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AKT3 MODULATORS

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  • Publication Date:
    March 6, 2025
  • Additional Information
    • Document Number:
      20250074905
    • Appl. No:
      18/707078
    • Application Filed:
      November 04, 2022
    • Abstract:
      Compounds of Formula Ia or Ib are described, where the various substituents are defined herein. The compounds can e modulate a property or effect of Akt3 in vitro or in vivo, and can also be used, individually or in combination with other agents, in the CN prevention or treatment of a variety of conditions. Methods for synthesizing the compounds are described. Pharmaceutical compositions and methods of using these compounds or compositions, individually or in combination with other agents or compositions, in the prevention or treatment of a variety of conditions are also described. [chemical expression included]
    • Claim:
      1. A compound of Formula Ia or Ib: [chemical expression included] or a pharmaceutically acceptable salt thereof; wherein: [chemical expression included] n is an integer from 0-4 where valence permits; each occurrence of X1, X2, X3, X4, X5, X6, X7, X8, and X9 is independently CR1 or N; each occurrence of R1 is independently selected from the group consisting of H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C10)bicycloalkyl, (C4-C14)tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C10)heterobicycloalkyl, (C4-C14)heterotricycloalkyl, (C4-C10)heterospiroalkyl, (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkenyl, (C4-C10)bicycloalkenyl, (C4-C10)heterobicycloalkenyl, (C4-C14)tricycloalkenyl, (C4-C14)heterotricycloalkenyl, aryl, heteroaryl, —ORa, —SRa, —N(Ra)2, —CORa, —CO2Ra, CON(Ra)2, —CN, —NC, NO2, N3, —SO2Ra, —SO2N(Ra)2, —N(Ra)SO2Ra, [chemical expression included] and a partially saturated bicyclic heteroaryl optionally substituted by one or more (C1-C6)alkyl, halogenated (C1-C6)alkyl, —SO2Ra, or —SO2N(Ra)2; (C3-C7)cycloalkyl, (C4-C10)bicycloalkyl, (C4-C14)tricycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C10)heterobicycloalkyl, (C4-C14)heterotricycloalkyl, (C4-C10)heterospiroalkyl, (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkenyl, (C4-C10)bicycloalkenyl, (C4-C10)heterobicycloalkenyl, (C4-C14)tricycloalkenyl, (C4-C14)heterotricycloalkenyl, aryl, and heteroaryl of R1 are each optionally substituted by one or more (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, —ORa, —CN, or —N(Ra)2; Q is C(Ra)2, O, NRa, N(C═O)Ra, or NSO2Ra; Y1, Y2, Y3, Y4, and Y5 are each independently N or CR2 where valance permits; except that when Y3 or Y4 is connected to -E-G, Y3 or Y4 is C; R2 is selected from the group consisting of H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, (C4-C10)bicycloalkyl, (C4-C10)bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C10)heterobicycloalkyl, (C4-C10)heterobicycloalkenyl, (C4-C10)heterospiroalkyl, (C4-C10)tricycloalkyl, (C4-C10)tricycloalkenyl, aryl, heteroaryl, —ORa, —SRa, —N(Ra)2, —CORa, —CO2Ra, CON(Ra)2, —CN, —NC, NO2, N3, —SO2Ra, —SO2N(Ra)2, —N(Ra)SO2Ra, [chemical expression included] -E-G- is connected to Y3 or Y4 and is —(C═O)NRx—, —NRx(C═O)—, —N(Rx)(C═O)N(Rx)—, —O(C=O)N(Rx)—, —N(Rx)(C═O)O—, —SO2NRx—, —NRxSO2—, or [chemical expression included] wherein each occurrence of Rx is independently H, (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, or heteroaryl; or wherein Rx and Y3, Rx and Y4, Rx and Z1, or Rx and Z4 taken together form a 5-6-membered heterocycle optionally substituted by one or more Ry, wherein each occurrence of Ry is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen; or wherein two Ry can optionally bond together to form a 3-6-membered cycloalkyl or heterocycloalkyl ring; W1, W2, W3, W4, and W5 are each independently CR6, N, or NR6 where valence permits; each occurrence of R6 is independently selected from the group consisting of H, halogen, (C1-C6)alkyl, and (C1-C6)haloalkyl; Z1, Z2, Z3, and Z4 are each independently N or CR3 where valance permits; R3 is selected from the group consisting of H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, (C4-C10)bicycloalkyl, (C4-C10)bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C10)heterobicycloalkyl, (C4-C10)heterobicycloalkenyl, (C4-C10)heterospiroalkyl, (C4-C10)tricycloalkyl, (C4-C10)tricycloalkenyl, aryl, heteroaryl, —ORa, —SRa, —N(Ra)2, —CORa, —CO2Ra, CON(Ra)2, —CN, —NC, NO2, N3, —SO2Ra, —SO2N(Ra)2, —N(Ra)SO2Ra, [chemical expression included] T is O, S, or NRa; each occurrence of L is independently O, S, NRa, or C(Ra)2; m is an integer from 0-3; wherein when m is 0, the structural moieties [chemical expression included] have the structures of [chemical expression included] respectively; U1, U2, U3, and U4 are each independently N or CR4 where valance permits; R4 is selected from the group consisting of H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, (C4-C10)bicycloalkyl, (C4-C10)bicycloalkenyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C10)heterobicycloalkyl, (C4-C10)heterobicycloalkenyl, (C4-C10)heterospiroalkyl, (C4-C10)tricycloalkyl, (C4-C10)tricycloalkenyl, aryl, heteroaryl, —ORa, —SRa, —N(Ra)2, —CORa, —CO2Ra, CON(Ra)2, —CN, —NC, NO2, N3, —SO2Ra, —SO2N(Ra)2, —N(Ra)SO2Ra, [chemical expression included] and each occurrence of Ra is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, aryl, or heteroaryl, or two Ra taken together form a 4-6-membered ring optionally substituted with halogen or (C1-C6)alkyl.
    • Claim:
      2. The compound of claim 1, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, U1, U2, U3, and U4 are each independently CH, C(halogen), C(C1-C6(alkyl)), or N.
    • Claim:
      3. The compound of claim 1, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, U1, U2, U3, and U4 are each independently CH or N.
    • Claim:
      4. The compound of claim 1, wherein [chemical expression included]
    • Claim:
      5. The compound of claim 4, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      6. The compound of claim 5, wherein n is 0, 1, or 2.
    • Claim:
      7. The compound of claim 4, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      8. The compound of claim 7, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      9. The compound of claim 1, wherein [chemical expression included]
    • Claim:
      10. The compound of claim 9, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included]
    • Claim:
      11. The compound of claim 10, wherein n is 0, 1, or 2.
    • Claim:
      12. The compound of claim 9, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included]
    • Claim:
      13. The compound of claim 9, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included]
    • Claim:
      14. The compound of claim 9, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      15. The compound of claim 1, wherein [chemical expression included]
    • Claim:
      16. The compound of claim 15, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      17. The compound of claim 15, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      18. The compound of claim 1, wherein Q is O.
    • Claim:
      19. The compound of claim 1, wherein Q is NRa, N(C═O)Ra, or NSO2Ra.
    • Claim:
      20. The compound of claim 1, wherein each occurrence of R1 is independently H, D, halogen, ORa, N(Ra)2, (C1-C6)alkyl, (C1-C6)alkynyl, (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkyl, (C4-C10)heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, aryl, (C4-C10)bicycloalkyl, (C4-C10)bicycloalkenyl, (C4-C10)heterobicycloalkenyl, (C4-C10)tricycloalkenyl, (C4-C10)heterotricycloalkenyl, —CN, N3, NO2, CORa, CO2Ra, CON(Ra)2, —SO2Ra, or —SO2N(Ra)2; wherein the (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkenyl, (C4-C10)bicycloalkenyl, (C4-C10)heterobicycloalkenyl, (C4-C10)tricycloalkenyl, and (C4-C10)heterotricycloalkenyl are each optionally substituted with one or more (C1-C6)alkyl.
    • Claim:
      21. The compound of claim 1, wherein each occurrence of R1 is independently H, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, (C4-C10)heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, N(Ra)2, or —CN; wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.
    • Claim:
      22. The compound of claim 1, wherein each occurrence of R1 is independently H, (C1-C6)alkyl, (C3-C7)heterocyclohaloalkyl, or (C3-C7)heterocycloalkyl; wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.
    • Claim:
      23. The compound of claim 1, wherein each occurrence of R1 is independently H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2, [chemical expression included]
    • Claim:
      24. The compound of claim 1, wherein each occurrence of R1 is independently H, D, F, CH3, NH2, NHCH3, N(CH3)2, [chemical expression included]
    • Claim:
      25. The compound of claim 1, wherein at least one occurrence of R1 is [chemical expression included] [chemical expression included] [chemical expression included]
    • Claim:
      26. The compound of claim 1, wherein at least one occurrence of R1 is [chemical expression included] wherein X is CR15, O, NR14, or S; each occurrence of R9 is independently H, (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, —ORa, —CN, or —N(Ra)2; R14 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, aryl, or heteroaryl; each occurrence of R15 is independently H, (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, —ORa, —CN, or —N(Ra)2; and q is 0, 1, 2, or 3.
    • Claim:
      27. The compound of claim 1, wherein X is O.
    • Claim:
      28. The compound of claim 26, wherein each occurrence of R9 is independently H, (C1-C6)alkyl, halogenated (C1-C6)alkyl, or halogen.
    • Claim:
      29. The compound of claim 26, wherein each occurrence of R9 is independently H, F, Cl, Br, CH3, CF3, OH, NH2, —NHCH3, or —N(CH3)2.
    • Claim:
      30. The compound of claim 26, wherein each occurrence of R9 is independently H, F, Cl, Br, or CH3.
    • Claim:
      31. The compound of claim 26, wherein each occurrence of R15 is independently H, (C1-C6)alkyl, halogenated (C1-C6)alkyl, or halogen.
    • Claim:
      32. The compound of claim 26, wherein each occurrence of R15 is independently H, F, Cl, Br, or CH3.
    • Claim:
      33. The compound of claim 26, wherein q is 0.
    • Claim:
      34. The compound of claim 26, wherein q is 1.
    • Claim:
      35. The compound of claim 26, wherein q is 2 or 3.
    • Claim:
      36. The compound of claim 26, wherein X is NR14 and R14 is H or (C1-C6)alkyl.
    • Claim:
      37. The compound of claim 1, wherein at least one occurrence of R1 is [chemical expression included] [chemical expression included] wherein X is O or NR14; and R14 is H or (C1-C6)alkyl.
    • Claim:
      38. The compound of claim 1, wherein at least one occurrence of R1 is [chemical expression included] [chemical expression included]
    • Claim:
      39. The compound of claim 1, wherein [chemical expression included] wherein R12 is (C3-C7)cycloalkenyl, (C3-C7)heterocycloalkenyl, (C4-C10)bicycloalkenyl, (C4-C10)heterobicycloalkenyl, (C4-C14)tricycloalkenyl, or (C4-C14)heterotricycloalkenyl, each of which is optionally substituted by one or more (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, —ORa, —CN, or —N(Ra)2.
    • Claim:
      40. The compound of claim 39, wherein R12 is [chemical expression included] wherein is CR15, O, NR14, or S; each occurrence of R9 is independently H, (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, —ORa, —CN, or —N(Ra)2; R14 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, aryl, or heteroaryl; each occurrence of R15 is independently H, (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, —ORa, —CN, or —N(Ra)2; and q is 0, 1, 2, or 3.
    • Claim:
      41. The compound of claim 39, wherein R12 is [chemical expression included] [chemical expression included] wherein X is O or NR14; and R14 is H or (C1-C6)alkyl.
    • Claim:
      42. The compound of claim 39, wherein R12 is [chemical expression included] [chemical expression included]
    • Claim:
      43. The compound of claim 25, wherein [chemical expression included]
    • Claim:
      44. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] wherein Q is O or NH.
    • Claim:
      45. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] wherein Q is O or NH.
    • Claim:
      46. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] wherein Q is O or NH and R1 is H, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, or halogen.
    • Claim:
      47. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] wherein Qi s O or NH.
    • Claim:
      48. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included] wherein Q is O or NH.
    • Claim:
      49. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      50. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included]
    • Claim:
      51. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      52. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included]
    • Claim:
      53. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      54. The compound of claim 1, wherein each occurrence of R2 is independently H, halogen, CH3, CF3, OH, NH2, —NHCH3, or —N(CH3)2.
    • Claim:
      55. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included]
    • Claim:
      56. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included]
    • Claim:
      57. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      58. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      59. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      60. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      61. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] wherein each occurrence of o is independently 1 or 2, J is C(Ry)2, and each occurrence of Ry is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen; or wherein two Ry can optionally bond together to form a 3-6-membered cycloalkyl or heterocycloalkyl ring.
    • Claim:
      62. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] wherein Y1, Y2, and Y5 are each independently N, CH, CCH3, or CF.
    • Claim:
      63. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] wherein each occurrence of o is independently 1 or 2, J is C(Ry)2, and each occurrence of Ry is independently H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen; or wherein two Ry can optionally bond together to form a 3-7-membered cycloalkyl or heterocycloalkyl ring.
    • Claim:
      64. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included] wherein Y1, Y2, Y3, and Y5 are each independently N, CH, CCH3, or CF.
    • Claim:
      65. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      66. The compound of claim 1, having the structure of Formula Ia.
    • Claim:
      67. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] [chemical expression included] wherein each occurrence of R3 and R4 are independently H, halogen, or (C1-C6)alkyl; T is O, S, NH, or N((C1-C6)alkyl); and each occurrence of L is independently O, S, NH, N((C1-C6)alkyl), or C(Ra)2, wherein each occurrence of Ra is independently H, OH, OCH3, halogen, or (C1-C6)alkyl.
    • Claim:
      68. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      69. The compound of claim 1 having the structure of Formula Ib.
    • Claim:
      70. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included] [chemical expression included] wherein each occurrence of R3 and R4 are independently H, halogen, or (C1-C6)alkyl; T is O, S, NH, or N((C1-C6)alkyl); and each occurrence of L is independently O, S, NH, N((C1-C6)alkyl), or C(Ra)2, wherein each occurrence of Ra is independently H, OH, OCH3, halogen, or (C1-C6)alkyl.
    • Claim:
      71. The compound of claim 1, wherein the structural moiety [chemical expression included] has the structure of [chemical expression included]
    • Claim:
      72. The compound of claim 1, wherein the compound of Formula Ia has the structure of [chemical expression included] wherein Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z4, U1, U2, U3, and U4 are each independently CH, CCH3, CF, or N; and Ra is H or CH3.
    • Claim:
      73. The compound of claim 1, wherein the compound of Formula Ib has the structure of [chemical expression included] wherein Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, U1, U2, U3, and U4 are each independently CH, CCH3, CF, or N; and Ra is H or CH3.
    • Claim:
      74. The compound of claim 1, wherein the compound of Formula Ia is [chemical expression included]
    • Claim:
      75. The compound of claim 1, wherein the compound of Formula Ia is [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included]
    • Claim:
      76. The compound of claim 1, wherein the compound of Formula Ia is [chemical expression included]
    • Claim:
      77. The compound of claim 1, wherein the compound of Formula Ib is [chemical expression included]
    • Claim:
      78. The compound of claim 1, wherein the compound of Formula Ib is [chemical expression included] [chemical expression included]
    • Claim:
      79. The compound of claim 1, wherein the compound of Formula Ib is [chemical expression included]
    • Claim:
      80-111. (canceled)
    • Current International Class:
      07; 07; 07
    • Accession Number:
      edspap.20250074905