DONG QING (US)
TRZOSS LYNNIE (US)
VA PORINO JINJO (US)
KALDOR STEPHEN W
WO2021013735A1 | 2021-01-28 | |||
WO2009076512A1 | 2009-06-18 | |||
WO2022225934A1 | 2022-10-27 |
CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein: R1 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR2; R2 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or R1 and R2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, fluoro, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; n is 1 or 2; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon or adjacent carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; p is 0-4; W is absent, -C(R9)2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NRW)-, or -NRW-; each R9 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R9 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; RW is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R10 is independently deuterium, 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-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; q is 0-4; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and 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 deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom form an oxo; pro 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, or cycloalkyl. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is C1-C6alkyl or cycloalkyl. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is C1alkyl or C3-C6alkyl. 5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is cycloalkyl. 6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is methyl or ethyl. 7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is ethyl. 8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is halogen. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is N. 10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is CR2. 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2 is hydrogen or C1-C6alkyl. 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2 is hydrogen. 14. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 and R2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. 15. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II), wherein: Ring B taken with X1 and X2 is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X1 is C, CH, or N; X2 is C, CH, or N; each R11 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; m is 0-3; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, fluoro, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; n is 1 or 2; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon or adjacent carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; p is 0-4; W is absent, -C(R9)2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NRW)-, or -NRW-; each R9 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R9 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; RW is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R10 is independently deuterium, 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-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; q is 0-4; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and 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 deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, - N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, - C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R on the same atom form an oxo. 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B taken with X1 and X2 is a 5-membered heterocycloalkyl. 17. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B taken with X1 and X2 is a 5-membered heteroaryl. 18. The compound of any one of claims 15-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X1 is C. 19. The compound of any one of claims 15-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X1 is CH. 20. The compound of any one of claims 15-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X1 is N. 21. The compound of any one of claims 15-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X2 is C. 22. The compound of any one of claims 15-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X2 is CH. 23. The compound of any one of claims 15-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X2 is N. 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N. 25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is CR4. 26. The compound of any one of claims 1-23 or 25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 27. The compound of any one of claims 1-23 or 25 or 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4 is hydrogen or C1-C6alkyl. 28. The compound of any one of claims 1-23 or 25-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4 is hydrogen. 29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is N. 30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is CR5. 31. The compound of any one of claims 1-28 or 30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 32. The compound of any one of claims 1-28 or 30 or 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5 is hydrogen or C1-C6alkyl. 33. The compound of any one of claims 1-28 or 30-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5 is hydrogen. 34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6 is hydrogen or C1-C6alkyl. 36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6 is hydrogen. 37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R7 is independently hydrogen, deuterium, fluoro, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R7 is independently hydrogen, deuterium, fluoro, or C1-C6alkyl. 39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R7 is hydrogen. 40. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. 41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1. 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2. 43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R8 is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R8 is independently deuterium, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R8 is independently C1-C6alkyl. 46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R8 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. 47. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R8 on adjacent carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. 48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1-4. 49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2. 50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1. 51. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 2. 52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -C(R9)2-, -O-, or -NRW-. 53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -O- or -NRW-. 54. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NRW)-. 55. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -O-. 56. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -NRW2-. 57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R9 is independently hydrogen, deuterium, fluoro, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R9 is independently hydrogen, deuterium, fluoro, or C1-C6alkyl. 59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R9 is hydrogen. 60. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R9 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. 61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RW is hydrogen or C1-C6alkyl. 62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RW is hydrogen. 63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is cycloalkyl or heterocycloalkyl. 64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is aryl or heteroaryl. 65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl. 66. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl. 67. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- or 6-membered heteroaryl. 68. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-membered heteroaryl. 69. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-membered heteroaryl. 70. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is not . 71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10 is independently deuterium, 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-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; provided that one R10 is not -C(=O)NHCH3. 72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10 is independently deuterium, 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, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. 73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10 is independently deuterium, halogen, -CN, -OH, -ORa, - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. 74. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10 is independently deuterium, halogen, -CN, -OC(=O)NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10 is independently deuterium, halogen, -CN, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. 76. The compound of any one of claims 1-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1-4. 77. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1 or 2. 78. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1. 79. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2. 80. A compound selected from a compound of table 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 81. A pharmaceutical composition comprising a compound of any one of claims 1-79, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. 82. A method of treating cancer in a subject in need thereof, the method comprising administering a compound of any one of claims 1-80, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 83. The method of claim 82, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, or lung cancer. 84. A method of treating a cancer comprising a BRCA1 and/or a BRCA2 mutation in a subject in need thereof, the method comprising administering a compound of any one of claims 1-80, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 85. The method of claim 84, wherein the cancer is bladder cancer, brain & CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterus cancer. |
Example 9 Step 1: Preparation of methyl 5-{[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl]oxy}pyridine-2-carboxylate: [00182] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (373 mg, 2.44 mmol, 1.00 equiv.), PPh 3 (1.28 g, 4.87 mmol, 2.00 equiv.) and tert-butyl (3R,4R)-3-fluoro-4-hydroxypyrrolidine-1- carboxylate (500 mg, 2.44 mmol, 1.00 equiv.) in toluene (10 mL) was added DBAD (1.12 g, 4.87 mmol, 2.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL). The mixture was washed with saturated NaHCO 3 (1x20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford methyl 5- {[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]ox y}pyridine-2-carboxylate (3.5 g, crude). LC- MS: (ES+H, m/z): [M+H] + =341.2. Step 2: Preparation of tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3- yl)oxy)pyrrolidine-1-carboxylate: [00183] To a stirred mixture of methyl 5-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl)oxy)picolinate (3.5 g, crude) in MeOH (30 mL) was added methylamine (10 mL, 25-30%wt in water) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was added saturated NH4Cl (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (1x50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (3R,4S)-3-fluoro-4-((6- (methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (2.2 g, crude). LC-MS: (ES+H, m/z): [M+H] + =340.2. Step 3: Preparation of 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamid e, HCl salt: [00184] To a stirred solution of tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3- yl)oxy)pyrrolidine-1-carboxylate (2.2 g, crude) in DCM (20 mL) were added HCl(gas)in 1,4-dioxane (10 mL, 4M) dropwise at room temperature. The resulting mixture was stirred for 30min at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with DCM (20 mL). The precipitated solid was collected by filtration and washed with hexane (3x5 mL). The precipitated solid was concentrated under reduced pressure to afford 5- (((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide, HCl salt (750 mg, 82.98%). LC-MS: (ES+H, m/z): [M+H] + =240.0. Step 4: Preparation of 5-(((3S,4R)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)-4- fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide: [00185] To a stirred mixture of 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamid e, HCl salt (300 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.90 mmol, 1.00 equiv.) in ACN (6 mL) were added DIEA (580 mg, 4.49 mmol, 5.00 equiv.) and KI (15 mg, 0.09 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction mixture was poured into water (50 mL) at room temperature. The resulting mixture was extracted with CH2Cl2/i-PrOH (3/1, 3x50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by PREP-HPLC, the pure fractions was concentrated then lyophilized to afford 5- (((3S,4R)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-y l)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N- methylpicolinamide (49.5 mg, 10.76%). LC-MS: (ES+H, m/z): [M+H] + =426.1. Optical rotation [a] 25 D (c = 0.5, MeOH): +19º; 1 H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.57 (q, 1H), 8.41 (d, 1H), 8.34 (d, 1H), 7.96 (d, 1H), 7.75 (d, 1H), 7.63 (dd, 2H), 5.57-5.26 (m, 1H), 5.18-5.03 (m, 1H), 3.88-3.71 (m, 2H), 3.10- 2.95 (m, 2H), 2.94-2.83 (m, 2H), 2.79 (d, 3H), 2.61-2.52 (m, 2H), 1.18 (t, 3H). 19 F NMR (282 MHz, DMSO- d 6 ) δ -195.59. Step 1: Preparation of tert-butyl (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3- yl}oxy)pyrrolidine-1-carboxylate: [00186] To a stirred mixture of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine -2-carboxylic acid (1.00 g, 3.24 mmol, 1.00 equiv.), 2,2-difluoroethanamine (0.29 g, 3.57 mmol, 1.10 equiv.) and DIEA (2.10 g, 16.22 mmol, 5.00 equiv.) in DCM (28 mL) was added T3P (6.19 g, 9.73 mmol, 3.00 equiv., 50%wt in EA) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl}oxy)py rrolidine- 1-carboxylate (310 mg, 25.74%) as an off-white oil. LC-MS: (ES+H, m/z): [M+H-t-Bu] + =316.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.97-8.84 (t, 1H), 8.39-8.27 (m, 1H), 8.02 (d, 1H), 7.62-7.58 (m, 1H), 6.29-5.78 (m, 1H), 3.74-3.34 (m, 8H), 2.20-2.03 (m, 1H), 1.40 (d, 9H). Step 2: Preparation of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2- carboxamide, TFA salt: [00187] To a stirred solution of tert-butyl (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3- yl}oxy)pyrrolidine-1-carboxylate (230 mg, 0.62 mmol, 1.00 equiv.) in DCM (6 mL) was added TFA (2 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =272.2. Step 3: Preparation of N-(2,2-difluoroethyl)-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-nap hthyridin-3- yl)methyl]pyrrolidin-3-yl]oxy}pyridine-2-carboxamide: [00188] To a stirred solution of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2- carboxamide, TFA slat (168 mg, crude) and 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (142 mg, 0.68 mmol, 1.0 equiv.) in MeCN (10 mL) was added KI (22 mg, 0.14 mmol, 0.20 equiv.) and DIEA (440 mg, 3.40 mmol, 5.00 equiv.) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, the pure fraction was concentrated then lyophilized to afford N-(2,2- difluoroethyl)-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyrid in-3-yl)methyl]pyrrolidin-3-yl]oxy}pyridine- 2-carboxamide (82.1 mg, 29.75%). LC-MS: (ES+H, m/z): [M+H] + =444.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.87 (s, 1H), 8.86 (t, 1H), 8.39 (d, 1H), 8.29 (d, 1H), 7.98 (d, 1H), 7.85-7.79 (m, 1H), 7.62-7.55 (m, 1H), 7.51 (dd, 1H), 6.40-5.85 (m, 1H), 5.08 (s, 1H), 3.81-3.58 (m, 4H), 2.92 (dd, 1H), 2.83-2.68 (q, 2H), 2.48- 2.25 (m, 2H), 2.14 (d, 3H), 1.74-1.88 (m, 1H). 19 F NMR (282 MHz, DMSO-d 6 ) δ-122.05 Example 11 Step1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl](methyl)amino}pyridine-2-carboxylate: [00189] A mixture of methyl 5-bromopyridine-2-carboxylate (800 mg, 3.70 mmol, 1.00 equiv.), tert-butyl (3R)-3-(methylamino)pyrrolidine-1-carboxylate (890 mg, 4.44 mmol, 1.20 equiv.), Cs 2 CO 3 (2.41 g, 7.41 mmol, 2.00 equiv.), RuPhos Palladacycle Gen.3 (310 mg, 0.37 mmol, 0.10 equiv.) in 1,4-dioxane (10 mL) was stirred overnight at 110°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20mL). The resulting mixture was filtered, the filter cake was washed with EtOAc (3x20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amin o}pyridine-2-carboxylate (488 mg, 39.29%). LC-MS: (ES+H, m/z): [M+H] + =336.25. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (d, 1H), 7.86 (d, 1H), 7.26 (dd, 1H), 4.79-4.6 (m, 1H), 3.80 (s,3H), 3.58-3.40 (m, 2H), 3.24-3.20 (m, 2H), 2.89 (s, 3H), 2.04 (d, 2H), 1.41 (s, 9H). Step2: Preparation of tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrroli dine- 1-carboxylate: [00190] A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amin o}pyridine-2- carboxylate (488 mg, 1.46 mmol, 1.00 equiv.) in MeOH (6 mL) and methylamine water solution (3 mL, 25-30%wt) was stirred for 4h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum to afford tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3- yl]amino}pyrrolidine-1-carboxylate (450 mg, 92.48%). LC-MS: (ES+H, m/z): [M+H] + = 335.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ8.34 (d, 1H), 8.18 (d, 1H), 7.81 (d, 1H), 7.31 (dd, 1H), 4.70-4.62 (m, 1H) 3.57-3.39 (m, 3H), 3.24-3.20 (m, 1H), 2.87 (d, 3H), 2.78 (d.3H), 2.05-2.02(m,2H), 1.41 (s, 9H). Step3: Preparation of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-car boxamide, HCl salt: [00191] A mixture of tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrroli dine-1- carboxylate (450 mg, 1.35 mmol, 1.00 equiv.) in HCl(gas)in 1,4-dioxane (5 mL, 4M) was stirred for 1h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum to afford N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-car boxamide, HCl salt (300 mg, crude). LC-MS: (ES+H, m/z): [M+H] + = 235.2. Step 4: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]p yrrolidin-3- yl](methyl)amino}-N-methylpyridine-2-carboxamide: [00192] A mixture of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-car boxamide (237 mg, 1.01 mmol, 1.5 equiv.), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv.), KI (20 mg, 0.12 mmol, 0.18 equiv.) and DIEA (261 mg, 2.02 mmol, 3.00 equiv.) in ACN (6 mL) was stirred for 1 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3x20 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC, the pure fraction was concentrated under reduced pressure then lyophilized to afford 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]p yrrolidin- 3-yl](methyl)amino}-N-methylpyridine-2-carboxamide (78.7 mg, 27.78%). LC-MS: (ES+H, m/z): [M+H] + = 421.15. Optical rotation [a] 25 D (c = 0.5, MeOH): +6.6º; 1 H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 8.11 (d, 1H), 7.88-7.71 (m, 2H), 7.63 (d, 1H), 7.23 (dd, 1H), 4.63-4.61 (m, 1H), 3.79 (d, 1H), 3.64 (d, 1H), 2.96 (s, 3H), 2.93-2.85 (m, 1H), 2.77 (d, 3H), 2.74-2.68 (m, 1H), 2.61-2.52 (m, 3H), 2.43-2.13 (m, 2H), 1.92-1.60 (m, 1H), 1.18 (t, 3H). Example 12 Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy }pyridine- 2-carboxylate: [00193] To a stirred mixture of NaH (139 mg, 3.47 mmol, 1.4 equiv., 60%wt) in DMF (10 mL) was added tert-butyl (3R)-3-hydroxy-3-methylpyrrolidine-1-carboxylate (500 mg, 2.48 mmol, 1.00 equiv.) in DMF (1 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30min at room temperature under nitrogen atmosphere. To the above mixture was added methyl 5-fluoropyridine- 2-carboxylate (462 mg, 2.98 mmol, 1.20 equiv.) dropwise at room temperature. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with MeOH at 0°C. The residue was purified by reversed combi-flash chromatography to afford methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy }pyridine-2- carboxylate (310 mg, 37.10%). LC-MS: (ES+H, m/z): [M+H] + =337.2. Optical rotation [a] 25 D (c = 0.5, MeOH): -23.9º; 1 H NMR (400 MHz, DMSO-d 6 ) δ8.35 (d, 1H), 8.01 (dd, 1H), 7.62 (dd, 1H), 3.85 (s, 3H), 3.68 (dd, 1H), 3.33 (m, 2H), 2.32-2.28 (m, 1H), 2.14-1.99 (m, 2H), 1.55 (s, 3H), 1.38 (d, 9H). Step 2: Preparation of tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrol idine- 1-carboxylate: [00194] A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy }pyridine-2- carboxylate (337 mg, 1.00 mmol, 1.00 equiv.) and CH3NH2 (5 mL,25-30%wt in water) in CH3OH (5 mL) was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with CH 2 Cl 2 (3 x 30mL). The combined organic layers were washed with brine (3x 30mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrol idine- 1-carboxylate (319 mg, 95.23%). LC-MS: (ES+H, m/z): [M+H] + =336.2. Step 3: Preparation of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-car boxamide, HCl salt: [00195] To a stirred solution of tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3- yl]oxy}pyrrolidine-1-carboxylate (300 mg, 0.89 mmol, 1.00 equiv.) in DCM (5 mL) was added HCl(gas)in 1,4-dioxane (2.5 mL, 4M) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30min at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl ether (20 mL) to afford N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-car boxamide, HCl salt (230 mg, 94.62%). LC-MS: (ES+H, m/z): [M+H] + =236.2. Step 4: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]- 3- methylpyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00196] A mixture of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-car boxamide, HCl salt (205 mg, 0.75 mmol, 1.00 equiv.), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (218 mg, 0.98 mmol, 1.30 equiv.), DIEA (488 mg, 3.77 mmol, 5.00 equiv.) and KI (25 mg, 0.15 mmol, 0.20 equiv.)in ACN (5 mL) was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, the pure fraction was concentrated then lyophilized to afford 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]- 3- methylpyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (140 mg, 44.03%). LC-MS: (ES+H, m/z): [M+H] + = 422.10. Optical rotation [a] 25 D (c = 0.5, MeOH): -21.6º; 1 H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.55 (d, 1H), 8.39 (d, 1H), 8.22 (dd, 1H), 7.95 (dd, 1H), 7.75 (s, 1H), 7.65-7.54 (m, 2H), 3.73 (s, 2H), 2.96 (d, 1H), 2.82-2.76 (m, 4H), 2.75-2.67 (m, 1H), 2.68-2.53 (m, 3H), 2.33-2.21 (m, 1H), 2.13-1.99 (m, 1H), 1.55 (s, 3H), 1.19 (t, 3H). [00197] The following examples were made using similar procedures as shown for example 12: Example 13 Step1: Preparation of tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate: [00198] To a stirred mixture of tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.00 g, 14.91 mmol, 1.00 equiv.) and CBr 4 (7.41 g, 22.34 mmol, 1.50 equiv.) in DCM (20 mL) was added a solution of PPh 3 (3.91 g, 14.91 mmol, 1.00 equiv.) in DCM(5 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=3:1, R f =0.4). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (3R)-3- (bromomethyl)pyrrolidine-1-carboxylate (2.5 g, 63.4%). 1 H NMR (300 MHz, Chloroform-d) δ 3.70-3.66 (m, 1H), 3.59-3.52 (m, 1H), 3.49-3.48 (m, 1H), 3.48-3.34 (m, 2H), 3.21-3.14 (m, 1H), 2.75-2.60 (m, 1H), 2.18- 2.10 (m, 1H), 1.90-1.70 (m, 1H), 1.54 (s, 9H). Step2: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyrid ine-2- carboxylate: [00199] A mixture of 1,2-dimethoxyethane dihydrochloride nickel (25 mg, 0.11 mmol, 0.10 equiv.) and 4- tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (31 mg, 0.11 mmol, 0.10 equiv.) in DME (3 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The nickel mixture was added to a mixture of tert- butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate (300 mg, 1.14 mmol, 1.00 equiv.), methyl 5- bromopyridine-2-carboxylate (245 mg, 1.14 mmol, 1.00 equiv.), tris(trimethylsilyl)silane (282 mg, 1.14 mmol, 1.00 equiv.), Cs 2 CO 3 (740 mg, 2.27 mmol, 2.00 equiv.) and Ir[dF(CF 3 )ppy] 2 (dtpby)PF 6 (38 mg, 0.03 mmol, 0.03 equiv.) at room temperature under nitrogen atmosphere. The reaction was stirred for 2 days and irradiated with blue LEDS (30 watts). The reaction was monitored by LCMS. The reaction was poured into water (20 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyrid ine-2-carboxylate (200 mg, 54.9%). LC-MS: (ES+H, m/z): [M+H] + = 321.1. Optical rotation [a] 25 D (c = 0.5, MeOH): +17.6º; 1 H NMR (400 MHz, DMSO-d 6 ) δ8.59 (dd, 1H), 8.07-7.95 (m, 1H), 7.85 (dd, 1H), 3.87 (s, 3H), 3.39-3.34 (m, 1H), 3.31-3.22 (m, 1H), 3.20-3.12 (m, 1H), 2.95-2.86 (m, 1H), 2.77 (t, 2H), 2.50-2.40 (m, 1H), 1.88-1.53 (m, 1H), 1.63-1.47 (m, 1H), 1.38 (s, 9H). Step3: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine- 1- carboxylate: [00200] To a stirred mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyrid ine- 2-carboxylate (190 mg, 0.66 mmol, 1.00 equiv.) in MeOH (2 mL) was added methylamine (2 mL, 25-30% wt in water) at room temperature under nitrogen atmosphere. The resulting mixture was stirred 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3- yl]methyl}pyrrolidine-1-carboxylate (190 mg, crude). LC-MS: (ES+H, m/z): [M+H] + = 320.3. Step4: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamid e, HCl salt: A mixture of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine- 1-carboxylate (190 mg, crude) in HCl(gas) in 1,4-dioxane (4M, 2 mL) was stirred for 0.5 h at room temperature. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure to afford N-methyl-5- [(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamide, HCl salt (190 mg, crude). LC-MS: (ES+H, m/z): [M+H] + = 220.1 Step 5: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]p yrrolidin-3- yl]methyl}-N-methylpyridine-2-carboxamide: [00201] A mixture of N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamid e, HCl salt (150 mg, crude), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.68 mmol, 1.00 equiv.), DIEA (436 mg, 3.38 mmol, 5.00 equiv.) and KI (22 mg, 0.14 mmol, 0.20 equiv.) in ACN (5 mL) was stirred for 1h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was poured into water (30 mL). The aqueous layer was extracted with EtOAc (4x20 mL). The combined organic layers were concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC, the pure fraction was concentrated then lyophilized to afford 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]p yrrolidin-3-yl]methyl}-N-methylpyridine-2- carboxamide (62.6 mg, 22.9%). LC-MS: (ES+H, m/z): [M+H] + = 406.10. Optical rotation [a] 25 D (c = 0.5, MeOH): +18.4º; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.83 (s, 1H), 8.69-8.66 (m, 1H), 8.47 (d, 1H), 8.36 (d, 1H), 7.92 (d, 1H), 7.81 (dd, 1H), 7.73 (s, 1H), 7.58 (d, 1H), 3.74-3.58 (m, 2H), 2.85-2.77 (m, 5H), 2.62-2.52 (m, 4H), 2.50-2.46 (m, 2H), 2.22-2.16 (m, 1H), 1.93-1.80 (m, 1H), 1.51-1.38 (m, 1H), 1.18 (t, 3H). Example 14 Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-ca rboxylate: [00202] To a stirred solution of methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.25 mmol, 1.00 equiv.) and tert-butyl 3-aminoazetidine-1-carboxylate (1.75 g, 10.18 mmol, 1.10 equiv.) in Toluene (20 mL) were added XantPhos (1.07 g, 1.85 mmol, 0.20 equiv.), Pd2(dba)3 (0.84 g, 0.90 mmol, 0.10 equiv.) and Cs2CO3 (9.05 g, 27.77 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred for 2h at 110°C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography. This resulted in methyl 5-{[1-(tert- butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate (1.00 g, 31.98%). LC-MS: (ES+H, m/z): [M+H] + =308.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.00 (d, 1H), 7.83 (d, 1H), 7.37 (d, 1H), 6.87 (dd, 1H), 4.30-4.23 (m, 3H), 3.79 (m, 3H), 3.68 (m, 2H), 1.39 (s, 9H). Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carbox ylate: [00203] To a stirred solution of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2- carboxylate (500 mg, 1.62 mmol, 1.00 equiv.) in MeOH (5 mL) was added Methylamine (5 mL, 25-30% wt in water) at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by reversed combi-flash chromatography. This resulted in tert-butyl 3-{[6- (methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate (500 mg, 94.30%). LC-MS: (ES+H, m/z): [M+H] + =307.1. Step 3: Preparation of 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide, HCl salt: [00204] Into a 100 mL round-bottom flask were added tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3- yl]amino}azetidine-1-carboxylate (500 mg, 1.63 mmol, 1.00 equiv.) and HCl(gas) in 1,4-dioxane (10 mL) at room temperature. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. This resulted in 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide, HCl salt (400 mg, crude). The crude resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =207.2. Step 4: Preparation of 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetid in-3-yl}amino)-N- methylpyridine-2-carboxamide: [00205] To a stirred solution of 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide, HCl salt (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (120 mg, 0.53 mmol, 1.00 equiv.) in ACN (5 mL) was added DIEA (348 mg, 2.69 mmol, 5.00 equiv.) and KI (9 mg, 0.05 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred for additional 2 h at 80°C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC, the pure fraction was concentrated under reduced pressure and lyophilized to afford 5-({1- [(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-y l}amino)-N-methylpyridine-2-carboxamide (65.6 mg, 30.30%). LC-MS: (ES+H, m/z): [M+H] + =393.2. 1 H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.36 (d,1H), 8.30 (d, 1H), 7.89 (d, 1H), 7.78-7.69 (t, 2H), 7.56 (s, 1H), 7.00-6.87 (m, 2H), 4.11 (q, 1H), 3.75-3.64 (m, 4H), 2.95 (t, 2H), 2.76 (d, 3H), 2.60-2.52 (m, 2H), 1.18 (t, 3H). Example 15 Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridi ne-2- carboxylate: [00206] To a stirred solution of NaH (1.08 g, 27.08 mmol, 1.40 equiv., 60%wt) in DMF (40 mL) was added tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (4.71 g, 25.14 mmol, 1.30 equiv.) in DMF (5 mL) dropwise at room temperature under nitrogen atmosphere. The above mixture was stirred for 30 min at room temperature under nitrogen atmosphere. Then to the resulting mixture was added methyl 5- fluoropyridine-2-carboxylate (3.00 g, 19.34 mmol, 1.00 equiv.) in DMF (5 mL) dropwise at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of MeOH (20 mL) at 0°C. The resulting mixture was diluted with EA (100 mL) and washed with water (3 x 30 mL). The organic layer was concentrated under vacuum. The residue was purified by reversed combi-flash chromatography to afford methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3- yl]oxy}pyridine-2-carboxylate (1.1 g, 17.64%) as a white oil. LC-MS: (ES+H, m/z): [M+H] + =323.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, 1H), 8.00 (d, 1H), 7.33 (dd, 1H), 4.10-4.02 (m, 4H), 3.85 (s, 3H), 1.65 (s, 3H), 1.39 (s, 9H). Step 2: Preparation of tert-butyl 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1 - carboxylate: [00207] To a stirred solution of methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridi ne-2- carboxylate (500 mg, 1.55 mmol, 1.00 equiv.) in MeOH (5 mL) was added CH3NH2 (5 mL, 25.0~30.0% wt in water) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum to afford tert-butyl 3-methyl-3-((6- (methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (508 mg, crude). The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =322.2. Step 3: Preparation of N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamid e, TFA salt: [00208] To a stirred solution of tert-butyl 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1 - carboxylate (468 mg, 1.46 mmol, 1.00 equiv.) in DCM (6 mL) was added TFA (2 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum to afford N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamid e, TFA salt (396 mg, crude). The crude product was used in the next step directly without further purification. LC- MS: (ES+H, m/z): [M+H] + =222.2. Step 4: Preparation of 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-met hylazetidin-3- yl}oxy)-N-methylpyridine-2-carboxamide: [00209] To a stirred solution of N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamid e, TFA salt (250 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (201 mg, 0.90 mmol, 1.00 equiv.) in MeCN (5 mL) were added DIEA (467 mg, 3.62 mmol, 4.00 equiv.) and KI (30 mg, 0.18 mmol, 0.20 equiv.) in portions at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with CH 2 Cl 2 /MeOH(10:1) (150mL). The filtrate was concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC, the pure fraction was concentrated then lyophilized to afford 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-met hylazetidin-3-yl}oxy)-N- methylpyridine-2-carboxamide (90.8 mg, 24.65%). LC-MS: (ES+H, m/z): [M+H] + =408.15. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.85 (s, 1H), 8.54 (q, 1H), 8.37 (d, 1H), 8.13 (d, 1H), 7.92 (d, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.28 (dd, 1H), 3.77 (s, 2H), 3.59-3.57 (m, 2H), 3.29-3.32 (m, 2H), 2.79 (d, 3H), 2.56-2.50 (m, 2H), 1.64 (s, 3H), 1.18-1.12 (t, 3H). Example 16
Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carb oxylate: [00210] A mixture of DEAD (5.69 g, 32.65 mmol, 5.00 equiv.) and PPh 3 (10.90 g, 39.18 mmol, 6.00 equiv.) in THF (100 ml) was stirred for 1h at 0 °C under nitrogen atmosphere. The mixture was added to methyl 5-hydroxypyridine-2-carboxylate (1.00 g, 6.53 mmol, 1.00 equiv.) and tert-butyl 3-hydroxyazetidine- 1-carboxylate (1.70 g, 9.79 mmol, 1.50 equiv.) in THF (100 ml) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-{[1-(tert- butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate (4.5 g, crude, contained TPPO). LC-MS: (ES+H, m/z): [M+H] + =309.1. Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxyl ate: [00211] A mixture of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carb oxylate (3.50 g, crude, contained TPPO) and CH3NH2 (20 mL, 25-30%wt in water) in MeOH (20 mL) was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was added saturated NH4Cl (100 mL), and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This result in tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxyl ate (3.3 g, crude, contained TPPO). LC-MS: (ES+H, m/z): [M+H] + =308.1 Step 3: Preparation of 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt: [00212] A mixture of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxyl ate (3.30 g, crude, contained TPPO) in DCM (10 mL) was added HCl(gas)in 1,4-dioxane (10 mL, 4M in dioxane) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (3 X 20mL). The precipitated solids were collected by filtration and concentrated under reduced pressure. This result in 5- (azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt (600 mg, crude). LC-MS: (ES+H, m/z): [M+H] + =208.2. Step 4: Preparation of 5-({1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl) methyl] azetidin-3- yl}oxy)-N-methylpyridine-2-carboxamide: [00213] A mixture of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (200 mg, 0.85 mmol, 1.00 equiv.), 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt (249 mg, crude), DIEA (550 mg, 4.26 mmol, 5.00 equiv.) and KI (28 mg, 0.17 mmol, 0.20 equiv.) in ACN (10 mL) was stirred for 2h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers was concentrated under reduced pressure. The residue was purified by flash chromatography. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MeOH (5mL) at 50 °C. The precipitated solids were collected by filtration and washed with MeOH (2x1 mL). The pure fractions were concentrated and lyophilized to afford 5-({1-[(7-cyclopropyl-6-oxo-5H-1,5- naphthyridin-3-yl) methyl]azetidin-3yl}oxy)-N-methylpyridine-2-carboxamide (35.9 mg, 10.24%). LC-MS: (ES+H, m/z): [M+H] + =406.25. 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.56 (q, 1H), 8.34 (d, 1H), 8.22 (d, 1H), 7.94 (d, 1H), 7.54 (d, 1H), 7.40 (q, 2H), 5.01 (p, 1H), 3.79-3.75 (m, 4H), 3.17-3.14 (m, 2H), 2.78 (d, 3H), 2.16-2.10 (m, 1H), 0.98-0.95 (m, 2H), 0.88-0.77 (m, 2H). [00214] The following examples were made using similar procedures as shown for example 16: Example 17 Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3- yl]oxy}pyridine-2-carboxylate: [00215] To a stirred mixture of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol, 1.00 equiv.) and methyl 5-hydroxypyridine-2-carboxylate (245 mg, 1.60 mmol, 1.00 equiv.) and PPh 3 (882 mg, 3.36 mmol, 2.10 equiv.) in THF (15 mL) were added DBAD (738 mg, 3.20 mmol, 2.00 equiv.) in THF (5 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (100 mL). The residue was washed with H 2 O (2x30 mL). dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}pyridine-2-carboxylate (1.5 g, crude) was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H]+ = 323.1. Step 2: Preparation of tert-butyl (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3- yl]oxy}azetidine-1-carboxylate: [00216] A solution of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}pyridine-2- carboxylate (1.5 g, crude) and CH3NH2 (7 mL, 25%-30%wt in water) in CH3CN (7 mL) was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The residue was washed with NH4Cl (aqueous) (2x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product tert-butyl (2R,3S)-2- methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-c arboxylate (1.5 g, crude) was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H]+ = 322.1. Step 3: Preparation of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide, TFA salt: [00217] To a stirred solution of tert-butyl (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3- yl]oxy}azetidine-1-carboxylate (1.5 g, crude) in DCM (10 mL) was added TFA (7 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl ether/n-hexane (3x10 mL). The resulting mixture was concentrated under vacuum. The crude product N-methyl-5-{[(2R,3S)-2-methylazetidin-3- yl]oxy}pyridine-2-carboxamide, TFA salt (0.6 g , crude) was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H]+ = 222.2. Step 4: Preparation of 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methy l]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00218] To a stirred mixture of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide, TFA salt (300 mg, 1.36 mmol, 1.00 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (332 mg, 1.49 mmol, 1.10 equiv.) in CH 3 CN (10 mL) were added KI (45 mg, 0.27 mmol, 0.20 equiv.) and DIEA (700 mg, 5.42 mmol, 4.00 equiv.) dropwise at room temperature. The mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by reversed combi-flash. The pure fraction was concentrated under vacuum then lyophilized to afford 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-car boxamide (56.8 mg, 10.22%). LC-MS: (ES+H, m/z): [M+H]+ = 408.2. Optical rotation [a] 25 D (c = 0.5, MeOH): -4.8º; 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.86 (s, 1H), 8.58-8.57 (q, 1H), 8.39 (d, 1H), 8.24 (d, 1H), 7.94 (d, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.43 (dd, 1H), 4.65-4.59 (m, 1H), 3.95-3.90 (m, 1H), 3.84-3.80 (m, 1H), 3.66-3.62 (m, 1H), 3.39-3.34 (m, 1H), 2.80-2.78 (m, 4H), 2.58-2.51 (m, 2H), 1.21-1.16 (m, 6H). [00219] The following examples were made using similar procedures as shown for example 17:
Example 18 Step 1: Preparation of methyl 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] oxy} pyridine-2-carboxylate: [00220] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (0.35 g, 2.28 mmol, 1.00 equiv.), tert-butyl (2S,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (0.43 g, 2.28 mmol, 1.00 equiv.) and PPh3 (1.20 g, 4.57 mmol, 2.00 equiv.) in toluene (10 mL) was added DBAD (1.05 g, 4.57 mmol, 2.00 equiv.) in toluene (5 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated under reduced pressure to afford methyl 5-{[(2S,3R)-1-(tert- butoxycarbonyl)-2-methylazetidin-3-yl] oxy} pyridine-2-carboxylate (2.00 g, crude). The crude product was used in the next step directly. LC-MS: (ES+H, m/z): [M+H] + =323.1. Step 2: Preparation of tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl) pyridin-3-yl] oxy} azetidine-1-carboxylate: [00221] A solution of methyl 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] oxy} pyridine-2- carboxylate (1.00 g, crude) and Methylamine (2 mL, 25-30%wt in water) in MeOH (2 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl) pyridin-3-yl] oxy} azetidine-1- carboxylate (1.00 g, crude) as a brown oil. The crude product was used in the next step directly. LC-MS: (ES+H, m/z): [M+H] + =322.1. Step 3: Preparation of N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl] oxy} pyridine-2-carboxamide, HCl salt: [00222] A solution of tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl) pyridin-3-yl] oxy} azetidine- 1-carboxylate (1.00 g, crude) in HCl (gas) in 1,4-dioxane (4 mL, 4M) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The product was precipitated by the addition of EtOAc. The precipitated solids were collected by filtration and washed with PE (3 x 10 mL) to afford N-methyl-5- {[(2S,3R)-2-methylazetidin-3-yl] oxy} pyridine-2-carboxamide, HCl salt (200 mg, 67.95%, 3 steps). LC- MS: (ES+H, m/z): [M+H] + =222.2. Step 4: Preparation of 5-{[(2S,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl) methyl]-2- methylazetidin-3-yl] oxy}-N-methylpyridine-2-carboxamide: [00223] To a stirred solution of N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl] oxy} pyridine-2- carboxamide, HCl salt (200 mg, 0.90 mmol, 1.10 equiv.) and DIEA (531 mg, 4.11 mmol, 5.00 equiv.) in MeCN (10 mL) ware added KI (27 mg, 0.16 mmol, 0.20 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5- naphthyridin-2-one (157 mg, 0.82 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, the pure fraction was concentrated then lyophilized to afford 5-{[(2S,3R)-1-[(7-ethyl-6- oxo-5H-1,5-naphthyridin-3-yl) methyl]-2-methylazetidin-3-yl] oxy}-N-methylpyridine-2-carboxamide (73.6 mg, 25.36%). LC-MS: (ES+H, m/z): [M+H] + =408.2. Optical rotation [a] 25 D (c = 0.5, MeOH): +8º; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 8.57 (d, 1H), 8.38 (s, 1H), 8.23(d, 1H), 7.94 (d, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.43 (dd, 1H), 4.62 (q, 1H), 3.92 (d, 1H), 3.82 (t, 1H), 3.65-3.62 (m, 1H), 3.38-3.35 (m, 1H), 2.80-2.75 (m, 4H), 2.55-2.52 (m, 2H), 1.27-1.08 (m, 6H). Example 19 Step 1: Preparation of methyl 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3- yl]oxy}pyridine-2-carboxylate: [00224] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (245 mg, 1.60 mmol, 1.00 equiv.) and tert-butyl (2R,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol, 1.00 equiv.) and Ph 3 P (840 mg, 3.20 mmol, 2.00 equiv.) in THF (5 mL) was added DBAD (738 mg, 3.20 mmol, 2.00 equiv.) in THF (2 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C. The resulting mixture was stirred overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was poured into water (50 mL), extracted with EtOAc (50 mL x3). The combined organic layers were concentrated under reduced pressure to afford methyl 5-{[(2R,3R)-1-(tert- butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxy late (1.6 g, contain Ph 3 PO) as a grey oil. The resulting mixture was used in the next step directly. LC-MS: (ES+H, m/z): [M+H] + =323.2. Step 2: Preparation of tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3- yl]oxy}azetidine-1-carboxylate: [00225] A solution of methyl 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}pyridine-2- carboxylate (1.60 g, 4.96 mmol, 1.00 equiv.) and methylamine (4 mL, 25-30%wt in water) in MeOH (4 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin- 3-yl]oxy}azetidine-1-carboxylate (1.53 g, contain Ph3PO) as a grey oil. The crude product was used in the next step directly. LC-MS: (ES+H, m/z): [M+H] + =322.2 Step 3: Preparation of N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide, TFA salt: [00226] A solution of tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}aze tidine-1- carboxylate (1.53 g, contain Ph3PO) and TFA(3 ml) in DCM (3 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with ether (3x10 mL) to afford N-methyl-5- {[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, TFA salt (810 mg, contain Ph 3 PO). LC-MS: (ES+H, m/z): [M+H] + =222.1. Step 4: Preparation of 5-{[(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methy l]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00227] To a stirred solution of N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide (546 mg, 2.47 mmol, 1.10 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (500 mg, 2.24 mmol, 1.00 equiv.) in MeCN (5 mL) was added KI (74 mg, 0.45 mmol, 0.20 equiv.) and DIEA (1.45 g, 11.22 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-{[(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methy l]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (26.2 mg, 2.86%). LC-MS: (ES+H, m/z): [M+H] + =408.20. 1 H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.56 (d, 1H), 8.37 (d, 1H), 8.26 (d, 1H), 7.95 (d, 1H), 7.74 (s, 1H), 7.59 (d, 1H), 7.42 (dd, 1H), 5.05-4.95 (m, 1H), 3.88 (d, 1H), 3.76 (q, 1H), 3.66 (d, 1H), 3.37-3.35 (m, 2H),2.79 (d, 3H), 2.60-2.51 (m, 2H), 1.18 (t, 3H), 1.04 (d, 3H). Example 20 Step 1: Preparation of methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)picolinate: [00228] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (400 mg, 2.61 mmol, 1.00 equiv.) and tert-butyl (2S,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (489 mg, 2.61 mmol, 1.00 equiv.) and PPh 3 (1.40 g, 5.22 mmol, 2.00 equiv.) in methylbenzene (10 mL) were added DBAD (1.20 g, 5.22 mmol, 2.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford crude product (3.6g, crude). The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =323.1. Step 2: Preparation of tert-butyl (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)aze tidine- 1-carboxylate: [00229] To a stirred solution of methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)picolinate (3.6 g, crude) in MeOH (10 mL) was added CH3NH2 (10 mL, 25-30%wt in water) at room temperature. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl (100 mL). The resulting mixture was extracted with DCM (3 x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude product (3.5 g, crude). The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =322.2 Step 3: Preparation of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide, HCl salt: [00230] To a stirred solution of tert-butyl (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-1-carboxylate (3.5 g, crude) in DCM (10 mL) was added HCl(gas)in 1,4-dioxane (10 mL, 4 M) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and was purified by trituration with ethyl acetate (20 mL) to afford crude product (1.6 g, crude). LC-MS: (ES+H, m/z): [M+H] + =222.0 Step 4: Preparation of 5-(((2S,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)-2- methylazetidin-3-yl)oxy)-N-methylpicolinamide: [00231] To a stirred mixture of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide (298 mg, assumed 100% yield, 1.35 mmol, 2.00 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv.) in MeCN (10 mL) were added KI (22 mg, 0.14 mmol, 0.20 equiv.) and DIEA (435 mg, 3.37 mmol, 5.00 equiv.) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC. The pure fractions were concentrated and lyophilized to afford 5- (((2S,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-y l)methyl)-2-methylazetidin-3-yl)oxy)-N- methylpicolinamide (29.1 mg, 10.60%). LC-MS: (ES+H, m/z): [M+H] + =408.2. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.80 (s, 1H), 8.57 (d, 1H), 8.37 (d, 1H), 8.26 (d, 1H), 7.96 (d, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.44 (dd, 1H), 5.08-5.03 (m, 1H), 3.88 (d, 1H), 3.80-3.74 (m, 1H), 3.66 (d, 1H), 3.34(s, 2H), 2.79 (d, 3H), 2.56 (d, 2H), 1.18 (t, 3H), 1.04 (d, 3H). Example 21 Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carb oxylate: [00232] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (5.00 g, 32.65 mmol, 1.00 equiv.), PPh3 (17.13 g, 65.30 mmol, 2.00 equiv.) and tert-butyl 3-hydroxyazetidine-1-carboxylate (5.66 g, 32.65 mmol, 1.00 equiv.) in Toluene (80 mL) was added DBAD (15.04 g, 65.30 mmol, 2.00 equiv.) in Toluene (40 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 60°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was poured into water (400 mL), extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to afford methyl 5-{[1- (tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylat e (45 g, crude) as a grey oil. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + = 309.1 Step 2: Preparation of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carb oxylic acid: [00233] A mixture of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carb oxylate (9.00 g, 8.76 mmol, 1.00 equiv., assumed 30% yield) and LiOH (0.84 g, 35.03 mmol, 4.00 equiv.) in THF (40 mL) and H 2 O (10 mL) was stirred for 3h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was poured into water (200 mL), extracted with EtOAc (1 x 200mL). The aqueous layer was acidified to pH 4~6 with HCl (aqueous.). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na 2 SO 4 .The resulting mixture was concentrated under reduced pressure to afford 5- {[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carbox ylic acid (2.3 g, 89.25%). LC-MS: (ES+H, m/z): [M+H] + = 295.1. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 8.33 (dd,1H), 8.02 (dd,1H), 7.38 (dd,1H), 5.20-5.17 (m,1H), 4.41-4.28 (m, 2H), 3.91-3.80 (m, 2H), 1.39 (s, 9H). Step 3: Preparation of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1- carboxylate: [00234] To a stirred mixture of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carb oxylic acid (500 mg, 1.70 mmol, 1.00 equiv.) and DIEA (1.10 g, 8.50 mmol, 5.00 equiv.) in DCM (15 mL) were added aminocyclopropane (107 mg, 1.87 mmol, 1.10 equiv.) and T3P (4.32 g, 6.80 mmol, 4.00 equiv., 50%wt in EA) at room temperature. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was poured into water (150 mL), and extracted with EtOAc (3 x200 mL). The combined organic layers were washed with brine (1x80 mL), dried over anhydrous Na 2 SO 4 . The resulting mixture was concentrated under reduced pressure to afford tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-car boxylate (780 mg, crude). LC-MS: (ES+H, m/z): [M+H] + = 334.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.55 (d, 1H), 8.21 (d, 1H), 7.97 (d, 1H), 7.40 (dd, 1H), 5.17-5.12 (m, 1H), 4.34 (dd, 2H), 3.84 (dd, 2H), 2.94-2.82 (m, 1H), 1.39 (s, 9H), 0.78-0.61 (m, 4H). Step 4: Preparation of 5-(azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide, TFA salt: [00235] A solution of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-car boxylate (700 mg, 2.10 mmol, 1.00 equiv.) and TFA (7.20 g, 63.00 mmol, 30.00 equiv.) in DCM (20 mL) was stirred for 2h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This resulted in 5- (azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide, TFA salt (1.2 g, crude) as a brown crude oil. LC- MS: (ES+H, m/z): [M+H]+ = 234.2 Step 5: Preparation of N-cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl )methyl]azetidin- 3-yl}oxy)pyridine-2-carboxamide: [00236] To a solution of 5-(azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide, TFA salt (300 mg, crude) and DIEA (871 mg, 6.74 mmol, 10.00 equiv.) in MeCN (2 mL) were added 7-(chloromethyl)-3-ethyl- 1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv.) and KI (22 mg, 0.14 mmol, 0.20 equiv.). The mixture was stirred for 2h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. After cooled to rt, the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed combi-flash, the pure fraction was concentrated then lyophilized to afford N- cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)m ethyl]azetidin-3-yl}oxy)pyridine-2- carboxamide (96.2 mg, 33.50%). LC-MS: (ES+H, m/z): [M+H] + = 420.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 8.52 (d, 1H), 8.37 (d, 1H), 8.20 (d, 1H), 7.95 (d, 1H), 7.74 (s, 1H), 7.57 (d, 1H),7.41 (dd, 1H), 5.02 (p, 1H), 3.83-3.75 (m, 4H), 3.24-3.12 (m, 2H), 2.87 (td, 1H), 2.57-2.52 (m, 2H), 1.18 (t, 3H), 0.68-0.65 (m, 4H). [00237] The following examples were made using similar procedures as shown for example 21:
Example 22 Step 1: Preparation of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate: [00238] To a stirred solution of benzonitrile, 4-fluoro- (1.00 g, 8.26 mmol, 1.00 equiv.) and tert-butyl 3- hydroxyazetidine-1-carboxylate (2.15 g, 12.39 mmol, 1.50 equiv.) in DMF (20 mL) was added K2CO3 (3.42 g, 24.77 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was poured into water (80mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate (170 mg, 7.51%). LC-MS: (ES+H, m/z): [M-tBu+ACN] + = 260.0. 1 H NMR (300 MHz, DMSO-d6) δ 7.84-7.75 (m, 2H), 7.05-6.98 (m, 2H), 5.17-5.05 (m, 1H), 4.49-4.24 (m, 2H), 3.86-3.76 (m, 2H), 1.39 (s, 9H). Step 2: Preparation of 4-(azetidin-3-yloxy)benzonitrile, TFA salt: [00239] To a stirred solution of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate (160 mg, 0.58 mmol, 1.00 equiv.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 4- (azetidin-3-yloxy)benzonitrile, TFA salt (232 mg, crude) as a brown oil. LC-MS: (ES+H, m/z): [M+H] + = 175.0 Step 3: Preparation of 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetid in-3- yl}oxy)benzonitrile: [00240] To a stirred solution of 4-(azetidin-3-yloxy)benzonitrile (221 mg, 0.58 mmol, 1.00 equiv., 46%wt) and DIEA (377 mg, 2.92 mmol, 5.00 equiv.) in MeCN (5mL) were added 7-(chloromethyl)-3-ethyl-1H-1,5- naphthyridin-2-one (130 mg, 0.58 mmol, 1.00 equiv.) and KI (4 mg, 0.02 mmol, 0.04 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was poured into water (60 mL). The resulting mixture was extracted with EtOAc (3 x 80mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC, the pure fractions was concentrated under reduced pressure then lyophilized to afford 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin- 3-yl)methyl]azetidin-3-yl}oxy)benzonitrile (86.7 mg, 41.24%, two steps). LC-MS: (ES+H, m/z): [M+H] + = 361.10. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.36 (d, 1H), 7.82-7.66 (m, 3H), 7.56 (s, 1H), 7.02 (d, 2H), 5.01-4.90 (m, 1H), 3.85-3.65 (m, 4H), 3.21-3.04 (m, 2H), 2.59-2.52 (m, 2H), 1.18 (t, 3H). The following examples were made using similar procedures as shown for example 22:
Example 43 Step 1: Preparation of tert-butyl (2R,3S)-3-((6-cyanopyridin-3-yl)oxy)-2-methylazetidine-1- carboxylate: [00241] To a stirred mixture of NaH (1.49 g, 37.37 mmol, 1.20 equiv., 60% in oil) in THF (30 mL) was added tert-butyl (2R,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (6.99 g, 37.35 mmol, 1.20 equiv.) in THF (30 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. To the above mixture was added 5-fluoropyridine-2-carbonitrile (3.8 g, 31.12 mmol, 1.00 equiv.) in THF (30 mL) dropwise over 15 min at 0°C. The resulting mixture was stirred for additional 1h at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (10 mL) at 0°C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (2R,3S)-3-((6-cyanopyridin-3-yl)oxy)-2- methylazetidine-1-carboxylate(6.24 g, 65.0%). LC-MS: (ES+H, m/z): [M+H-tBu] + =234.1. Step 2: Preparation of 5-(((2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)ox y)picolinic acid: [00242] To a stirred mixture of tert-butyl (2R,3S)-3-[(6-cyanopyridin-3-yl)oxy]-2-methylazetidine-1- carboxylate (6.6 g, 22.81 mmol, 1.00 equiv.) in water (40 mL) was added NaOH (20 mL, 2N in water) in portions at room temperature. The resulting mixture was stirred for 2h at 100°C under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature. To the above mixture was added THF (40mL) and Boc2O (9.96 g, 45.62 mmol, 2.00 equiv.) in portions over 10 min at 0°C. The resulting mixture was stirred for additional 6h at room temperature. The reaction was monitored by LCMS. The mixture was acidified to pH 3-4 with citric acid. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-(((2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)ox y)picolinic acid (6.2 g, 88.2 %). LC-MS: (ES+H, m/z): [M+H] + =309.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.33 (d, 1H), 8.02 (d, 1H), 7.38 (dd, 1H), 4.82-4.65 (m, 1H), 4.30-4.21 (m, 2H), 3.72-3.56 (m, 1H), 1.45 (s, 3H), 1.37 (s, 9H). Step 3: Preparation of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2- methylazetidine-1-carboxylate: [00243] To a stirred solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}pyridine- 2-carboxylic acid (600 mg, 1.95 mmol, 1.00 equiv.) and HATU (1.11 g, 2.92 mmol, 1.50 equiv.) and DIEA (503 mg, 3.89 mmol, 2.00 equiv.) in DCM (5 mL) were added aminocyclopropane (133 mg, 2.33 mmol, 1.20 equiv.) at 0°C. The resulting mixture was stirred for 1.5h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with CH2Cl2 (100 mL). The resulting mixture was washed with water (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-meth ylazetidine-1-carboxylate (600 mg, 88.7%). LC-MS: (ES+H, m/z): [M+H]+ = 348.1 Step 4: Preparation of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine -2-carboxamide HCl salt: [00244] To a stirred solution of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2- methylazetidine-1-carboxylate (500 mg, 1.44 mmol, 1.00 equiv.) in DCM (3 mL) were added HCl(gas)in 1,4-dioxane (5 mL, 4mol/L) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with Et 2 O (2 X 10 mL). The resulting mixture was concentrated under reduced pressure to afford N-cyclopropyl-5-{[(2R,3S)- 2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, HCl salt (400 mg, crude). LC-MS: (ES+H, m/z): [M+H] + = 248.2. Step 5: Preparation of N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyri din-3-yl)methyl]- 2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide: [00245] To a stirred mixture of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine -2- carboxamide HCl salt (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv.) in CH 3 CN (8 mL) were added KI (56 mg, 0.34 mmol, 0.5 equiv.) and DIEA (697 mg, 5.39 mmol, 8 equiv.) dropwise at room temperature. The resulting mixture was stirred for 2h at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. After that The residue was purified by reversed combi-flash chromatography. the pure fraction was concentrated under vacuum to afford N-cyclopropyl-5-{[(2R,3S)-1- [(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylaze tidin-3-yl]oxy}pyridine-2-carboxamide (109.3 mg, 37.3%). LC-MS: (ES+H, m/z): [M-H]+ = 434.25, Optical rotation [a] 25 D (c = 0.25, DCM/MeOH=10/1): -12º; 1 H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.54-8.52 (d, 1H), 8.39-8.38 (d, 1H), 8.22-8.21 (d, 1H), 7.96-7.93 (d, 1H), 7.74 (s, 1H), 7.59-7.58 (d, 1H), 7.45-7.42 (dd, 1H), 4.64-4.58 (q, 1H), 3.94-3.90 (d, 1H), 3.83-3.79 (t, 1H), 3.66-3.62 (d, 1H), 3.39-3.34 (q, 1H), 2.91-2.76 (m, 2H), 2.58-2.50 (m, 2H), 1.21-1.16 (m, 6H), 0.71-0.60 (m, 4H). Example 44 Step 1: Preparation of methyl 5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinate, HCl salt: [00246] To a stirred mixture of tert-butyl 3-{[6-(dihydroxymethyl)piperidin-3-yl]oxy}-2-methylazetidine - 1-carboxylate (600 mg, 1.90 mmol, 1.00 equiv.) in MeOH (10 mL) was added SOCl2 (1.13 g, 9.48 mmol, 5.00 equiv.) dropwise at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum and the crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =223.2. Step 2: Preparation of methyl 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 - yl)methyl)-2-methylazetidin-3-yl)oxy)picolinate: [00247] To a stirred mixture of methyl 5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (380 mg, 1.71 mmol, 1.00 equiv.), KI (28 mg, 0.17 mmol, 0.10 equiv.) and 7-(chloromethyl)-3-ethyl-1H- 1,5-naphthyridin-2-one (456 mg, 2.05 mmol, 1.20 equiv.) in CH 3 CN (5 mL) was added DIEA (884 mg, 6.84 mmol, 4.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methy l]- 2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (400 mg, 57.3%) as a brown oil. LC-MS: (ES+H, m/z): [M+H] + =409.2 Step 3: Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)-2- methylazetidin-3-yl)oxy)picolinic acid: [00248] To a stirred solution of methyl 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methy l]- 2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (300 mg, 0.73 mmol, 1.00 equiv.) in MeOH (3 mL) was added NaOH (aqueous., 3 mL, 2N in H2O) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The aqueous layer was extracted with CH2Cl2 (2x30 mL). The mixture was acidified to pH 6-7 with HCl (aqueous.). The aqueous layer was concentrated under vacuum. The residue was purified by trituration with MeOH (40mL). The resulting mixture was filtered, the filter cake was washed with MeOH (1x20 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =395.2. Step 4: Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)-2- methylazetidin-3-yl)oxy)-N-(oxetan-3-yl)picolinamide: [00249] To a stirred mixture of 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methy l]-2- methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid (200 mg, 0.51 mmol, 1.00 equiv.), DIEA (262 mg, 2.03 mmol, 4.00 equiv.) and oxetan-3-amine (45 mg, 0.61 mmol, 1.20 equiv.) in DMF (5 mL) was added HATU (289 mg, 0.76 mmol, 1.50 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were washed with water (1x30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by Prep-HPLC to afford 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-(oxetan-3-yl)picol inamide (15.6 mg, 6.6%). LC-MS: (ES+H, m/z): [M+H] + =450.2. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 9.29 (d, 1H), 8.39 (d, 1H), 8.28 (d, 1H), 7.94 (d, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.45 (dd, 1H), 5.01 (q, 1H), 4.75-4.61 (m, 5H), 3.93 (d, 1H), 3.82 (t, 1H), 3.65 (d, 1H), 2.80 (t, 1H), 2.57 (d, 2H), 1.24-1.14 (m, 6H). Example 54 and 55
Step 1: Preparation of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid: [00250] To a solution of methyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.15 g, 4.95 mmol, 1.00 equiv.) in MeOH (15 mL) and H2O (3 mL) was added NaOH (0.59 g, 14.86 mmol, 3.00 equiv.) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The residue was acidified to pH 4 with 6N HCl (aqueous.). The resulting mixture was filtered, the solid was concentrated under reduced pressure to afford 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800.0 mg, crude). LC- MS: (ES+H, m/z): [M+H] + = 218.9. 1 H NMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H), 12.08 (s, 1H), 8.89 (d, 1H), 8.15 (d, 1H), 7.82 (s, 1H), 2.62-2.54 (m, 2H), 1.20 (t, 3H). Step 2: Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carb oxamide: [00251] To a solution of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800 mg, crude) and N,O- dimethylhydroxylamine (336 mg, 5.50 mmol, 1.50 equiv.) in DMF (8 mL) was added EDCI (2.10 g, 11.00 mmol, 3.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carb oxamide (540 mg, 45.44%). LC-MS: (ES+H, m/z): [M+H] + = 262.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.02 (s, 1H), 8.64 (d, 1H), 7.89 (dd, 1H), 7.80 (s, 1H), 3.58 (s, 3H), 3.31(s, 3H), 2.57 (q, 2H), 1.20 (t, 3H). Step 3: Preparation of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one: [00252] To a solution of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carb oxamide (540 mg, 2.07 mmol, 1.00 equiv.) in THF (5 mL) was added CH 3 MgBr (1.4 mL, 4.13 mmol, 2.00 equiv., 3M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at 0°C. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (397 mg, 88.83%). LC-MS: (ES+H, m/z): [M+H] + = 217.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 8.98 (s, 1H), 8.09 (d, 1H), 7.84 (d, 1H), 2.67 (s, 3H), 2.58 (q, 2H), 1.20 (t, 3H). Step 4: Preparation of 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)eth yl]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00253] A mixture of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (400 mg, 1.85 mmol, 1.00 equiv.) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide (614 mg, 2.78 mmol, 1.50 equiv.) in DCM (5 mL) was stirred for 15 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. To the above mixture was added tetrakis(propan-2- yloxy)titanium (1.58 g, 5.55 mmol, 3.00 equiv.). The resulting mixture was stirred for 4 h at 80°C under nitrogen atmosphere. The residue was dissolved in EtOH (10 mL). To the above mixture was added NaBH3CN (233 mg, 3.70 mmol, 2.00 equiv.). The resulting mixture was stirred for 4h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (20 mL) at room temperature. The resulting mixture was filtered, the filter cake was washed with CH2Cl2/MeOH=1:1 (3x40 mL). The filtrate was concentrated under reduced pressure. The crude product (350 mg) was purified by Prep-HPLC to afford 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)eth yl]-2-methylazetidin-3-yl]oxy}-N- methylpyridine-2-carboxamide (160 mg, 20.52%). Step 5: Preparation of 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)ethyl]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide and 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo- 5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N -methylpyridine-2-carboxamide: [00254] The racemate 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)eth yl]-2-methylazetidin- 3-yl]oxy}-N-methylpyridine-2-carboxamide (160 mg) was separated by Prep-Chiral-HPLC to afford 5- {[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl )ethyl]-2-methylazetidin-3-yl]oxy}-N- methylpyridine-2-carboxamide (66.6 mg, ee=100%). and 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methyl pyridine-2-carboxamide (48.6 mg, ee=100%). [00255] Example 54: LC-MS: (ES+H, m/z): [M+H] + = 422.15. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.81 (s, 1H), 8.55 (d, 1H), 8.39 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.41-7.35 (m, 1H), 4.55 (d, 1H), 3.72-3.40 (m, 4H), 2.77 (d, 3H), 2.56 (m, 2H), 1.43 (d, 3H), 1.28 (d, 3H), 1.17 (t, 3H). [00256] Example 55: LC-MS: (ES+H, m/z): [M+H] + = 422.15. 1 H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.58 (q, 1H), 8.45 (d, 1H), 8.24 (d, 1H), 7.96 (d, 1H), 7.74 (s, 1H), 7.63 (d, 1H), 7.45 (dd, 1H), 4.55 (q, 1H), 4.02 (t, 1H), 3.60-3.49 (m, 1H), 3.25 (t, 1H), 2.92-2.73 (m, 4H), 2.60-2.52 (m, 2H), 1.19 (q, 6H), 0.70 (d, 3H). [00257] The following examples were made using similar procedures as shown for example 54 and 55: Example 63 Step 1: Preparation of tert-butyl (2R,3R)-2-methyl-3-{[4- (trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylate : To a stirred solution of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol, 1.00 equiv.) and Et 3 N (1.62 g, 16.02 mmol, 3.00 equiv.) and DMAP (0.03 g, 0.26 mmol, 0.05 equiv.) in DCM (20 mL) was added 4-(trifluoromethyl)benzenesulfonyl chloride (1.44 g, 5.87 mmol, 1.10 equiv.) in DCM(10 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 0°C under nitrogen atmosphere. The reaction was monitored by TLC (PE/EA=2/1, KMnO4). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)benzenesulfonyl]oxy} azetidine-1-carboxylate (1.7 g, 76.4%). 1 H NMR (300 MHz, Chloroform-d) δ 8.08-8.04 (m, 2H), 7.88-7.85 (m, 2H), 5.13-5.12 (m, 1H), 4.52-4.50 (m, 1H), 4.13 (dd, 1H), 3.86 (dd, 1H), 1.43 (s, 9H), 1.36 (d, 3H). Step 2: Preparation of tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2- methylazetidine-1-carboxylate: [00258] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-{[4- (trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylate (1.00 g, 2.52 mmol, 1.00 equiv.) and methyl 1H-pyrrolo[3,2-b]pyridine-5-carboxylate (445 mg, 2.52 mmol, 1.00 equiv.) in DMF (20 mL) was added Cs2CO3 (1.65 g, 5.05 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred for 2h at 110°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with H2O (3 x 100 mL). The organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (2R,3S)-3-[5- (methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidi ne-1-carboxylate (460 mg, 52.2%). LC-MS: (ES+H, m/z): [M+H] + = 346.1 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.24 (d, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 6.83 (d, 1H), 5.08-5.06 (m, 1H), 4.53-4.50 (m, 1H), 4.27-4.25 (m, 1H), 4.21-4.10 (m, 1H), 3.89 (s, 3H), 1.47 (d, 3H), 1.43 (s, 9H). Step 3: Preparation of tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin -1- yl]azetidine-1-carboxylate: [00259] To a stirred solution of tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2- methylazetidine-1-carboxylate (460 mg, 1.39 mmol, 1.00 equiv.) and ACN (3 mL) was added CH3NH2 in water (3 mL, 30%wt) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 6h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with sat. NH4Cl (aqueous.50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (2R,3S)-2-methyl-3-[5- (methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carb oxylate (450 mg, 93.2%). LC-MS: (ES+H, m/z): [M+H] + = 345.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.66-8.64 (m, 1H), 8.18 (d, 1H), 8.09-8.03 (m, 1H), 7.90 (d, 1H), 6.75 (d, 1H), 5.07-5.03 (m, 1H), 4.53-4.51(m, 1H), 4.27 (t, 1H), 4.14 (dd, 1H), 2.84 (d, 3H), 1.47 (d, 3H), 1.43 (s, 9H). Step 4: Preparation of N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyri dine-5- carboxamide hydrochloride: [00260] To a stirred mixture of tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin - 1-yl]azetidine-1-carboxylate (450 mg, 1.30 mmol, 1.00 equiv.) and HCl(gas)in 1,4-dioxane (5 mL, 4M/L in dioxane). The resulting mixture was stirred for 1h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane/Et 2 O=1:1 (50 mL). The crude product N-methyl-1-[(2R,3S)-2-methylazetidin-3- yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride (320 mg) was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + = 245.1 Step 5: Preparation of 1-[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl ]-2- methylazetidin-3-yl]-N-methylpyrrolo[3,2-b]pyridine-5-carbox amide: [00261] To a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv.) and N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyri dine-5-carboxamide hydrochloride (241 mg, assumed 100% yield, 0.98 mmol, 1.10 equiv.) and KI (29 mg, 0.18 mmol, 0.20 equiv.) in ACN (5 mL) was added DIEA (580 mg, 4.49 mmol, 5.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford crude product. The residue was dissolved in DMSO (3 mL). The residue was purified by Prep-HPLC. The pure fraction was concentrated under vacuum then lyophilized to afford 1- [(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]- 2-methylazetidin-3-yl]-N-methylpyrrolo[3,2- b]pyridine-5-carboxamide (126.2 mg, 32.2%). LC-MS: (ES+H, m/z): [M+H] + = 431.15. Optical rotation [a] 25 D (c = 0.5, MeOH): -26.4º; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 8.65 (d, 1H), 8.45 (d, 1H), 8.18-8.11 (m, 2H), 7.87 (d, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 6.75 (d, 1H), 4.86 (d, 1H), 4.1 (d, 1H), 3.82-3.76 (m, 2H), 3.68-3.63 (m, 1H), 3.31-3.29 (m, 1H), 2.84 (d, 3H), 2.56-2.51 (m, 2H), 1.2-1.16 (m, 6H). [00262] The following examples were made using similar procedures as shown for example 63: Example 66 Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-3- fluoropyridine-2-carboxylate: [00263] A solution of methyl 3-fluoro-5-hydroxypyridine-2-carboxylate (500 mg, 2.92 mmol, 1.00 equiv.), tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (547 mg, 2.92 mmol, 1.00 equiv.) and PPh3 (1.53 g, 5.84 mmol, 2.00 equiv.) in PhMe (20 mL) was treated with DBAD (1.35 g, 5.84 mmol, 2.00 equiv.) in PhCH3 (5 mL) at 0 °C. The resulting mixture was stirred for 2 h at 60 °C. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (1 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] oxy}-3-fluoropyridine- 2-carboxylate (4.2 g, crude) as a black oil. The crude resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + = 341.05. Step 2: Preparation of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-3- fluoropyridine-2-carboxylic acid: [00264] A solution of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] oxy}-3- fluoropyridine-2-carboxylate (4.00 g, Crude) in THF (14 mL) was treated with NaOH (0.94 g, 23.50 mmol, 2.00 equiv.) in H2O (7 mL) at 0 °C. The resulting mixture was stirred for 1h at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 ml). The resulting mixture was extracted with EtOAc (3 x 70 mL). The aqueous layer was acidified to pH 4 with HCl (aqueous.1mol/L). The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (1x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin- 3-yl] oxy}-3-fluoropyridine-2-carboxylic acid (900 mg, 94.2%, over two steps). LC-MS: (ES+H, m/z): [M+H] + =327.1. Step 3: Preparation of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]ox y}-2- methylazetidine-1-carboxylate: [00265] A solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] oxy}-3-fluoropyridine- 2-carboxylic acid (600 mg, 1.83 mmol, 1.00 equiv.) in DMF (10 mL) was treated with HATU (1.05 g, 2.75 mmol, 1.50 equiv.) for 10 min at room temperature followed by the addition of aminocyclopropane (524 mg, 9.19 mmol, 5.00 equiv.) and DIEA (950. mg, 7.35 mmol, 4.00 equiv.) at room temperature. The resulting mixture was stirred for additional 1.5h at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (1x 80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl] oxy}-2- methylazetidine-1-carboxylate (600 mg, 89.3%). LC-MS: (ES+H, m/z): [M+H] + =366.10. 1 H NMR (300 MHz, DMSO-d6): δ 8.48 (d,1H), 8.12 (dd,1H), 7.40 (dd,1H), 4.83- 4.78 (m,1H), 4.31-4.22 (m, 2H), 3.64 (dd,1H), 2.87-2.81 (m, 1H), 1.39 (s, 9H), 1.43 (d, 3H), 0.71- 0.65 (m, 2H), 0.62-0.57 (m, 2H). Step 4: Preparation of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl] oxy} pyridine-2- carboxamide hydrochloride: A solution of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl] oxy}-2- methylazetidine-1-carboxylate (600 mg, 1.64 mmol, 1.00 equiv.) in EA (20 mL) was treated with HCl(gas)in 1,4-dioxane (10 mL,4M) at 0°C. The resulting mixture was stirred for 1.5h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl] oxy} pyridine-2-carboxamide hydrochloride (600 mg, Crude). LC-MS: (ES+H, m/z): [M+H] + =266.05. Step 5: Preparation of N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyri din-3-yl) methyl]- 2-methylazetidin-3-yl] oxy}-3-fluoropyridine-2-carboxamide: [00266] To a stirred mixture of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl] oxy} pyridine- 2-carboxamide hydrochloride (285 mg, assumed 100% yield, 1.07 mmol, 1.20 equiv.) and DIEA (464 mg, 3.59 mmol, 4.00 equiv.) in MeCN (10 mL) were added 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv.) and KI (29.82 mg, 0.18 mmol, 0.20 equiv.) at room temperature. The resulting mixture was stirred for additional 2h at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 40 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography. The resulting mixture was concentrated under reduced pressure. This resulted in N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H- 1,5-naphthyridin-3-yl) methyl]-2-methylazetidin-3-yl] oxy}-3-fluoropyridine-2-carboxamide (112.9 mg, 27.8%). LC-MS: (ES+H, m/z): [M+H] + =452.20. Optical rotation [a] 25 D (c = 0.1, MeOH): -6.0º; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.86 (s, 1H), 8.46 (d, 1H), 8.38 (d, 1H), 8.15 (d, 1H), 7.74 (s, 1H), 7.58 (d, 1H), 7.41 (dd, 1H), 4.64 (q, 1H), 3.91 (d, 1H), 3.82 (t, 1H), 3.64 (d, 1H), 3.38 (t, 1H), 2.85-2.75 (m, 2H), 2.56- 2.53 (m, 2H), 1.28 (m, 6H), 0.69-0.63 (m, 2H), 0.61-0.56 (m, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ - 118.55. Example 75 Step 1: Preparation of 7-bromo-1H-1,5-naphthyridin-2-one: [00267] To a stirred mixture of 5-aminopyridin-2-ol (5.00 g, 45.41 mmol, 1.00 equiv.) in AcOH (60 mL) was added 2,2,3-tribromopropanal (13.38 g, 45.40 mmol, 1.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 70°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-bromo-1H-1,5-naphthyridin-2-one (2.50 g, 24.4%). LC-MS: (ES+H, m/z): [M+H] + =225.00/227.00. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 9.8 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 9.8 Hz, 1H). Step 2: Preparation of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one: [00268] To a stirred mixture of 7-bromo-1H-1,5-naphthyridin-2-one (2.30 g, 10.22 mmol, 1.00 equiv.) in MeCN (20 mL) and H 2 O (6 mL) were added sodium difluoromethanesulfinate (3.53 g, 20.44 mmol, 2.00 equiv., 80%wt) and potassium peroxydisulfate (11.05 g, 40.88 mmol, 4.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered; the filter cake was washed with DCM/MeOH (10:1) (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (490 mg, 17.4%). LC- MS: (ES+H, m/z): [M+H] + =275.00/277.00. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.40 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.17-6.76 (m, 1H). 19 F NMR (282 MHz, DMSO- d 6 ) δ-119.76. Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-o ne: [00269] To a stirred solution of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (2.20 g, 7.99 mmol, 1.00 equiv.) in 1,4-dioxane (30 mL) were added (tributylstannyl)methanol (2.83 g, 8.79 mmol, 1.10 equiv.) and 2nd Generation XPhos Precatalyst (314 mg, 0.40 mmol, 0.05 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-(difluoromethyl)-7-(hydroxymethyl)- 1H-1,5-naphthyridin-2-one (650 mg, 35.9%). LC-MS: (ES+H, m/z): [M+H] + =227.1. 1 H NMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.18- 6.78 (m, 1H), 5.57 (t, J = 5.6 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -119.24. Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-on e: [00270] To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-o ne (290 mg, 1.28 mmol, 1.00 equiv.) in DCM (5 mL) were added DMF (9 mg, 0.12 mmol, 0.10 equiv.) and SOCl2 (0.93 mL, 12.82 mmol, 10.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 7-(chloromethyl)-3- (difluoromethyl)-1H-1,5-naphthyridin-2-one (310 mg,crude). LC-MS: (ES+H, m/z): [M+H] + =245.1. Step 5: Preparation of N-cyclopropyl-5-{[(2R,3S)-1-{[7-(difluoromethyl)-6-oxo-5H-1, 5-naphthyridin- 3-yl]methyl}-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamid e: [00271] To a stirred solution of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-on e (110 mg, 0.45 mmol, 1.00 equiv.), N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine -2-carboxamide (144 mg, 0.58 mmol, 1.30 equiv.) and KI (14 mg, 0.09 mmol, 0.20 equiv.) in ACN (5 mL) was added DIEA (290 mg, 2.25 mmol, 5.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The residue was dissolved in water (50 mL). The solution was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford crude product (90 mg). The crude product was isolated by PREP_HPLC to afford N-cyclopropyl-5-{[(2R,3S)-1-{[7-(difluoromethyl)-6-oxo-5H-1, 5-naphthyridin-3-yl]methyl}-2- methylazetidin-3-yl]oxy}pyridine-2-carboxamide (54.6 mg, 26.39%, 99.0% purity, [a]D 25 = -9.800 (C=1, MeOH:DCM=1:1) test in PHA). LC-MS: (ES+H, m/z): [M+H] + =456.15. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.30 (s, 1H), 8.54-8.47 (m, 2H), 8.22 (d, 1H), 8.16 (s, 1H), 7.95 (d, 1H), 7.68 (d, 1H), 7.44 (dd, 1H), 6.98 (t, 1H), 4.72-4.51 (m, 1H), 3.98 (d, 1H), 3.89-3.78 (m, 1H), 3.71 (d, 1H), 3.45-3.35 (m, 1H), 2.95-2.74 (m, 2H), 1.22 (d, 3H), 0.73-0.55 (m, 4H). 19 F NMR (282 MHz, DMSO-d 6 ) δ -119.30. Example 76 Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine: [00272] To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv.) in MeOH (50 mL) was added NaOMe (15.76 g, 87.49 mmol, 1.10 equiv., 30%wt) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=1:1, R f = 0.4). The resulting mixture was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (1x200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 3-bromo- 2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70(s, 3H). Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylet hen-1-amine: [00273] A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv.) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: [00274] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethy lamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by TLC. The reaction was quenched by the addition of sat. sodium hyposulfite (aqueous.) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H). Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: [00275] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv.) in EtOH (100 mL) were added SnCl2 (26.25 g, 134.09 mmol, 5.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford crude product. The crude product was purified by trituration with hexane (50 mL) to afford ethyl 7-bromo-6- methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, over three steps). LC-MS: (ES+H, m/z): [M+H] + =311.0/313.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 4.42 (q, 2H), 4.12 (s, 3H), 1.39 (t 3H). Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate: [00276] To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv.) in DMF (10 mL) was added CuCl (0.57 g, 5.78 mmol, 1.50 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120°C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3x30 mL of Water (10% NH3 ^H 2 O). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 77.78%). LC-MS: (ES+H, m/z): [M+H] + =267.0. 1 H NMR (300 MHz, DMSO-d6) δ 9.27 (d, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 4.41 (q, 2H), 4.12 (s, 3H), 1.37 (t, 3H). Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate: [00277] To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv.) in CH 3 CN (8 mL) was added TMSI (1.80 g, 9.00 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50°C.The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was washed with 3x50 mL of water (10% Et 3 N). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 97.64%). LC- MS: (ES+H, m/z): [M+H] + =252.9. 1 H NMR (300 MHz, DMSO-d 6 ) δ12.61 (s, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 8.20 (s, 1H), 4.39 (q, 2H), 1.36 (t, 3H). Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: [00278] To a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv.) in THF (6 mL) was added LiAlH4 (2.5 mL, 5.85 mmol, 2.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at 0°C. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1 M HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 40.53%). LC-MS: (ES+H, m/z): [M+H] + =211.00. 1 H NMR (400 MHz, DMSO-d6) δ12.49 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.69 (d, 1H), 5.53 (t, 1H), 4.64 (d, 2H). Step 8: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: [00279] To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv.) in CH2Cl2 (5 mL) was added SOCl2 (423 mg, 3.56 mmol, 3.00 equiv.) and DMF (8 mg, 0.11 mmol, 0.10 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude). The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =228.95. Step 9: Preparation of 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyridin-3-yl)meth yl]-2- methylazetidin-3-yl]oxy}-N-cyclopropylpyridine-2-carboxamide : [00280] A mixture of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine -2-carboxamide hydrochloride (178 mg, 0.72 mmol, 1.10 equiv.), 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (150 mg, 0.65 mmol, 1.00 equiv.), KI (21 mg, 0.13 mmol, 0.20 equiv.) and DIEA (423 mg, 3.27 mmol, 5.00 equiv.) in ACN (3 mL) was stirred for 8 h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was cooled down to r.t. and poured into 50 mL of water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-cyclo propylpyridine-2-carboxamide (82.1 mg, 27.93%). LC-MS: (ES+H, m/z): [M+H] + =440.15. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.45 (s, 1H), 8.52 (d, 1H), 8.46 (d, 1H), 8.27 (s, 1H), 8.21 (d, 1H), 7.95 (d, 1H), 7.66 (d, 1H), 7.44 (dd, 1H), 4.62 (q, 1H), 3.95 (d, 1H), 3.82 (t, 1H), 3.67 (d, 1H), 3.40 (q, 1H), 2.93-2.74 (m, 2H), 1.21 (d, 3H), 0.76-0.57 (m, 4H). Example 106
Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide: [00281] To a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 equiv.) in DCM (300 mL) was added Pyridine (14.99 g, 189.45 mmol, 1.80 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5 min at room temperature under nitrogen atmosphere. To the above mixture was added (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 equiv.) dropwise over 5 min at room temperature. The resulting mixture was stirred for additional 2h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with water (3x500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (24.6 g, 81.1%). LC-MS: (ES+H, m/z): [M+H] + =288.0/290.0. Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one: [00282] A mixture of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (17.00 g, 59.00 mmol, 1.00 equiv.) in H2SO4 (85 mL) was stirred for 3h at room temperature under nitrogen atmosphere. The resulting mixture was added to ice water (1L) dropwise and stirred for 1h. The precipitated solids were collected by filtration and washed with water (3x200 mL). The resulting mixture was concentrated under reduced pressure to afford 7-bromo-8-fluoro-1H-quinolin-2-one (14.30 g, crude). LC-MS: (ES+H, m/z): [M+H] + =242.0/244.0. Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one: [00283] To a stirred mixture of 7-bromo-8-fluoro-1H-quinolin-2-one (3.00 g, 12.39 mmol, 1.00 equiv.) and NCS (2.65 g, 19.83 mmol, 1.60 equiv.) in CH 3 COOH (50 mL) was added 2,2-dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-bromo-3- chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude). LC-MS: (ES+H, m/z): [M+H] + =275.9/277.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.52-7.42 (m, 2H). Step 4: Preparation of 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one: [00284] To a stirred mixture of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, 8.97 mmol, 1.00 equiv.), CsF (4.09 g, 26.91 mmol, 3.00 equiv.), Pd(dppf)Cl 2 (0.33 g, 0.44 mmol, 0.05 equiv.) and 2-ethenyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 8.97 mmol, 1.00 equiv.) in dioxane (50 mL) was added H 2 O (5 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-chloro-7-ethenyl-8-fluoro-1H- quinolin-2-one (750 mg, 37.3%). LC-MS: (ES+H, m/z): [M+H] + =224.0. 1 H NMR (300 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.53-7.46 (m, 2H), 6.95 (dd, J = 17.7, 11.2 Hz, 1H), 6.07 (dd, J = 17.7, 1.0 Hz, 1H), 5.57 (dd, J = 11.2, 1.0 Hz, 1H). Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde: [00285] To a stirred mixture of 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv.), K2OsO2(OH)4 (123 mg, 0.33 mmol, 0.10 equiv.), NaIO4 (2.87 g, 13.41 mmol, 4.00 equiv.) and 2,6- dimethylpyridine (718 mg, 6.70 mmol, 2.00 equiv.) in THF (15 mL) was added H2O (1.5 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (630 mg, 83.2%). LC-MS: (ES-H, m/z): [M- H]- =224.1. Step 6: Preparation of 5-{[(2R,3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)met hyl]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00286] A mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (100 mg, 0.44 mmol, 1.00 equiv.) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide (98 mg, 0.44 mmol, 1.00 equiv.) in DCM (10 mL) was stirred for 10 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. To the above mixture was added CH 3 COOH (13 mg, 0.22 mmol, 0.50 equiv.) and EtOH (10 mL) at room temperature. The resulting mixture was stirred for additional 4h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. To the above mixture was added NaBH 3 CN (56 mg, 0.88 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The reaction was monitored by LCMS. The reaction was quenched with Water (3 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-{[(2R,3S)-1-[(3-chloro- 8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]-2-methylazetidin-3-y l]oxy}-N-methylpyridine-2-carboxamide (180 mg, crude). The crude product was purified by Prep-HPLC to afford 5-{[(2R,3S)-1-[(3-chloro-8-fluoro- 2-oxo-1H-quinolin-7-yl)methyl]-2-methylazetidin-3-yl]oxy}-N- methylpyridine-2-carboxamide (97.2 mg, 50.8%). LC-MS: (ES+H, m/z): [M+H] + =431.05. Optical rotation [a] 25 D (c = 0.27, MeOH): +38.5º; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (s, 1H), 8.57 (q, J = 4.7 Hz, 1H), 8.35 (d, J = 1.3 Hz, 1H), 8.22 (d, J= 2.9 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 8.7, 2.9 Hz, 1H), 7.24 (dd, J = 8.1, 6.3 Hz, 1H), 4.58 (q, J = 5.9 Hz, 1H), 3.96-3.87 (m, 1H), 3.81 (t, J = 6.4 Hz, 1H), 3.73-3.64 (m, 1H), 3.39-3.34 (m, 1H), 2.79 (dd, J = 8.1, 5.7 Hz, 4H), 1.20 (d, J = 6.2 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -135.11. [00287] The following examples were made using similar procedures as shown for example 106: Example 110 Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-6- fluoropyridine-2-carboxylate: [00288] To a stirred mixture of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}pyridine- 2-carboxylic acid (800 mg, 2.59 mmol, 1.00 equiv) in DMF (10 mL) were added DIEA (1.00 g, 10.38 mmol, 4.00 equiv) and CH3I (320 µL, 5.19 mmol, 2.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (100 mL) and washed with brine (50x2 mL). The organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography to afford methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}- 6-fluoropyridine-2-carboxylate (500 mg, 56.6%). LC-MS: (ES+H, m/z): [M+H] + =323.1. Step 2: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-6- fluoropyridine-2-carboxylate: [00289] To a stirred mixture of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3- yl]oxy}pyridine-2-carboxylate (400 mg, 1.24 mmol, 1.00 equiv) in MeCN (10 mL) was added difluorosilver (904 mg, 6.20 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 40°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with CH 2 Cl 2 (250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3- yl]oxy}-6-fluoropyridine-2-carboxylate (250 mg, 59.2%). LC-MS: (ES+H, m/z): [M+H] + =341.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.99 (d, J = 8.2 Hz, 1H), 7.53 (dd, J = 10.1, 8.2 Hz, 1H), 4.89-4.79 (m, 1H), 4.37- 4.19 (m, 2H), 3.85 (s, 3H), 3.73-3.67 (m, 1H), 1.45 (d, J = 6.5 Hz, 3H), 1.39 (s, 9H). 19 F NMR (400 MHz, DMSO-d 6 ) δ -82.91. Step 3: Preparation of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-6- fluoropyridine-2-carboxylic acid: [00290] To a stirred mixture of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-6- fluoropyridine-2-carboxylate (900 mg, 2.64 mmol, 1.00 equiv) in THF (5 mL) was added LiOH.H2O (222 mg, 5.28 mmol, 2.00 equiv) (in 1mL water) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL). The aqueous layer was acidified to pH 3 with HCl (aq.1N). The aqueous layer was extracted with EA (2x100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-6- fluoropyridine-2-carboxylic acid (800 mg, 92.7%). LC-MS: (ES-H, m/z): [M-H]- =325.3. Step 4: Preparation of tert-butyl (3S)-3-({2-fluoro-6-(methyl-d3carbamoyl)pyridin-3-yl}oxy)-2- methylazetidine-1-carboxylate: [00291] To a stirred mixture of 5-{[(2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]ox y}-6- fluoropyridine-2-carboxylic acid (400 mg, 1.22 mmol, 1.00 equiv) and Methan-d3-amine,hydrochloride (259 mg, 3.67 mmol, 3.00 equiv) in CH 2 Cl 2 (5 mL) were added DIEA (792 mg, 6.13 mmol, 5.00 equiv) and T3P (1 g, 3.67 mmol, 3.00 equiv, 50% in CH 2 Cl 2 ) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was diluted with ethyl acetate (100 mL) and was washed with brine (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford tert-butyl (3S)-3-({2-fluoro-6- (methyl-d3carbamoyl)pyridin-3-yl}oxy)-2-methylazetidine-1-ca rboxylate (350 mg, 83.4%). LC-MS: (ES+H, m/z): [M+H-tBu] + =287.1. Step 5: Preparation of 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}p yridine-2- carboxamide hydrochloride: [00292] To a stirred mixture of tert-butyl (3S)-3-({2-fluoro-6-[(2H3)methylcarbamoyl]pyridin-3-yl}oxy)- 2-methylazetidine-1-carboxylate (350 mg, 1.02 mmol, 1.00 equiv) in CH 2 Cl 2 (5 mL) was added HCl(gas)in 1,4-dioxane (5 mL, 4M in dioxane) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to afford 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}p yridine-2-carboxamide hydrochloride (300 mg, crude). The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =243.2. Step 6: Preparation of 5-{[(2R,3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)me thyl]-2- methylazetidin-3-yl]oxy}-6-fluoro-N-methyl-d3 pyridine-2-carboxamide: [00293] To a stirred mixture of 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}p yridine-2- carboxamide hydrochloride (200 mg, 0.71 mmol, assumed 100% yield, 1.00 equiv) and 7-(bromomethyl)-3- ethyl-8-fluoro-1H-quinoxalin-2-one (204 mg, 0.71 mmol, 1.00 equiv) in MeCN (5 mL) were added KI (23 mg, 0.14 mmol, 0.20 equiv) and DIEA (463 mg, 3.59 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with CH2Cl2/MeOH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The crude product (400 mg) was purified by HP-FLASH, the pure fraction was concentrated under vacuum and lyophilized to afford 5- {[(2R,3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)meth yl]-2-methylazetidin-3-yl]oxy}-6-fluoro-N- methyl-d3 pyridine-2-carboxamide (163.8 mg, 50.5%). LC-MS: (ES+H, m/z): [M+H] + =447.15. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.44 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 10.2, 8.2 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 4.60 (q, J = 5.9 Hz, 1H), 3.90 (d, 1H), 3.81 (t, J = 6.4 Hz, 1H), 3.69 (d, 1H), 3.40 (q, J= 6.0 Hz, 1H), 2.81 (q, J = 7.3 Hz, 3H), 1.23-1.19 (m, 6H). 19 F NMR (400 MHz, DMSO-d6) δ -84.70, 136.09. Example Step 1-Step2: Preparation of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide: [00294] To a stirred solution of 2H-pyrazole-3-carboxylic acid (3.00 g, 26.76 mmol, 1.00 equiv.) in SOCl 2 (30 mL) was stirred overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with toluene (3 x 50 mL). The resulting mixture was concentrated under reduced pressure. The crude product 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]dodeca-3,5,9,11-tetr aene-2,8-dione (2.3 g) was used in the next step directly without further purification. [00295] To a stirred solution of 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]dodeca-3,5,9,11-tetr aene-2,8-dione (2.30 g, 12.22 mmol, 1.00 equiv.) and 3-bromo-2,6-difluoroaniline (5.09 g, 24.45 mmol, 2.00 equiv.) in THF (100 mL,) was added NaHMDS (2mol/L, 30.56 mL, 61.12 mmol, 5.00 equiv.) dropwise at -10°C. The resulting mixture was stirred for additional 2h at -10°C. The reaction was monitored by LCMS. The mixture was neutralized to pH 7 with CH3COOH. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (6 g, 74.4%). LC- MS: (ES+H, m/z): [M+H] + =301.9. 1 H NMR (300 MHz, DMSO-d6) δ 13.49 (s, 1H), 10.01 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.78-7.66 (m, 1H), 7.25 (td, J = 9.1, 1.9 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H). 19 F NMR (282 MHz, DMSO-d6) δ -109.45, -117.16. Step 3: Preparation of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one: [00296] To a stirred solution of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (5.80 g, 19.20 mmol, 1.00 equiv.) in DMA (2 mL) was added NaH (1.15 g, 28.80 mmol, 1.50 equiv, 60%) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (50 mL) at 0°C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (20 mL). The residue was purified by reverse flash chromatography to afford 7-bromo-6-fluoro-5H- pyrazolo[1,5-a]quinoxalin-4-one (1.5 g, 26.3%). LC-MS: (ES+H, m/z): [M+H] + =281.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.21 (s, 1H). Step 4: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-on e: [00297] To a stirred solution of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (1.00 g, 3.54 mmol, 1.00 equiv.) and (tributylstannyl)methanol (1366 mg, 4.25 mmol, 1.20 equiv.) in dioxane (16 mL) was added 2nd Generation XPhos Precatalyst (279 mg, 0.35 mmol, 0.10 equiv.) at RT under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with DCM/MeOH=(1:5) (3x150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-on e (400 mg, 45.9%). LC-MS: (ES+H, m/z): [M+H] + =234.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.5, 1.4 Hz, 1H), 7.38 (dd, J = 8.5, 7.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 5.42 (t, J = 5.8 Hz, 1H), 4.63(dd, J = 5.8, 1.5 Hz, 2H). Step 5: Preparation of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one : [00298] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-on e (300 mg, 1.28 mmol, 1.00 equiv.) in DCM (8 mL) were added SOCl2 (765 mg, 6.43 mmol, 5.00 equiv.) and DMF (5 mg, 0.07 mmol, 0.05 equiv.) dropwise at RT. The resulting mixture was stirred overnight at RT. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with DCM (3x30 mL). The crude product(7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxal in-4-one ) was used in the next step directly without further purification. LC-MS: (ES+H, m/z): [M+H] + =252.0 Step 6: Preparation of 5-{[(2R,3S)-1-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin- 7-yl}methyl)-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00299] To a stirred solution of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (120 mg, 0.47 mmol, 1.00 equiv) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide hydrochloride (147 mg, 0.57 mmol, 1.20 equiv) in MeCN (6 mL) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (246 mg, 1.90 mmol, 4.00 equiv) at RT under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-{[(2R,3S)-1-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin- 7-yl}methyl)-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (88 mg, 42.2%). LC-MS: (ES+H, m/z): [M+H] + =437.1. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.99-7.88 (m, 2H), 7.43 (dd, J = 8.7, 2.9 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 4.59 (d, J = 5.9 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.83 (t, J = 6.3 Hz, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.41-3.38 (m, 1H), 2.85-2.75 (m, 4H), 1.22 (d, J = 6.1 Hz, 3H). 19 F NMR (282 MHz, DMSO-d 6 ) δ - 131.63. [00300] The following examples were made using similar procedures as shown for example 113: Example 115 Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate: [00301] A solution of methyl 3-amino-2-fluorobenzoate (20.00 g, 118.23 mmol, 1.00 equiv) and NIS (23.94 g, 106.41 mmol, 0.90 equiv) in AcOH (250 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography to afford methyl 3-amino-2-fluoro-4- iodobenzoate (4.00 g, 11.4%). LC-MS: (ES+H, m/z): [M+H] + =295.80. 1 H NMR (300 MHz, DMSO- d6) δ 7.52(dd, J = 8.4, 1.5 Hz, 1H), 6.81(dd, J = 8.3, 6.7 Hz, 1H), 5.43(s, 2H), 3.83 (s, 3H). Step 2: Preparation of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate: [00302] Into a 250 mL round-bottom flask were added methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 13.55 mmol, 1.00 equiv), 3-furoic acid (1.52 g, 13.55 mmol, 1.00 equiv), T3P (43.14 g, 67.78 mmol, 5.00 equiv, 50% in EA) and DIEA (2.08 g, 16.10 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 2- fluoro-3-(furan-3-amido)-4-iodobenzoate (4.50 g, 85.3%). LC-MS: (ES+H, m/z): [M+H] + =389.85. 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.99 (s, 1H), 8.40 (s, 1H), 7.91 (dd, J= 8.4, 1.2 Hz, 1H), 7.83 (t, J = 1.7 Hz, 1H), 7.61 (dd, J = 8.4, 7.0 Hz, 1H), 7.02-6.96 (m, 1H), 3.86 (s, 3H). Step 3: Preparation of methyl 3-[N-(tert-butoxycarbonyl) furan-3-amido]-2-fluoro-4-iodobenzoate: [00303] To a stirred mixture of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate (2.60 g, 6.68 mmol, 1.00 equiv) and (Boc) 2 O (2.92 g, 13.36 mmol, 2.00 equiv) in DCE (50 mL) was added DMAP (0.82 g, 6.68 mmol, 1.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE: EA=5:1). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 3-[N-(tert-butoxycarbonyl) furan-3-amido]-2-fluoro-4- iodobenzoate (3.00 g, 91.7%). Step 4: Preparation of methyl 6-fluoro-4-oxo-5H-furo[3,2-c] quinoline-7-carboxylate: [00304] To a stirred solution of methyl 3-[N-(tert-butoxycarbonyl) furan-3-amido]-2-fluoro-4- iodobenzoate (3.00 g, 6.13 mmol, 1.00 equiv) in DMF (30 mL) was added PCy3 (344 mg, 1.22 mmol, 0.20 equiv), Pd(OAc)2 (275 mg, 1.22 mmol, 0.20 equiv), K2CO3 (1.69 g, 12.26 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2h at 120°C. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 6- fluoro-4-oxo-5H-furo[3,2-c] quinoline-7-carboxylate (310 mg, 19.3%). LC-MS: (ES+H, m/z): [M+H+MeCN] + =302.95. Step 5: Preparation of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c] quinoline-7-carboxylate: [00305] To a stirred solution of methyl 6-fluoro-4-oxo-5H-furo[3,2-c] quinoline-7-carboxylate (200 mg, 0.76 mmol, 1.00 equiv) in CF3CH2OH (50 mL) was added Pd/C (163 mg, 10%) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered; the filter cake was washed with CH 2 Cl 2 /MeOH (10:1, 3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c] quinoline-7-carboxylate (70 mg, 34.7%). LC-MS: (ES+H, m/z): [M+H] + =263.95. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.68 (s, 1H), 7.58 (dd, J = 8.4, 6.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 4.85 (t, J = 9.4 Hz, 2H), 3.89 (s, 3H), 3.10 (t, J = 9.4 Hz, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -124.45. Step 6: Preparation of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c] quinolin-4-one: [00306] To a stirred solution of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c] quinoline-7-carboxylate (60 mg, 0.22 mmol, 1.00 equiv) in THF (5 mL) was added LiAlH 4 (0.18 mL, 0.45 mmol, 2.00 equiv, 2.5M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of HCl.aq. (1M, 0.5 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 6-fluoro-7-(hydroxymethyl)-2H,3H,5H- furo[3,2-c] quinolin-4-one (50 mg, 93.2%). LC-MS: (ES+H, m/z): [M+H] + =236.0 Step 7: Preparation of 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c] quinolin-4-one: [00307] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c] quinolin-4-one (50 mg, 0.21 mmol, 1.00 equiv) and DMF (2 mg, 0.02 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl 2 (253 mg, 2.13 mmol, 10.00 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 7-(chloromethyl)-6- fluoro-2H,3H,5H-furo[3,2-c] quinolin-4-one (50 mg, 92.7%). LC-MS: (ES+H, m/z): [M+H] + =254.0 Step 8: Preparation of 5-{[(2R,3S)-1-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c] quinolin-7-yl} methyl)-2- methylazetidin-3-yl] oxy}-N-methylpyridine-2-carboxamide: [00308] A solution of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl] oxy} pyridine-2-carboxamide (62 mg, 0.28 mmol, 1.10 equiv) in MeCN (3 mL) was treated with DIEA (132 mg, 1.02 mmol, 4.00 equiv) for 5 min at room temperature under nitrogen atmosphere followed by the addition of KI (4 mg, 0.02 mmol, 0.10 equiv) and 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c] quinolin-4-one (65 mg, 0.25 mmol, 1.00 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5- {[(2R,3S)-1-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c] quinolin-7-yl} methyl)-2-methylazetidin-3-yl] oxy}-N- methylpyridine-2-carboxamide (62.0 mg, 54.0%). LC-MS: (ES+H, m/z): [M+H] + =439.10. 1 H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.46-7.34 (m, 2H), 7.24-7.15 (m, 1H), 4.82 (t, J = 9.3 Hz, 2H), 4.58 (q, J = 5.9 Hz, 1H), 3.96-3.76 (m, 2H), 3.69 (d, J = 13.3 Hz, 1H), 3.40-3.36 (m, 1H), 3.07 (t, J = 9.2 Hz, 2H), 2.81-2.74 (m, 4H), 1.19 (d, J = 6.2 Hz, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -133.55. [00309] The following examples were made using similar procedures as shown for example 113: Example 121 Step 1: Preparation of ethyl 4-fluoro-2H-pyrazole-3-carboxylate: [00310] To a stirred solution of 4-fluoro-2H-pyrazole-3-carboxylic acid (850 mg, 6.53 mmol, 1.00 equiv) in EtOH (15 mL) was added SOCl2 (4.66 g, 39.21 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 70 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to afford ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, Y=96.7%). LC-MS: (ES- H, m/z): [M-H]- =157.1. 1 H NMR (300 MHz, DMSO-d6) δ 7.60 (d, J = 4.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). Step 2: Preparation of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylateðyl 1-benzyl-4-fluoro- 1H-pyrazole-5-carboxylate & ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate: [00311] To a stirred solution of ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, 6.32 mmol, 1.00 equiv) and K 2 CO 3 (2.62 g, 18.97 mmol, 3.00 equiv) in DMF (30 mL) was added (bromomethyl)benzene (2.16 g, 12.64 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (150 mL). The resulting mixture was washed with 2x100 mL of water, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford a mixture of ethyl 1-benzyl-4-fluoro-1H- pyrazole-3-carboxylate & ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate (1.30 g, Y=82.8%). LC-MS: (ES+H, m/z): [M+H] + =249.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.50 – 7.29 (m, 6H), 7.28 – 7.20 (m, 4H), 5.69 (s, 1H), 5.32 (s, 2H), 4.46 (q, J = 7.2 Hz, 2H), 4.36 (q, J = 7.1 Hz, 1H), 1.43 (t, J = 7.1Hz, 3H), 1.36 (t, J = 7.1 Hz, 2H). Step 3: Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid & 1-benzyl-4-fluoro-1H- pyrazole-5-carboxylic acid: [00312] To a stirred solution of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate & ethyl 1-benzyl-4- fluoro-1H-pyrazole-5-carboxylate (1.30 g, 5.23 mmol, 1.00 equiv) in THF (15 mL) was added LiOH (15 mL, 30.00 mmol, 5.73 equiv, 2M in water) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (1x80 mL). The aqueous layer was acidified to pH 6 with citric acid. The aqueous layer was extracted with EtOAc (3x100 mL). The organic layers were dried Na2SO4. The resulting mixture was concentrated under reduced pressure to afford 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid & 1-benzyl- 4-fluoro-1H-pyrazole-5-carboxylic acid (1.10 g, Y=95.4%). LC-MS: (ES-H, m/z): [M-H]- =219.1. Step 4: Preparation of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-c arboxamide & 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole -3-carboxamide: [00313] To a stirred solution of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid & 1-benzyl-4-fluoro-1H- pyrazole-5-carboxylic acid (1.10 g, 4.99 mmol, 1.00 equiv) in T3P (40 mL, 50% in EA) were added DIEA (1.94 g, 14.98 mmol, 3.00 equiv) and 3-bromo-2,6-difluoroaniline (1.25 g, 5.99 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with EtOAc (120 mL). The resulting mixture was washed with 2x100 mL of water, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford a mixture of 2- benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-car boxamide & 1-benzyl-N-(3-bromo-2,6- difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (1.60 g, Y=78.0%). LC-MS: (ES+H, m/z): [M+H] + =410.0/412.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 10.06 (s, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.84 – 7.67 (m, 2H), 7.45 – 7.28 (m, 7H), 7.28 – 7.15 (m, 3H), 5.56 (s, 1H), 5.40 (s, 2H). Step 5: Preparation of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate & ethyl 3-(1- benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzo ate: [00314] To a solution of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-c arboxamide & 1- benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3 -carboxamide (1.20 g, 2.92 mmol, 1.00 equiv) in EtOH (8 mL) was added Pd(dppf)Cl2 (214 mg, 0.29 mmol, 0.10 equiv) in a pressure tank. The mixture was purged with nitrogen for 10 min and then was pressurized to 50 atm with carbon monoxide at 120 °C for overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford a mixture of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4- difluorobenzoate & ethyl 3-(1-benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluoro benzoate (1.10 g, Y=93.2%). LC-MS: (ES+H, m/z): [M+H] + =404.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 10.00 (s, 2H), 8.21 (d, J = 4.4 Hz, 2H), 7.99 – 7.86 (m, 3H), 7.78 (d, J = 4.3 Hz, 1H), 7.46 – 7.25 (m, 16H), 7.23 – 7.16 (m, 2H), 5.56 (s,2H), 5.40 (s, 4H), 4.38-4.3 (m, 6H), 1.35-1.28 (m, 9H). Step 6: Preparation of ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amido)benzoate: [00315] To a solution of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate & ethyl 3-(1- benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzo ate (500 mg, 1.24 mmol, 1.00 equiv) in 20 mL MeOH/HCl=10:1 was added Pd(OH)2/C (1.04 g, 1.49 mmol, 1.20 equiv, 20%) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for overnight, filtered through a Celite pad, washed with DCM: MeOH=10:1(3x50 mL). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amido)benzoate (150 mg, Y=38.6%). LC-MS: (ES+H, m/z): [M+H] + =314.1. Step 7: Preparation of ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxyla te: [00316] To a stirred solution of ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amido)benzoate (160 mg, 0.51 mmol, 1.00 equiv) in DMF (10 mL) was added Cs2CO3 (499 mg, 1.53 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CH 2 Cl 2 : IPA=10:1 (3 x 30 mL). The combined organic layers were washed with water (2x40 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 3,6-difluoro-4-oxo-5H- pyrazolo[1,5-a]quinoxaline-7-carboxylate (60 mg, Y=40.0%). LC-MS: (ES-H, m/z): [M-H]- =292.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.11 (s, 1H), 8.32 (d, J = 3.8 Hz, 1H), 7.99 (dd, J = 8.8, 1.3 Hz, 1H), 7.77 (dd, J = 8.8, 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). Step 8: Preparation of 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin- 4-one: [00317] To a stirred solution of ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxyla te (60 mg, 0.20 mmol, 1.00 equiv) in THF (4 mL) was added LiEt 3 BH (0.61 mL, 0.61 mmol, 3.00 equiv, 1M in THF) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of Water (0.2mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5- a]quinoxalin-4-one (50 mg, Y= 97.2%). LC-MS: (ES-H, m/z): [M-H]- =249.9. Step 9: Preparation of 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4 -one: [00318] To a stirred solution of 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin- 4-one (50 mg, 0.19 mmol, 1.00 equiv) and DMF (1 mg, 0.02 mmol, 0.10 equiv) in DCM (1 mL) were added SOCl2 (118 mg, 0.99 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 7-(chloromethyl)-3,6-difluoro-5H- pyrazolo[1,5-a]quinoxalin-4-one (50 mg, crude). LC-MS: (ES-H, m/z): [M-H]- =268.0. Step 10: Preparation of 5-{[(2R,3S)-1-({3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxa lin-7-yl}methyl)- 2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide: [00319] To a stirred mixture of 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4 -one (120 mg, 0.44 mmol, 1.00 equiv) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-ca rboxamide hydrochloride (126 mg, 0.49 mmol, 1.10 equiv) in MeCN (5 mL) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (115 mg, 0.89 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with MeCN (3 x 5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MeCN (10 mL). The precipitated solids were collected by filtration and washed with MeCN (3x5 mL) to afford 5-{[(2R,3S)-1-({3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxa lin-7-yl}methyl)-2-methylazetidin-3- yl]oxy}-N-methylpyridine-2-carboxamide (87 mg, 43.0%). LC-MS: (ES+H, m/z): [M+H] + =455.10. 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.25 – 8.19 (m, 2H), 7.98 – 7.86 (m, 2H), 7.43 (dd, J = 8.7, 2.9 Hz, 1H), 7.33 (dd, J = 8.5, 6.8 Hz, 1H), 4.59 (q, J = 5.9 Hz, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.82 (t, J = 6.4 Hz, 1H), 3.68 (d, J = 13.0 Hz, 1H), 3.38 (d, J = 6.0 Hz, 1H), 2.82-2.78 (m, 4H), 1.22 (d, J = 6.2 Hz, 3H). 19 F NMR (282 MHz, DMSO-d 6 ) δ -131.38, -168.36. Example A: Cell Growth Inhibition Assay [00320] The objective of this study is to evaluate the effect of invention compounds on cell proliferation through the cell viability assay in DLD-1 BRCA2(-/-) and parental isogenic pair and MDA-MB-436 (mutated BRCA1) cell lines. The CellTiter-Glo (CTG) based cell viability assay is designed to determine the number of viable cells in the culture because of compound effect, by quantifying ATP, which indicates the presence of metabolically active cells. [00321] DLD-1 BRCA2(-/-) and parental isogenic pair were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both are culture at 37℃ with 5% CO2. Invention compounds were distributed to the 384 well plate (Corning, 3764) using Echo acoustic liquid handler to form a 1:3 serially diluted final concentration with top dose of 10 or 30 µM. The cells were seeded into the plate in the density of 50 cells/well (DLD-1 parental), 200 cells/well (DLD-1 BRCA2-/-), or 500 cells/well (MDA-MB-436). After a short spun, the cells were cultured in a well moisturized incubator at 37℃ with 5% CO 2 for 7 days without disturbance. The cell viability was measured by CellTiter Glo 2.0 assay kit (Promega, G9243), and growth inhibition rate was calculated and plotted against final compound concentration, and the data were fitted in Xfit to generate IC 50. Example B: Biochemical (FP) Assay [00322] Assays based on fluorescent polarization (FP) have been widely utilized in drug discovery due to the homogenous format, robust performance and lack of interference seen in other assays. To characterize our compounds, we utilized an assay measuring the displacement of a commercially available fluorescently labeled PARP 1/2 inhibitor (PARPi-FL, Tocris Biosciences, #6461) as exemplified in assays performed in WO2014/064149 and WO2021/013735A1. The assay was performed utilizing the following method: [00323] Compounds were dissolved in DMSO an Echo550 liquid handler was utilized to make serial dilations in the desired concentration range in Optiplate-384F plates.100% DMSO was used for the high (with protein) and low (without protein) control samples.20nL of compound or DMSO alone was added to individual assay plate wells. [00324] PARP1 and PARP2 protein were expressed, purified, and diluted in assay buffer containing 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCI 2 , 150 mM NaCI to a final concentration of 20nM. The PARPi-FL was then added at a final concentration of 3nM. [00325] The assay plate is centrifuged at 1000rpm for 1min and incubated for 4h at room temperature. [00326] The fluorescent polarization is read using an Envision plate reader using the following settings: Excitation filter - FITC FP 480-Ex Slot 3 Emission filter - FITC FP P-pol 535-Em Slot 4 2nd Emission filter - FITC FP S-pol 535-Em Slot 3 Mirror module - FITC FP Dual Enh-Slot 1 [00327] The inhibition rate is calculated using the percentage of permuted Mahalanobis distances greater than the control samples (mP value) following the equation below: [00328] [00329] XLFit (equation 201) is used to calculate a reported IC50 for each compound. [00330] The data from examples A and B are provided in Table 2. TABLE 2