 4.24 (m, 2H), 3.13 (d, J = 5.2 Hz, 1H), 2.44 – 2.36 (m, 2H), 1.81 – 1.70 (m, 1H), 1.17 (s, 9H), 1.12 – 1.06 (m, 3H), 0.83 – 0.78 (m, 3H), 0.77 – 0.72 (m, 3H). Example 217. Synthesis of (((((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)methyl acetate (Compound 366). Step 1. Synthesis of tert-butyl ((S)-1-((7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)amino)-3-(4-fluorophenyl)- 1-oxopropan-2-yl)carbamate (366.1). [00709] Compound 366.1 was prepared according to the procedure of Example 97, Step 1, using 137.1. MS (ESI): mass calcd. for C26H29FN6O7, 556.55, m/z found 557.1 [M+H] + . Step 2. Synthesis of (((((2R,3S,4R,5R)-5-(4-((S)-2-((tert-butoxycarbonyl)amino)-3 -(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)methyl acetate (366.2). [00710] To a solution of 366.1 (50 mg, 0.089 mmol) in DCM (2 mL) was added pyridine (142.06 mg, 1.796 mmol) and [(chlorocarbonyl)oxy]methyl acetate (20.55 mg, 0.134 mmol) at 0 o C, the mixture was stirred at 25 o C for 4 h. The reaction was washed with DCM (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 366.2 (6 mg, 9% yield) as a white solid. MS (ESI): mass calcd. for C30H33FN6O11, 672.62, m/z found 673.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 8.44 (s, 1H), 7.42 (t, J = 5.6 Hz, 2H), 7.19 – 7.15 (m, 2H), 7.12 (t, J = 8.4 Hz, 2H), 7.03 –7.01 (m, 1H), 6.51 (d, J = 5.2 Hz, 1H), 5.67 (s, 2H), 5.55 –5.50 (m, 1H), 4.83 – 4.80 (m, 1H), 4.69 (t, J = 4.4 Hz , 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.33 – 4.27 (m, 2H), 3.96 –3.92 (m, 1H), 3.11 (d, J = 11.4 Hz, 1H), 2.86 – 2.77 (m, 1H), 1.32 (s, 9H). Step 3. Synthesis of (((((2R,3S,4R,5R)-5-(4-((S)-2-amino-3-(4- fluorophenyl)propanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)methyl acetate (Compound 366). [00711] Compound 366 was prepared according to the procedure of Example 19, Step 2, using 366.2. MS (ESI): mass calcd. for C25H25FN6O9, 572.51, m/z found 573.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.59 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 7.38 (dd, J = 8.0, 6.0 Hz, 2H), 7.17 (s, 1H), 7.06 – 7.03 (m, 3H), 6.77 (d, J = 4.4 Hz, 1H), 6.38 (d, J = 6.0 Hz, 1H), 5.67 (s, 2H), 5.50 (d, J = 5.6 Hz, 1H), 4.93 – 4.90 (m, 1H), 4.65 (t, J = 5.2 Hz, 1H), 4.44 – 4.42 (m, 1H), 4.35 – 4.20 (m, 2H), 3.93 –3.92 (m, 1H), 3.18 (dd, J = 14.0, 3.6 Hz, 1H), 3.07 – 2.98 (m, 1H), 2.08 (s, 3H). 19 F NMR (377 MHz, DMSO) δ - 116.75 (s, 1F). Example 218. Synthesis of (((7-((2R,3R,4S,5R)-5-((2-(1-aminocyclohexyl)acetoxy)methyl) -2-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triaz in-4-yl)carbamoyl)oxy)methyl pivalate (Compound 367). Step 1. Synthesis of (((7-((2R,3R,4R,5R)-5-((2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetoxy)methyl)-2-cyano-3,4- bis((trimethylsilyl)oxy)tetrahydrofuran-2-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)carbamoyl)oxy)methyl pivalate (367.1). [00712] Compound 367.1 was prepared according to the procedure of Example 206, Step 1, using 363.1 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C38H60N6O11Si2, 833.10, m/z found 833.3 [M+H] + . Step 2. Synthesis of Synthesis of (((7-((2R,3R,4S,5R)-5-((2-(1-aminocyclohexyl)acetoxy)methyl) -2- cyano-3,4-dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4 ]triazin-4-yl)carbamoyl)oxy)methyl pivalate (Compound 367). [00713] The title compound 367 was prepared according to the procedure of Example 19, Step 2, using 367.1. MS (ESI): mass calcd. for C 27 H 36 N 6 O 9 , 588.62, m/z found 589.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.12 (d, J = 4.4 H 1H) 697 (d J 48 H 1H) 643 640 ( , 1H), 5.80 (s, 2H), 4.71 (d, J = 4.4 Hz, 1H), 4.35 – 4.14 (m, 3H), 3.96 (t, J = 5.2 Hz, 1H), 2.40 (s, 2H), 1.66 – 1.21 (m, 10H), 1.17 (s, 9H). Example 219. Synthesis (2R,3S,4R,5R)-2-((2-(1-aminocyclohexyl)acetoxy)methyl)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxytet rahydrofuran-3-yl 2-cyclohexylacetate (Compound 368). Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-(1-((tert-butoxycarbonyl)amino)cyclohexyl)acetate (368.1). [00714] The title compound 368.1 was prepared according to the procedure of Example 17, Step 1, using 288.1 and TsOH·H 2 O. MS (ESI): mass calcd. for C 25 H 34 N 6 O 7 , 530.25 m/z found 531.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (d, J = 4.8 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.32 – 6.26 (m, 2H), 5.35 (d, J = 6.0 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.29 – 4.21 (m, 2H), 4.16 – 4.10 (m, 1H), 3.96 – 3.90 (m, 1H), 2.60 (s, 2H), 2.02 – 1.96 (m, 2H), 1.49 – 1.16 (m, 17H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -((2-(1-((tert- butoxycarbonyl)amino)cyclohexyl)acetoxy)methyl)-5-cyano-4-hy droxytetrahydrofuran-3-yl 2- cyclohexylacetate (368.2). [00715] To a solution of 368.1 (250 mg, 0.471 mmol) in THF (10 mL) was added cyclohexylacetic acid (70.4 mg, 0.494 mmol), EDCI (271 mg, 1.414 mmol) and DMAP (172.7 mg, 1.414 mmol), the mixture was stirred at 25 ℃ for 16 h. After completion, the mixture was concentrated in vacuo to afford a residue. Then the reaction residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x3). The organic layer was dried over sodium sulphate and concentrated under reduce pressure to afford a crude. The residue was purified by Prep-HPLC [Gradient: 40 - 70% ACN in water (0.1% FA)] to obtain 368.2 (65 mg, 20% yield) as a white solid... MS (ESI): mass calcd. for C33H46N6O8, 654.34 m/z found 655.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.59 (d, J = 5.6 Hz, 1H), 6.27 (s, 1H), 5.11 (d, J = 4.4 Hz, 2H), 4.44 (d, J = 3.6 Hz, 1H), 4.26 (dd, J = 12.0, 3.6 Hz, 1H), 4.19 (dd, J = 12.0, 5.6 Hz, 1H), 2.62 – 2.54 (m, 2H), 2.26 (d, J = 6.8 Hz, 2H), 1.95 (s, 2H), 1.77 (dd, J = 11.6, 8.0 Hz, 3H), 1.62 (t, J = 14.8 Hz, 3H), 1.40 – 1.06 (m, 20H), 1.01 – 0.88 (m, 2H). Step 3. Synthesis of (2R,3S,4R,5R)-2-((2-(1-aminocyclohexyl)acetoxy)methyl)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxytet rahydrofuran-3-yl 2-cyclohexylacetate (368). [00716] The title compound 368 was prepared according to the procedure of Example 209, Step 2, using 368.2. MS (ESI): mass calcd. for C 28 H 38 N 6 O 6 , 554.29 m/z found 555.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.68 – 6.56 (m, 1H), 5.21 – 5.01 (m, 2H), 4.50 – 4.41 (m, 1H), 4.32 – 4.22 (m, 2H), 2.39 – 2.37 (m, 2H), 2.26 (d, J = 6.8 Hz, 2H), 1.78 – 1.46 (m, 8H), 1.46 – 1.06 (m, 11H), 1.03 – 0.89 (m, 2H). Example 220. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2- cyclohexylacetate (Compound 369). Step 1. Synthesis of (6aR,8R,9R,9aS)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -9-hydroxy-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisi locine-8-carbonitrile (369.1). [00717] To a solution of 6.3 (4 g, 0.013 mol) and imidazole(5.6 g, 0.082 mol) in DMF(40 mL) was added chloro[(chlorodiisopropylsilyl)oxy]diisopropylsilane (5.19 g, 0.016 mmol) at 0 o C,the mixture was stirred at 25 o C for 4 h. The reaction was extracted with EA (10 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE from 0% to 30%) to obtain 369.1 as a white solid (5.00 g, 65% yield). MS (ESI): mass calcd. for C24H39N5O5Si2, 533.78, m/z found 534.2 [M+H] + . Step 2. Synthesis of (6aR,8R,9R,9aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -8-cyano-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisi locin-9-yl 2-cyclohexylacetate (369.2). [00718] The compound 369.2 was prepared according to the procedure of Example 19, Step 1, using 369.1 and 2-cyclohexylacetic acid. MS (ESI): mass calcd. for C 32 H 51 N 5 O 6 Si 2 , 657.96, m/z found 658.3 [M+H] + .1H NMR (400 MHz, DMSO) δ 8.01 (d, J = 18.8 Hz, 2H), 7.89 (s, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 5.87 (d, J = 5.2 Hz, 1H), 4.54 (dd, J = 8.8, 5.2 Hz, 1H), 4.14 (t, J = 10.4 Hz, 2H), 4.01 – 3.91 (m, 1H), 2.35 (d, J = 6.4 Hz, 2H), 1.88 – 1.72 (m, 3H), 1.62 –1.60 (m, 3H), 1.23 – 1.09 (m, 3H), 1.08 – 0.84 (m, 30H). Step 3. Synthesis of (6aR,8R,9R,9aR)-8-(4-(((acetoxymethoxy)carbonyl)amino)pyrrol o[2,1- f][1,2,4]triazin-7-yl)-8-cyano-2,2,4,4-tetraisopropyltetrahy dro-6H-furo[3,2- f][1,3,5,2,4]trioxadisilocin-9-yl 2-cyclohexylacetate (369.3). [00719] The compound 369.3 was prepared according to the procedure of Example 206, Step 1, using 369.2 and ((chlorocarbonyl)oxy)methyl acetate. MS (ESI): mass calcd. for C36H55N5O10Si2, 774.03, m/z found 774.3 [M+H] + . Step 4. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2- cyclohexylacetate (Compound 369). [00720] The compound 369 was prepared according to the procedure of Example 97, Step 1, using 369.3. MS (ESI): mass calcd. for C24H29N5O9, 531.52, m/z found 532.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 8.43 (s, 1H), 7.31 –7.30 (m, 1H), 7.11 –7.10 (m, 1H), 6.58 (d, J = 6.8 Hz, 1H), 5.81 (s, 2H), 5.26 – 5.14 (m, 1H), 5.04 (t, J = 5.6 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.28 –4.26 (m, 1H), 3.75 – 3.43 (m, 2H), 2.27 (d, J = 6.8 Hz, 2H), 2.12 (s, 3H), 1.85 – 1.58 (m, 6H), 1.28 – 1.09 (m, 3H), 0.96 –0.90 (m, 2H). Example 221. Synthesis of (((7-((2R,3R,4S,5R)-2-cyano-4-(2-cyclohexylacetoxy)-3-hydrox y-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)carbamoyl)oxy)methyl pivalate (Compound 370). Step 1. Synthesis of (((7-((6aR,8R,9R,9aR)-8-cyano-9-(2-cyclohexylacetoxy)-2,2,4, 4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisi locin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)carbamoyl)oxy)methyl pivalate (370.1). [00721] The compound 370.1 was prepared according to the procedure of Example 206, Step 1, using 369.2 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C39H61N5O10Si2, 816.11, m/z found 816.3[M+H] + . Step 2. Synthesis of (((7-((2R,3R,4S,5R)-2-cyano-4-(2-cyclohexylacetoxy)-3-hydrox y-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]tri azin-4-yl)carbamoyl)oxy)methyl pivalate (Compound 370). [00722] The title compound 370 was prepared according to the procedure of Example 97, Step 1, using 370.1. MS (ESI): mass calcd. for C27H35N5O9, 573.60, m/z found 574.3 [M+H] 1H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 8.42 (s, 1H), 7.30 – 7.28 (s, 1H), 7.11 – 7.09 (s, 1H), 6.58 (d, J = 6.4 Hz, 1H), 5.84 (s, 2H), 5.31 – 5.13 (m, 1H), 5.03 (t, J = 5.6 Hz, 1H), 4.94 (t, J = 6.0 Hz, 1H), 4.28 (d, J = 3.6 Hz, 1H), 3.69 – 3.46 (m, 2H), 2.26 (d, J = 6.8 Hz, 2H), 1.88 – 1.70 (m, 3H), 1.62 – 1.58 (m, 3H), 1.25 – 1.10 (m, 12H), 1.02 – 0.91 (m, 2H). Example 222. Synthesis ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (S)-2-amino-3,3-dimethylbutanoate (Compound 371). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoate (371.1). [00723] To a solution of 6.4 (1.50 g, 4.53 mmol) in THF (80 mL) was added (2S)-2-{[(tert- butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (1.35 g, 5.85 mmol), EDCI (2.59 g, 13.5 mmol) and DMAP (1.65 g, 13.5 mmol), the mixture was stirred at 25 ℃ for 16 h. After completion, the mixture was concentrated in vacuo to afford a residue. Then the reaction residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x3). The organic layer was dried over sodium sulphate and concentrated under reduce pressure to afford a crude. The residue was purified by Prep-HPLC [Gradient: 5-40% ACN in water (0.1% FA)] to obtain 371.1 (1.80 g, 69% yield) as a white solid. MS (ESI): mass calcd. for C 26 H 36 N 6 O 7 , 544.26 m/z found 545.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.95 (br s, 3H), 7.09 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 5.44 (d, J = 6.4 Hz, 1H), 4.94 (dd, J = 6.4, 3.2 Hz, 1H), 4.52 (s, 1H), 4.27 – 4.20 (m, 1H), 4.17 – 4.11 (m, 1H), 3.82 (d, J = 8.4 Hz, 1H), 1.64 (s, 3H), 1.40 – 1.26 (m, 1H), 0.87 (s, 9H). Step 2. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoate (371.2). [00724] The title compound 371.2 was prepared according to the procedure of Example 17, Step 1, using 371.1 and TsOH·H 2 O. MS (ESI): mass calcd for C 23 H 32 N 6 O 7 50423 m/z found 505.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.33 (d, J = 6.0 Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.40 – 4.14 (m, 3H), 3.96 – 3.80 (m, 2H), 1.43 – 1.29 (m, 9H), 0.89 (s, 9H). Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoate (371.3). [00725] The title compound 371.3 was prepared according to the procedure of Example 17, Step 2, using 371.2 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C31H44N6O8, 628.32 m/z found 629.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br s, 3H), 7.07 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.88 (d, J = 4.8 Hz, 1H), 6.66 – 6.59 (m, 1H), 5.09 (d, J = 5.2 Hz, 2H), 4.46 (d, J = 4.0 Hz, 1H), 4.33 – 4.25 (m, 2H), 3.84 (d, J = 8.4 Hz, 1H), 2.25 (d, J = 6.4 Hz, 2H), 1.80 – 1.68 (m, 3H), 1.66 – 1.55 (m, 3H), 1.37 (s, 7H), 1.29 – 1.04 (m, 5H), 1.02 – 0.91 (m, 2H), 0.85 (s, 9H). Step 4. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (S)-2-amino-3,3-dimethylbutanoate (371). [00726] The title compound 371 was prepared according to the procedure of Example 209, Step 2, using 371.3. MS (ESI): mass calcd. for C28H38N6O6, 528.27 m/z found 529.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.62 (d, J = 6.0 Hz, 1H), 5.13 – 5.07 (m, 2H), 4.49 – 4.44 (m, 1H), 4.37 – 4.17 (m, 2H), 2.96 (s, 1H), 2.25 (d, J = 6.4 Hz, 2H), 1.81 – 1.55 (m, 6H), 1.31 – 1.07 (m, 3H), 1.00 – 0.89 (m, 2H), 0.86 – 0.78 (m, 9H). Example 223. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3- (2-cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl L-phenylalaninate (Compound 372). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (tert-butoxycarbonyl)-L-phenylalaninate (372.1). [00727] The title compound 372.1 was prepared according to the procedure of Example 19, Step 1, using 6.4 and (tert-butoxycarbonyl)-L-phenylalanine. MS (ESI): mass calcd. for C29H34N6O7, 578.63, m/z found 579.2 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L-phenylalaninate (372.2). [00728] The title compound 372.2 was prepared according to the procedure of Example 17, Step 1, using 372.2. MS (ESI): mass calcd. for C26H30N6O7, 538.56, m/z found 539.2 [M+H] + . Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (tert-butoxycarbonyl)-L- phenylalaninate (372.3). [00729] The title compound 372.3 was prepared according to the procedure of Example 19, Step 1, using 372.2 and 2-cyclohexylacetic acid. MS (ESI): mass calcd. for C34H42N6O8, 662.74, m/z found 663.4 [M+H] + . Step 4. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl L-phenylalaninate (Compound 372). [00730] Compound 372 was prepared according to the procedure of Example 19, Step 2, using 372.3. MS (ESI): mass calcd. for C29H34N6O6, 562.63, m/z found 563.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (brs, 3H), 7.22 – 7.09 (m, 5H), 6.93 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 5.08 –5.05 (m, 2H), 4.44 (dd, J = 8.0, 4.0 Hz, 1H), 4.22 – 4.17 (m, 2H), 3.55 (t, J =6.4 Hz, 1H), 2.75 – 2.69 (m, 2H), 2.27 (d, J = 6.8 Hz, 2H), 1.83 – 1.59 (m, 6H), 1.25 – 1.07 (m, 3H), 1.00 – 0.89 (m, 2H). Example 224. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5- cyano-3-(2-cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl) methyl (S)-2-amino-3,3- dimethylbutanoate (Compound 373). Step 1. Synthesis of ((2R,3R,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3-(2- cyclohexylacetoxy)-4-((trimethylsilyl)oxy)tetrahydrofuran-2- yl)methyl (S)-2-((tert- butoxycarbonyl)amino)-3,3-dimethylbutanoate (373.1). [00731] The title compound 373.1 was prepared according to the procedure of Example 209, Step 1, using 371.3 and acetyl chloride. MS (ESI): mass calcd. for C 36 H 54 N 6 O 9 Si, 742.37 m/z found 743.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.38 (s, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.19 – 7.06 (m, 2H), 5.31 (d, J = 5.2 Hz, 1H), 5.18 (t, J = 5.2 Hz, 1H), 4.54 (dd, J = 9.2, 4.8 Hz, 1H), 4.36 (s, 2H), 3.88 (d, J = 8.4 Hz, 1H), 2.39 (s, 3H), 2.29 – 2.21 (m, 2H), 1.80 – 1.67 (m, 3H), 1.70 – 1.54 (m, 3H), 1.45 – 1.30 (m, 9H), 1.23 – 1.05 (m, 3H), 1.04 – 0.92 (m, 2H), 0.87 (s, 9H), -0.03 (s, 9H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3-(2- cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (S)-2-amino-3,3-dimethylbutanoate (373). [00732] The title compound 373 was prepared according to the procedure of Example 209, Step 2, using 373.1. MS (ESI): mass calcd. for C28H38N6O7, 570.28 m/z found 571.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.40 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.80 – 6.68 (m, 1H), 5.17 – 5.11 (m, 1H), 5.09 – 5.04 (m, 1H), 4.54 – 4.48 (m, 1H), 4.33 – 4.22 (m, 2H), 2.98 – 2.96 (m, 1H), 2.40 (s, 3H), 2.28 – 2.25 (m, 2H), 1.80 – 1.69 (m, 3H), 1.67 – 1.56 (m, 3H), 1.27 – 1.08 (m, 3H), 1.00 – 0.89 (m, 2H), 0.85 – 0.79 (m, 9H). Example 225. Synthesis of (((7-((2R,3R,4S,5R)-5-(((L-phenylalanyl)oxy)methyl)-2-cyano- 4-(2- cyclohexylacetoxy)-3-hydroxytetrahydrofuran-2-yl)pyrrolo[2,1 -f][1,2,4]triazin-4- yl)carbamoyl)oxy)methyl pivalate (Compound 374). Step 1. Synthesis of (((7-((2R,3R,4R,5R)-5-((((tert-butoxycarbonyl)-L-phenylalany l)oxy)methyl)-2- cyano-4-(2-cyclohexylacetoxy)-3-((trimethylsilyl)oxy)tetrahy drofuran-2-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)carbamoyl)oxy)methyl pivalate (374.1). [00733] The title compound 374.1 was prepared according to the procedure of Example 206, Step 1, using 372.3 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C 44 H 60 N 6 O 12 Si, 893.08, m/z found 893.4 [M+H] + . Step 2. Synthesis of (((7-((2R,3R,4S,5R)-5-(((L-phenylalanyl)oxy)methyl)-2-cyano- 4-(2- cyclohexylacetoxy)-3-hydroxytetrahydrofuran-2-yl)pyrrolo[2,1 -f][1,2,4]triazin-4- yl)carbamoyl)oxy)methyl pivalate (Compound 374). [00734] Compound 374.1 was prepared according to the procedure of Example 19, Step 2, using 374.1. MS (ESI): mass calcd. for C36H44N6O10, 720.78, m/z found 721.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.27 (d, J = 4.0 Hz, 1H), 7.18 – 7.06 (m, 6H), 6.69 (d, J = 6.0 Hz, 1H), 5.83 (s, 2H), 5.15 – 4.97 (m, 2H), 4.48 –4.46 (m, 1H), 4.25 – 4.17 (m, 2H), 3.55 (t, J = 6.8 Hz, 1H), 2.82 – 2.70 (m, 2H), 2.27 (d, J = 6.8 Hz, 2H), 1.87 – 1.57 (m, 7H), 1.26 –1.17 (m, 11H), 0.99 – 0.90 (m,2H). Example 226. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)tetrahydrofuran-2- yl)methyl 2-cyclohexyl-2-methylpropanoate (Compound 375). Ste p 1. Synthesis of (((7-((2R,3R,4R,5R)-2-cyano-5-(((2-cyclohexyl-2-methylpropan oyl)oxy)methyl)- 3,4-bis((trimethylsilyl)oxy)tetrahydrofuran-2-yl)pyrrolo[2,1 -f][1,2,4]triazin-4- yl)carbamoyl)oxy)methyl pivalate (375.1). [00735] The title compound 375.1 was prepared according to the procedure of Example 206, Step 1, using 269 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C35H55N5O9Si2, 746.02, m/z found 746.4 [M+H] + . Step 2. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)tetrahydrofuran-2- yl)methyl 2-cyclohexyl-2-methylpropanoate (Compound 375). [00736] The title compound 375 was prepared according to the procedure of Example 19, Step 2, using 375.1. MS (ESI): mass calcd. for C 29 H 39 N 5 O 9 , 601.66, m/z found 602.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.27 (s, 1H), 8.40 (s, 1H), 7.31 – 7.30 (m, 1H), 7.05 – 7.04 (m, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.84 (s, 2H), 5.43 (d, J = 6.0 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.34 – 4.25 (m, 1H), 4.19 (d, J = 3.6 Hz, 2H), 3.99 –3.96 (m, 1H), 1.67 – 1.47 (m, 3H), 1.45 – 1.29 (m, 3H), 1.17 (s, 9H), 1.05 – 0.78 (m, 11H). Example 227. Synthesis of ((2R,3S,4R,5R)-5-(4-((butoxycarbonyl)amino)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-cyclohexyl-2- methylpropanoate (Compound 379). [00737] The title compound was prepared according to the procedure of Example 57, using 2- cyclohexyl-2-methylpropanoyl chloride. MS (ESI): mass calcd. for C27H37N5O7, 543.27, m/z found 544.2 [M+H] + . Example 228. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((((5-methyl-2-oxo-1,3- dioxol-4- yl)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl) -2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (Compound 383). [00738] The title compound was prepared according to the procedure of Example 206, using (5-methyl- 2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate in Step 1. MS (ESI): mass calcd. for C 31 H 32 N 6 O 11 , 664.21, m/z found 665.2 [M+H] + . Example 229. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5- (4-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino )pyrrolo[2,1-f][1,2,4]triazin-7- yl)tetrahydrofuran-3-yl L-valinate (Compound 385). [00739] The title compound was prepared according to the procedure of Example 209, using (5-methyl- 2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate in Step 1. MS (ESI): mass calcd. for C 31 H 38 N 6 O 11 , 670.26, m/z found 671.2 [M+H] + . Example 230. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydr oxy-5- (4-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino )pyrrolo[2,1-f][1,2,4]triazin-7- yl)tetrahydrofuran-3-yl L-valinate (Compound 392). [00740] The title compound was prepared according to the procedure of Example 18, using Compound 411.2 in Step 1. MS (ESI): mass calcd. for C 26 H 36 N 6 O 6 , 528.27, m/z found 529.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.93 (br s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.58 (d, J = 6.0 Hz, 1H), 5.19 – 5.14 (m, 1H), 5.11 (t, J = 6.0 Hz, 1H), 4.45 (dd, J = 8.8, 4.4 Hz, 1H), 4.32 – 4.18 (m, 2H), 2.96 (s, 1H), 2.26 (d, J = 6.8 Hz, 2H), 1.78 – 1.70 (m, 3H), 1.69 – 1.54 (m, 3H), 1.29 – 1.08 (m, 3H), 1.28 – 1.10 (m, 2H), 0.85 – 0.74 (m, 9H). Example 231. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)tetrahydrofuran-2- yl)methyl (S)-2-amino-3,3-dimethylbutanoate (Compound 395).
[00741] The title compound was prepared according to the procedure of Example 218, using Compound 411.2 in Step 1. MS (ESI): mass calcd. for C 25 H 34 N 6 O 9 , 562.24, m/z found 563.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.29 (d, J = 4.4 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.84 (s, 2H), 5.46 (d, J = 5.6 Hz, 1H), 4.72 – 4.67 (m, 1H), 4.31 – 4.23 (m, 3H), 3.94 (d, J = 4.4 Hz, 1H), 3.07 (s, 1H), 1.17 (s, 9H), 0.84 (s, 9H). Example 232. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-2- ((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (S)-2-amino-3,3-dimethylbutanoate (Compound 397). [00742] The title compound was prepared according to the procedure of Example 16, using (R)-Boc- tert-leucine in Step 1. MS (ESI): mass calcd. for C 26 H 36 N 6 O 6 , 528.27, m/z found 529.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.98 – 7.93 (m, 3H), 6.94 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.63 – 6.60 (m, 1H), 5.22 – 4.98 (m, 2H), 4.46 (dd, J =8.4, 4.4 Hz, 1H), 4.30 (dd, J = 12.4, 3.6 Hz, 1H), 4.25 – 4.15 (m, 1H), 3.08 (s, 1H), 2.15 (dd, J = 6.8, 3.6 Hz, 2H), 1.58 – 1.57 (m, 6H), 1.11 – 1.08 (m, 3H), 1.00 – 0.77 (m, 11H). Example 233. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy )methyl)tetrahydrofuran-3-yl (S)-2- amino-3,3-dimethylbutanoate (Compound 399).
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4-hydroxy- 2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoate (399.1). [00743] The title compound was prepared according to the procedure of Example 212, using Compound 11 and (R)-Boc-tert-leucine. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy )methyl)tetrahydrofuran-3-yl (S)-2- ((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoate (399.2). [00744] The title compound was prepared from Compound 399.1 according to the procedure of Example 206, Step 1. Step 3. Synthesis of (2R,3S,4R,5R)-5-(4-(((acetoxymethoxy)carbonyl)amino)pyrrolo[ 2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy )methyl)tetrahydrofuran-3-yl (S)-2- amino-3,3-dimethylbutanoate (Compound 399). [00745] The title compound was prepared according to the procedure of Example 206, Step 2. MS (ESI): mass calcd. for C 30 H 34 N 6 O 10 , 638.23, m/z found 639.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.42 – 7.14 (m, 6H), 7.04 (d, J = 4.4 Hz, 1H), 6.70 (d, J = 6.4 Hz, 1H), 5.81 (s, 2H), 5.20 – 5.10 (m, 1H), 5.04 (t, J= 6.0 Hz, 1H), 4.51 (dd, J = 8.0, 4.4 Hz, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.25 (dd, J = 12.4, 5.2 Hz, 1H), 3.66 (s, 2H), 3.11 (s, 1H), 2.12 (s, 3H), 0.93 (s, 9H). Example 234. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2, 1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydro furan-3-yl (S)-2-amino-3,3- dimethylbutanoate (Compound 401). [00746] The title compound was prepared according to the procedure of Example 198, utilizing Compound 399.1 in Step 2. MS (ESI): mass calcd. for C 30 H 36 N 6 O 7 , 592.26, m/z found 593.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H) 841 (s 1H) 732 – 715 (m 6H) 708 (d J = 4.8 Hz, 1H), 6.71 (d, J = 6.4 Hz, 1H), 5.17 – 5.08 (m, 1H), 5.05 (t, J= 6.0 Hz, 1H), 4.52 (dd, J = 8.0, 4.4 Hz, 1H), 4.33 (dd, J = 12.0, 3.6 Hz, 1H), 4.25 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s, 2H), 3.18 – 3.11 (m, 1H), 3.09 (s, 1H), 1.16 (d, J = 6.8 Hz, 6H), 0.93 (s, 9H). Example 235. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2, 1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydro furan-3-yl (S)-2-amino-3,3- dimethylbutanoate (Compound 402). [00747] The title compound was prepared according to the procedure of Example 224, utilizing ((chlorocarbonyl)oxy)methyl acetate in place of acetyl chloride in Step 1. MS (ESI): mass calcd. for C30H40N6O10, 644.28, m/z found 645.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.73 (d, J = 6.4 Hz, 1H), 5.81 (s, 2H), 5.22 – 5.09 (m, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.51 (dd, J = 8.4, 4.4 Hz, 1H), 4.33 – 4.22 (m, 2H), 3.00 – 2.94 (m, 1H), 2.35 – 2.24 (m, 2H), 2.12 (s, 3H), 1.83 – 1.68 (m, 3H), 1.67 – 1.56 (m, 3H), 1.27 – 1.08 (m, 3H), 1.01 – 0.92 (m, 2H), 0.86 – 0.75 (m, 9H). Example 236. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-isobutyramidopyrrolo[2, 1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydro furan-3-yl (S)-2-amino-3,3- dimethylbutanoate (Compound 409). Step 1: Synthesis of ((2R,3R,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5-cyano-3,4- bis((trimethylsilyl)oxy)tetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (409.1) [00748] The compound 409.1 was prepared according to the procedure of Example 206, Step 1, using 10 and butyryl chloride. MS (ESI): mass calcd. for C30H47N5O6Si2, 629.31, m/z found 630.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.38 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 4.93 (d, J = 4.0 Hz, 1H), 4.41 (dd, J = 12.4, 3.2 Hz, 1H), 4.28 (dt, J = 7.2, 3.6 Hz, 1H), 4.18 – 4.09 (m, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.15 (d, J = 6.8 Hz, 2H), 1.70 – 1.54 (m, 8H), 1.17 – 1.01 (m, 3H), 0.91 (dt, J = 12.8, 7.2 Hz, 5H), 0.17 – 0.04 (m, 18H). Step 2: Synthesis of ((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (409.2) [00749] Compound 409.2 was prepared according to the procedure of Example 209, Step 2, using 409.1. MS (ESI): mass calcd. for C24H31N5O6, 485.23 m/z found 486.2 [M+H] + . Step 3. Synthesis of (((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-5-cyano-2- ((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl) oxy)methyl pivalate (409). [00750] The title compound was prepared according to the procedure of Example 24, Step 1, using 409.2 and iodomethyl pivalate. MS (ESI): mass calcd. for C 30 H 41 N 5 O 8 , 599.30 m/z found 600.3 [M+H]+. 1 H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.38 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.65 (d, J = 6.4 Hz, 1H), 5.36 (d, J = 6.4 Hz, 1H), 5.29 (d, J = 6.4 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.39 – 4.37 (m, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.18 – 4.08 (m, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.10 (dd, J = 6.8, 2.8 Hz, 2H), 1.69 – 1.52 (m, 9H), 1.12 – 1.10 (s, 11H), 0.94 (t, J = 7.6 Hz, 3H), 0.85 – 0.80 (m, 2H). Example 237. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (S)-2-amino-3,3-dimethylbutanoate (Compound 410). [00751] The title compound was prepared according to the procedure of Example 132, using (R)-Boc- tert-leucine in Step 1. MS (ESI): mass calcd. for C18H24N6O5, 404.18, m/z found 405.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.40 – 6.30 (m, 1H), 5.45 – 5.35 (m, 1H), 4.71 (s, 1H), 4.30 – 4.19 (m, 3H), 3.96 – 3.92 (m, 1H), 3.01 (s, 1H), 0.84 (s, 9H). Example 238. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (R)-2-amino-3,3-dimethylbutanoate (Compound 411).
[00752] The title compound was prepared according to the procedure of Example 132, using (S)-Boc- tert-leucine in Step 1. MS (ESI): mass calcd. for C18H24N6O5, 404.18, m/z found 405.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 6.50 – 6.20 (m, 1H), 5.50 – 5.25 (m, 1H), 4.72 (d, J = 5.2 Hz, 1H), 4.30 – 4.18 (m, 1H), 3.99 – 3.94 (m, 1H), 3.07 – 3.00 (m, 1H), 0.85 (s, 9H). Example 239. Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5- (((2-cyclohexyl-2-methylpropanoyl)oxy)methyl)tetrahydrofuran -3,4-diyl diacetate (Compound 412). [00753] To a solution of 269 (600 mg, 1.35 mmol) in NMP (3 mL), 4M HCl solution in 1-4 dixane (0.7 mL, 4 M) was added and stirred at 20 ℃ for 15 minutes. The reaction mixture was cooled at 0 ℃ and acetyl chloride (2.89 mL, 40.6 mmol) was added at once. The reaction was stirred at 20 ℃ for 16 h. The reaction was diluted with ACN (1 mL) and purified by prep-HPLC (column: Gemini - C18150 × 21.2 mm, 5um; mobile phase: ACN - H 2 O (0.1% FA); gradient: 20% – 65%) to obtain 413 (48.25 mg, 6.6% yield) as a white solid. MS (ESI): mass calcd. for C26H33N5O7, 527.24 m/z found 528.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.14 – 7.82 (m, 3H), 6.94 (d, J = 4.8 Hz, 1H), 6.76 (d, J = 4.8 Hz, 1H), 6.04 (d, J = 6.0 Hz, 1H), 5.42 – 5.39 (m, 1H), 4.64 (q, J = 3.6 Hz, 1H), 4.31 – 4.20 (m, 2H), 2.12 (d, J = 1.6 Hz, 6H), 1.61 – 1.49 (m, 3H), 1.46 – 1.34 (m, 3H), 1.15 – 0.93 (m, 9H), 0.90 – 0.78 (m, 2H). Example 240. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3- (2-cyclohexylacetoxy)-4-hydroxytetrahydrofuran-2-yl)methyl (S)-2-acetamido-3,3- dimethylbutanoate (Compound 413). [00754] The title compound 413 was prepared according to the procedure of Example 17, Step 2, using 371. MS (ESI): mass calcd. for C28H38N6O7, 570.28, m/z found 571.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.07 (d, J = 8.4 Hz, 1H), 7.92 (br s, 3H), 6.92 (d, J = 4.4 Hz, 1H), 6.88 (d, J = 4.8 Hz, 1H), 6.65 – 6.60 (m, 1H), 5.13 – 5.01 (m, 2H), 4.48 – 4.45 (m, 1H), 4.30 (d, J = 4.4 Hz, 2H), 4.15 (d, J = 8.4 Hz, 1H), 2.25 (d, J = 6.8 Hz, 2H), 1.89 (s, 3H), 1.83 – 1.57 (m, 6H), 1.27 – 1.09 (m, 3H), 0.98 – 0.93 (m, 2H), 0.86 (s, 9H) Example 241. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-cyclohexylacetamido)pyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)met hyl (S)-2-amino-3,3-dimethylbutanoate (Compound 414). Step 1. Synthesis of ((3aR,4R,6R,6aR)-6-cyano-6-(4-(2-cyclohexylacetamido)pyrrolo [2,1- f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3 ]dioxol-4-yl)methyl (S)-2-((tert- butoxycarbonyl)amino)-3,3-dimethylbutanoate (414.1). [00755] The title compound 414.1 was prepared according to the procedure of Example 210, Step 1, using 371.7 and 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C34H48N6O8, 668.35 m/z found 669.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.43 (s, 1H), 7.24 (d, J = 4.8 Hz, 1H), 7.14 – 7.08 (m, 2H), 5.44 (d, J = 6.4 Hz, 1H), 4.94 (dd, J = 6.4, 2.8 Hz, 1H), 4.61 – 4.55 (m, 1H), 4.24 (dd, J = 12.0, 4.4 Hz, 1H), 4.13 (dd, J = 12.0, 6.8 Hz, 1H), 3.80 (d, J = 8.4 Hz, 1H), 2.57 (d, J = 6.8 Hz, 2H), 1.88 – 1.78 (m, 1H), 1.76 – 1.67 (m, 3H), 1.66 – 1.57 (m, 5H), 1.38 – 1.32 (m, 11H), 1.30 – 1.21 (m, 4H), 1.05 – 0.95 (m, 2H), 0.86 (s, 9H). Step 2. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-cyclohexylacetamido)pyrrolo[2 ,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)met hyl (S)-2-amino-3,3-dimethylbutanoate (414). [00756] The title compound 416 was prepared according to the procedure of Example 210, Step 2, using 414.1. MS (ESI): mass calcd. for C26H36N6O6, 528.27 m/z found 529.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.39 (s, 1H), 7.26 (d, J = 4.8 Hz, 1H), 7.09 (d, J = 4.4 Hz, 1H), 6.46 (d, J = 5.6 Hz, 1H), 5.50 – 5.40 (m, 1H), 4.69 (t, J = 4.8 Hz, 1H), 4.32 – 4.19 (m, 3H), 3.97 – 3.90 (m, 1H), 2.99 (s, 1H), 2.57 (d, J = 6.8 Hz, 2H), 1.88 – 1.78 (m, 1H), 1.77 – 1.57 (m, 5H), 1.31 – 1.09 (m, 3H), 1.06 – 0.94 (m, 2H), 0.90 – 0.80 (m, 9H). Example 242. Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-3- (propionyloxy)tetrahydrofuran-2-yl)methyl (S)-2-amino-3,3-dimethylbutanoate (Compound 415). Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-4- hydroxy-3-(propionyloxy)tetrahydrofuran-2-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoate (415.1). [00757] The title compound 415.1 was prepared according to the procedure of Example 17, Step 2, using 371.2 and propionyl chloride. MS (ESI): mass calcd. for C 26 H 36 N 6 O 8 , 560.26 m/z found 561.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (br s, 3H), 7.07 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H), 5.13 – 5.08 (m, 2H), 4.50 – 4.42 (m, 1H), 4.30 (d, J = 4.4 Hz, 2H), 3.84 (d, J = 8.4 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.42 – 1.20 (m, 9H), 1.07 (t, J = 7.6 Hz, 3H), 0.86 (s, 9H). Step 2. ((2R,3R,4R,5R)-5-cyano-5-(4-((((pivaloyloxy)methoxy)carbonyl )amino)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3-(propionyloxy)-4-((trimethylsilyl)o xy)tetrahydrofuran-2-yl)methyl (S)-2- ((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoate (415.2). [00758] The title compound 415.2 was prepared according to the procedure of Example 209, Step 1, using 417.1 and ((chlorocarbonyl)oxy)methyl pivalate. MS (ESI): mass calcd. for C36H54N6O12Si, 790.36 m/z found 791.3 [M+H] + . Step 3. Synthesis of ((2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4- ((((pivaloyloxy)methoxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-3- (propionyloxy)tetrahydrofuran-2-yl)methyl (S)-2-amino-3,3-dimethylbutanoate (415). [00759] The title compound 415 was prepared according to the procedure of Example 209, Step 2, using 415.2. MS (ESI): mass calcd. for C28H38N6O10, 618.26 m/z found 619.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 7.20 – 7.18 (m, 1H), 7.05 – 7.02 (m, 1H), 6.68 (d, J = 6.4 Hz, 1H), 5.81 (s, 2H), 5.16 (t, J = 5.2 Hz, 1H), 5.07 (t, J = 5.6 Hz, 1H), 4.51 – 4.48 (m, 1H), 4.32 – 4.21 (m, 2H), 2.96 (s, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.17 (s, 9H), 1.08 (t, J = 7.6 Hz, 3H), 0.81 (s, 9H). [00760] Compounds 11, 13, 17-26, 28-32, 41, 42, 44-48, 53, 57, 60, 62, 63, 65, 68, 70, 71, 96, 174, 175, 177, 178, 183, 187, 195, 207, 211, 227, and 235 were prepared in a similar manner to the preceding Example procedures, and MS (ESI) data are shown in Table 1. EXAMPLE I: Oral Composition of a Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb), and (VIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00761] To prepare a pharmaceutical composition for oral delivery, 400 mg of compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and the following ingredients are mixed intimately and pressed into single scored tablets. Tablet Formulation Ingredient Quantity per tablet (mg) compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 [00762] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Capsule Formulation Ingredient Quantity per capsule (mg) compound 200 lactose spray dried 148 magnesium stearate 2 EXAMPLE II: Evaluation of cellular permeability in Caco-2 cell monolayers. [00763] The bidirectional permeability of compounds across the Caco-2 cell monolayer was assessed. The Caco-2 model is a widely used in vitro model for small intestinal absorption and potential for efflux. [00764] Cell culture. Caco-2 cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS), 1% Penicillin-Streptomycin and 1% MEM NEAA. The cells were incubated at 37 °C, 5% CO2/95% air and saturated humidity. After reaching 80-90% confluency, the cells were gently detached with trypsin. Cells at passage 39 were seeded on the 24-well BD insert system at the density of 8×104 cells/cm2 and cultured for 19 days with medium changed every 2-3 days. Measure the transepithelial electrical resistance (TEER) value of each well. The wells can be used only when their TEER values are greater than 600 Ohms/cm 2 . [00765] Transport assay. After removing the cell culture medium from the 24-well insert plate, the cells were rinsed with warm transport buffer. Appropriate dosing and receiving solutions were applied to the donor and receiver chambers to initiate the transport assay in apical to basolateral (A to B) or basolateral to apical (B to A) directions (500 and 1300 µL for apical and basolateral wells, respectively). Duplicate wells in each direction were used for the test compound and control compound. The plate was incubated in CO 2 incubator at 37 °C, with 5% CO 2 /95% air and saturated humidity without shaking. The sample after 10-minute incubation was used as the T0 sample, and the sample after 90-minute incubation was used as the T90 sample. T0 and T90 samples were collected from the donor and receiver side of each well at the designed timepoint, mixed with the transport buffer and acetonitrile/MeOH (1:1, v/v) and the internal standard for LC/MS/MS analysis. All samples were vortexed and centrifuged at 4000 rpm at 4 °C for 15 minutes, diluted with pure water and stored at 4 °C before bioanalysis by LC/MS/MS. [00766] Sample analysis. The concentrations of test compounds and control compounds in Caco-2 cells were quantitatively determined by LC/MS/MS method after protein precipitation. [00767] Calculations. The apparent permeability (Papp, cm/s), efflux ratio (ER) and recovery parameters were calculated for Caco-2 drug transport assay using the following equations: P a E P app(Ato B ) where VR is the solution volume in the receiver chamber (0.4 mL on the apical side, 1.2 mL on the basolateral side); Area is the surface area for the insert membrane, i.e., 0.3 cm 2 for the area of the monolayer; Time is incubation time, expressed in seconds, i.e., 5400 s (90 min) for the current experiment; C0 is the initial concentration of test compound or peak area ratio of control compounds in the donor chamber (µM); VD is the volume in the donor chambers (0.4 mL on the apical side, 1.2 mL on the basolateral side); C D and C R are the final concentrations of test compounds or peak area ratio of control compounds in donor and receiver chambers, respectively. [00768] Data for representative compounds is shown in Table 2. Compounds with Papp < 1.0 are classified as low permeability, Papp between 1-10 are classified as medium permeability, and Papp ≥ 10 are classified as high permeability. An efflux ratio (ER) > 2 indicates the compounds are poten l substrates for intestinal cell efflux transporters. Table 2. Bidirectional Caco-2 permeability assay results. Compound No. P app , A-B (x10 -6 cm s -1 ) Papp, B-A, (x10 -6 cm s -1 ) ER 6 . . . 70 1.8 1.6 0.82 Compound No. P app , A-B (x10 -6 cm s -1 ) Papp, B-A, (x10 -6 cm s -1 ) ER 7 2 . . . 257 0.03 14 46 Compound No. P app , A-B (x10 -6 cm s -1 ) Papp, B-A, (x10 -6 cm s -1 ) ER 2 3 . . 355 1.5 049 0.33 Compound No. P app , A-B (x10 -6 cm s -1 ) Papp, B-A, (x10 -6 cm s -1 ) ER 3 . . . EXAMPLE III: Evaluation of oral bioavailability in Sprague-Dawley rats. [00769] The single dose pharmacokinetics of Example Compounds were evaluated in fasted male Sprague-Dawley rats following oral gavage. Compounds were be dosed as solutions or acceptable suspensions in vehicles generally-regarded as safe for in vivo studies. Groups of three rats per compound were utilized, and blood samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24 h post-dose, stored on ice prior to plasma preparation by centrifugation at 4 °C at 6000 rpm for 5 min. Plasma samples were stored at -80 °C. Concentrations of Example Compounds and corresponding nucleosides resulting from metabolic processing were determined using ultra-high performance liquid chromatography-triple- quadrupole mass spectrometry, with an internal standard. Pharmacokinetic parameters were derived from the resulting plasma concentration/time graphs, and include the following: plasma half-life (t1/2), time to maximum plasma concentration (T max ), maximum plasma concentration (C max ), area under the curve of the plasma concentration/time graph (AUClast, through last timepoint obtained, and AUCInf, including the extrapolated area), and mean residence time (MRTInf). The resulting AUCInf for the resulting nucleosides were be compared with that resulting from intravenous bolus administration of the corresponding nucleosides in three rats, d l bi il bilit (F %) b l l ted as AUCinf,PO ^^ ^^ ^^ ^^ ( ^^ ^^) ^^ ^^ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^) ^^ = × × AUCinf,IV ) [00770] Rat pharmacokinetic parameters f shown in Table 3. Bioavailabilities were calculated using the following AUCinf values following 3 mg/kg IV dosing of parent nucleosides: Compounds 6-15, 18, 20, 25, 29-32, 41, and 44-47 used 2110 ng*h/mL; Compounds 3, 180, 221, and 254 used 2069 ng*h/mL. Table 3. Pharmacokinetic parameters following oral dosing of 10 mg/kg in Sprague-Dawley rats. Cmax and AUCinf derived for parent nucleosides, and formula weight-corrected bioavailabilities of Compounds are shown. Com o nd N mber C (n /mL) AUC (n *h/mL) F (%) 289 606 2020 43
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