COMPOUNDS AND USES THEREOF

Abstract

The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.

Claims

1. A compound having the structure Formula I: ##STR00831## wherein R.sup.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.10 carbocyclyl; Z.sup.1 is CR.sup.2 or N; R.sup.2 is H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; ##STR00832## X.sup.1 is CR.sup.X1 or N; X.sup.2 is O or S; R.sup.X1 is H or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.3 is H, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted amino, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; and G is optionally substituted C.sub.3-C.sub.10 carbocyclyl, C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl, or a pharmaceutically acceptable salt thereof.

2. A compound having the structure of Formula II:
A-L-B   Formula II, wherein L is a linker; B is a degradation moiety; and A has the structure of Formula III: ##STR00833## wherein R.sup.1 is, independently, H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.10 carbocyclyl; Z.sup.1 is CR.sup.2 or N; R.sup.2 is H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; ##STR00834## X.sup.1 is CR.sup.X1 or N; X.sup.2 is O or S; R.sup.X1 is H or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.3″ is H, ##STR00835## cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted amino, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; R.sup.3′ is absent, optionally substituted C.sub.1-C.sub.6 alkylene, optionally substituted C.sub.2-C.sub.9 heteroarylene, or optionally substituted C.sub.1-C.sub.6 heteroalkylene; G″ is ##STR00836## optionally substituted C.sub.3-C.sub.10 carbocyclyl, C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; G′ is optionally substituted C.sub.3-C.sub.10 carbocyclylene, C.sub.2-C.sub.9 heterocyclylene, optionally substituted C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene; and A.sup.1 is a bond between A and the linker, wherein G″ is ##STR00837## or R.sup.3″ is ##STR00838## or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R.sup.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, or optionally substituted C.sub.3-C.sub.10 carbocyclyl.

4. The compound of claim 3, wherein R.sup.1 is H.

5. The compound of claim 3, wherein R.sup.1 is optionally substituted C.sub.1-C.sub.6 alkyl.

6. The compound of claim 5, wherein R.sup.1 is ##STR00839##

7. The compound of claim 6, wherein R.sup.1 is optionally substituted C.sub.2-C.sub.6 alkenyl.

8. The compound of claim 7, wherein R.sup.1 is ##STR00840##

9. The compound of claim 8, wherein R.sup.1 is optionally substituted C.sub.3-C.sub.10 carbocyclyl.

10. The compound of claim 9, wherein R.sup.1 is ##STR00841##

11. The compound of claim 3, wherein R.sup.1 is H or ##STR00842##

12. The compound of claim 11, wherein R.sup.1 is H.

13. The compound of claim 11, wherein R.sup.1 is ##STR00843##

14. The compound of any one of claims 1 to 13, wherein Z.sup.1 is N.

15. The compound of any one of claims 1 to 13, wherein Z.sup.1 is CR.sup.2.

16. The compound of claim 15, wherein R.sup.2 is H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.6-C.sub.10 aryl.

17. The compound of claim 16, wherein R.sup.2 is H, halogen, or optionally substituted C.sub.1-C.sub.6 alkyl.

18. The compound of claim 17, wherein R.sup.2 is H, F, or ##STR00844##

19. The compound of claims 2 to 18, wherein the compound of Formula III has the structure of Formula IIIA: ##STR00845## or a pharmaceutically acceptable salt thereof.

20. The compound of claims 2 to 18, wherein the compound of Formula III has the structure of Formula IIIB: ##STR00846## or a pharmaceutically acceptable salt thereof.

21. The compound of claims 2 to 18, wherein the compound of Formula IIIC: ##STR00847## or a pharmaceutically acceptable salt thereof.

22. The compound of claims 2 to 18, wherein the compound of Formula IIID: ##STR00848## or a pharmaceutically acceptable salt thereof.

23. The compound of claims 2 to 18, wherein the compound of Formula IIIE: ##STR00849## or a pharmaceutically acceptable salt thereof.

24. The compound of claims 2 to 18, wherein the compound of Formula IIIF: ##STR00850## or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 2 to 24, wherein X.sup.1 is CH or N.

26. The compound of any one of claims 2 to 24, wherein X.sup.1 is CH.

27. The compound of any one of claims 2 to 26, wherein X.sup.2 is O.

28. The compound of any one of claims 2 to 26, wherein X.sup.2 is S.

29. The compound of any one of claims 2 to 28, wherein R.sup.3″ is H, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted amino, optionally substituted C.sub.3-C.sub.10 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heteroaryl.

30. The compound of any one of claims 2 to 29, wherein R.sup.3″ is H.

31. The compound of any one of claims 2 to 29, wherein R.sup.3″ is cyano.

32. The compound of any one of claims 2 to 29, wherein R.sup.3″ is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.10 heterocyclyl.

33. The compound of any one of claims 2 to 32, wherein R.sup.3″ is ##STR00851##

34. The compound of any one of claims 2 to 32, wherein R.sup.3″ is ##STR00852##

35. The compound of any one of claims 2 to 32, wherein R.sup.3″ is ##STR00853##

36. The compound of claim 32, wherein R.sup.3″ is optionally substituted C.sub.1-C.sub.6 heteroalkyl.

37. The compound of claim 36, wherein R.sup.3″ is ##STR00854## wherein W.sup.1 is NR.sup.4 or O; W.sup.2 is NH, O, or S; W.sup.3 is NR.sup.7 or O; R.sup.4 is H or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.5 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl; R.sup.6 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl; R.sup.7 is H or optionally substituted C.sub.1-C.sub.6 alkyl; and R.sup.8 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl.

38. The compound of claim 37, wherein W.sup.1 is NR.sup.4.

39. The compound of claim 38, wherein R.sup.4 is H, ##STR00855##

40. The compound of claim 39, wherein R.sup.6 is H, ##STR00856##

41. The compound of claim 40, wherein R.sup.3″ is ##STR00857##

42. The compound of claim 41, wherein R.sup.3″ is ##STR00858##

43. The compound of any one of claims 2 to 42, wherein G″ is ##STR00859##

44. The compound of claim 43, wherein G′ is optionally substituted C.sub.6-C.sub.10 arylene or optionally substituted C.sub.2-C.sub.9 heteroarylene.

45. The compound of claim 44, wherein G′ is optionally substituted C.sub.6-C.sub.10 arylene.

46. The compound of claim 45, wherein G′ is ##STR00860## wherein each of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G6′ is, independently, H, A.sup.1, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.G1′ and R.sup.G2′, R.sup.G2′ and R.sup.G3′, R.sup.G3′ and R.sup.G4′, and/or R.sup.G4′ and R.sup.G6′, together with the carbon atoms to which each is attached, combine to form ##STR00861## and ##STR00862## is optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.1, wherein one of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is A.sup.1, or ##STR00863## is substituted with A.sup.1.

47. The compound of claim 46, wherein each of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is, independently, H, A.sup.1, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, or optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl; or R.sup.G1′ and R.sup.G2′, R.sup.G2′ and R.sup.G3′, R.sup.G3′ and R.sup.G4′, and/or R.sup.G4′ and R.sup.G5′, together with the carbon atoms to which each is attached, combine to form ##STR00864## and ##STR00865## is optionally substituted C.sub.2-C.sub.9 heteroaryl or optionally substituted C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.1, wherein one of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is A.sup.1, or ##STR00866## is substituted with A.sup.1.

48. The compound of claim 47, wherein each of RG1, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is, independently, H, A.sup.1, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, or optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl.

49. The compound of claim 48, wherein each of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is, independently, H, A.sup.1, F, Cl, ##STR00867##

50. The compound of claim 49, wherein each of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is, independently, H, A.sup.1, F, ##STR00868##

51. The compound of claim 50, wherein each of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is, independently, H, A.sup.1, F, Cl, ##STR00869##

52. The compound of claim 51, wherein R.sup.G3′ is A.sup.1.

53. The compound of claim 51, wherein R.sup.G1′ is H; R.sup.G2′ is ##STR00870## R.sup.G3′ is A.sup.1; R.sup.G4′ is ##STR00871## and R.sup.G5′ is H.

54. The compound of claim 51, wherein R.sup.G1′ is H; R.sup.G2′ is ##STR00872## R.sup.G3′ is A.sup.1; R.sup.G4′ is H; and R.sup.G5′ is ##STR00873##

55. The compound of claim 51, wherein R.sup.G1′ is H; R.sup.G2′ is ##STR00874## R.sup.G3′ is A.sup.1; R.sup.G4′ is Cl or F; and R.sup.G5′ is H.

56. The compound of claim 51, wherein R.sup.G1′ is H; R.sup.G2′ is ##STR00875## R.sup.G3′ is A.sup.1; R.sup.G4′ is H; and R.sup.G5′ is H.

57. The compound of claim 51, wherein R.sup.G1′ is H; R.sup.G2′ is ##STR00876## R.sup.G3′ is A.sup.1; R.sup.G4′ is ##STR00877## and R.sup.G5′ is H.

58. The compound of claim 47, wherein R.sup.G1′ and R.sup.G2′, R.sup.G2′ and R.sup.G3′, R.sup.G3′ and R.sup.G4′, and/or R.sup.G4′ and R.sup.G5′, together with the carbon atoms to which each is attached, combine to form ##STR00878## and ##STR00879## is optionally substituted C.sub.2-C.sub.9 heterocyclyl, which is optionally substituted with A.sup.1, ##STR00880## wherein one of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G5′ is A.sup.1, or is substituted with A.sup.1.

59. The compound of claim 47, wherein R.sup.G1′ and R.sup.G2′, R.sup.G2′ and R.sup.G3′, R.sup.G3′ and R.sup.G4′, and/or ##STR00881## R.sup.G4′ and R.sup.G5′, together with the carbon atoms to which each is attached, combine to form and ##STR00882## is optionally substituted C.sub.2-C.sub.9 heteroaryl, which is optionally substituted with A.sup.1, wherein one of R.sup.G1′, R.sup.G2′, R.sup.G3′, R.sup.G4′, and R.sup.G6′ is A.sup.1, or ##STR00883## is substituted with A.sup.1.

60. The compound of claim 58, wherein G′ is ##STR00884## wherein R.sup.G6′ is H, A.sup.1, or optionally substituted C.sub.1-C.sub.6 alkyl.

61. The compound of claim 59, wherein G′ is ##STR00885## wherein R.sup.G6′ is H, A.sup.1, or optionally substituted C.sub.1-C.sub.6 alkyl

62. The compound of claim 60 or 61, wherein R.sup.G6′ is H, A.sup.1, or ##STR00886##

63. The compound of claim 62, wherein R.sup.G6′ is H.

64. The compound of claim 44, wherein G′ is optionally substituted C.sub.2-C.sub.9 heteroarylene.

65. The compound of claim 64, wherein G′ is ##STR00887## wherein each of R.sup.G7′, R.sup.G8′, R.sup.G9′, R.sup.G10′, and R.sup.G11′ is, independently, H, A.sup.1, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.G7′ and R.sup.G9′, R.sup.G9′ and R.sup.G9′, R.sup.G9′ and R.sup.G19′, and/or R.sup.G10′ and R.sup.G11′, together with the carbon atoms to which each is attached, combine to form ##STR00888## and ##STR00889## is optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.1, wherein one of R.sup.G7′, R.sup.G8′, R.sup.G9′, R.sup.G10′, and R.sup.G11′ is A.sup.1; or ##STR00890## is substituted with A.sup.1.

66. The compound of claim 65, wherein each of R.sup.G7′, R.sup.G8′, R.sup.G9′, R.sup.G10′, and R.sup.G11′ is, independently, H, A.sup.1, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, or optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl.

67. The compound of claim 65 or 66, wherein G′ is ##STR00891##

68. The compound of any one of claims 65 to 67, wherein R.sup.G7′ is H; R.sup.G8′ is ##STR00892## R.sup.G9′ is A.sup.1; and R.sup.G11′ is H.

69. The compound of claim 64, wherein G′ is ##STR00893## wherein each of R.sup.G12′, R.sup.G13′, and R.sup.G14′ is, independently, H, A.sup.1, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.G12′ and R.sup.G14′, together with the carbon atoms to which each is attached, combine to form ##STR00894## and ##STR00895## is optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.1, wherein one of R.sup.G12′, R.sup.G13′, and R.sup.G14′ is A.sup.1; or ##STR00896## is substituted with A.sup.1.

70. The compound of any one of claims 2 to 28, wherein R.sup.3″ is ##STR00897## and R.sup.3′ is absent.

71. The compound of claim 70, wherein G″ is optionally substituted C.sub.6-C.sub.10 aryl or optionally substituted C.sub.2-C.sub.9 heteroaryl.

72. The compound of claim 71, wherein G″ is optionally substituted C.sub.6-C.sub.10 aryl.

73. The compound of claim 72, wherein G″ is ##STR00898## wherein each of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.G1 and R.sup.G2, R.sup.G2 and R.sup.G3, R.sup.G3 and R.sup.G4, and/or R.sup.G4 and R.sup.G5, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl.

74. The compound of claim 73, wherein each of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, or optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl; or R.sup.G1 and R.sup.G2, R.sup.G2 and R.sup.G3, R.sup.G3 and R.sup.G4, and/or R.sup.G4 and R.sup.G5, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.2-C.sub.9 heteroaryl or optionally substituted C.sub.2-C.sub.9 heterocyclyl.

75. The compound of claim 74, wherein each of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, or optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl.

76. The compound of claim 75, wherein each of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is, independently, H, F, Cl, ##STR00899##

77. The compound of claim 76, wherein each of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is, independently, H, F, ##STR00900##

78. The compound of claim 77, wherein each of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is, independently, H, F, Cl, ##STR00901##

79. The compound of claim 78, wherein two or more of R.sup.G1, R.sup.G2, R.sup.G3, R.sup.G4, and R.sup.G5 is H.

80. The compound of claim 79, wherein R.sup.G1 is H; R.sup.G2 is ##STR00902## R.sup.G3 is ##STR00903## R.sup.G4 is ##STR00904## and R.sup.G5 is H.

81. The compound of claim 79, wherein R.sup.G1 is H; R.sup.G2 is ##STR00905## R.sup.G3 is ##STR00906## R.sup.G4 is H; and R.sup.G5 is ##STR00907##

82. The compound of claim 79, wherein R.sup.G1 is H; R.sup.G2 is ##STR00908## R.sup.G3 is ##STR00909## R.sup.G4 is Cl or F; and R.sup.G5 is H.

83. The compound of claim 79, wherein R.sup.G1 is H; R.sup.G2 is ##STR00910## R.sup.G3 is ##STR00911## R.sup.G4 is H; and R.sup.G5 is H.

84. The compound of claim 79, wherein R.sup.G1 is H; R.sup.G2 is ##STR00912## R.sup.G3 is ##STR00913## R.sup.G4 is ##STR00914## and R.sup.G5 is H.

85. The compound of claim 74, wherein R.sup.G1 and R.sup.G2, R.sup.G2 and R.sup.G3, R.sup.G3 and R.sup.G4, and/or R.sup.G4 and R.sup.G5, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.2-C.sub.9 heterocyclyl.

86. The compound of claim 74, wherein R.sup.G1 and R.sup.G2, R.sup.G2 and R.sub.G3, R.sup.G3 and R.sup.G4, and/or R.sup.G4 and R.sup.G5, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.2-C.sub.9 heteroaryl.

87. The compound of claim 85, wherein G″ is ##STR00915## wherein R.sup.G6 is H or optionally substituted C.sub.1-C.sub.6 alkyl.

88. The compound of claim 86, wherein G″ is ##STR00916## wherein R.sup.G6 is H or optionally substituted C.sub.1-C.sub.6 alkyl.

89. The compound of claim 87 or 88, wherein R.sup.G6 is H or ##STR00917##

90. The compound of claim 89, wherein R.sup.G6 is H.

91. The compound of claim 71, wherein G″ is optionally substituted C.sub.2-C.sub.9 heteroaryl.

92. The compound of claim 91, wherein G″ is ##STR00918## wherein each of R.sup.G7, R.sup.G8, R.sup.G9, R.sup.G10, and R.sup.G11 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.G7 and R.sup.G8, R.sup.G8 and R.sup.G9, R.sup.G9 and R.sup.G10, and/or R.sup.G10 and R.sup.G11, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or C.sub.2-C.sub.9 heterocyclyl.

93. The compound of claim 92, wherein each of R.sup.G7, R.sup.G8, R.sup.G9, R.sup.G10, and R.sup.G11 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, or optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl.

94. The compound of claim 92 or 93, wherein G″ is ##STR00919##

95. The compound of claim 94, wherein R.sup.G7 is H; R.sup.G8 is ##STR00920## R.sup.G9 is H; and R.sup.G11 is H.

96. The compound of claim 91, wherein G″ is ##STR00921## wherein each of R.sup.G12, R.sup.G13, and R.sup.G14 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.3-C.sub.6 carbocyclyl, optionally substituted —C.sub.1-C.sub.3 alkyl-C.sub.2-C.sub.5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.G12 and R.sup.G14, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl.

97. The compound of any one of claims 70 to 96, wherein R.sup.7′ is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.3-C.sub.10 carbocyclyl.

98. The compound of claim 97, wherein R.sup.7′ is H or optionally substituted C.sub.1-C.sub.6 alkyl.

99. The compound of claim 98, wherein R.sup.7′ is H, ##STR00922##

100. The compound of claim 99, wherein R.sup.7′ is H or ##STR00923##

101. The compound of claim 100, wherein R.sup.7′ is H.

102. The compound of claim 100, wherein R.sup.7′ is ##STR00924##

103. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIAa: ##STR00925## or a pharmaceutically acceptable salt thereof.

104. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIc: ##STR00926## or a pharmaceutically acceptable salt thereof.

105. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIe: ##STR00927## or a pharmaceutically acceptable salt thereof.

106. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIf: ##STR00928## or a pharmaceutically acceptable salt thereof.

107. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIg: ##STR00929## or a pharmaceutically acceptable salt thereof.

108. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIh: ##STR00930## or a pharmaceutically acceptable salt thereof.

109. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIj: ##STR00931## or a pharmaceutically acceptable salt thereof.

110. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIn: ##STR00932## or a pharmaceutically acceptable salt thereof.

111. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIo: ##STR00933## or a pharmaceutically acceptable salt thereof.

112. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIs: ##STR00934## or a pharmaceutically acceptable salt thereof.

113. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIu: ##STR00935## or a pharmaceutically acceptable salt thereof.

114. The compound of any one of claims 2 to 102, wherein A has the structure of Formula IIIv: ##STR00936## or a pharmaceutically acceptable salt thereof.

115. The compound of any one of claims 2 to 114, wherein the degradation moiety is a ubiquitin ligase binding moiety.

116. The compound of claim 115, wherein the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.

117. The compound of claim 115 or 116, wherein the degradation moiety comprises the structure of Formula Y: ##STR00937## wherein A.sup.2 is a bond between the degradation moiety and the linker; v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; T.sup.1 is a bond or ##STR00938## T.sup.2 is ##STR00939## R.sup.5A is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; each R.sup.J1 is, independently, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; J.sup.A is absent, O, optionally substituted amino, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; and J is absent, optionally substituted C.sub.3-C.sub.10 carbocyclylene, optionally substituted C.sub.6-C.sub.10 arylene, optionally substituted C.sub.2-C.sub.9 heterocyclylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene, or a pharmaceutically acceptable salt thereof.

118. The compound of claim 117, wherein T.sup.2 is ##STR00940##

119. The compound of claim 118, wherein T.sup.2 is ##STR00941##

120. The compound of claim 118, wherein T.sup.2 is ##STR00942##

121. The compound of any one of claims 117 to 120, wherein the structure of Formula Y has the structure of Formula Y1: ##STR00943## or a pharmaceutically acceptable salt thereof.

122. The compound of claim 121, wherein T.sup.1 is a bond.

123. The compound of claim 121, wherein T.sup.1 is ##STR00944##

124. The compound of any one of claims 117 to 123, wherein the structure of Formula Y has the structure of Formula Y2: ##STR00945## or a pharmaceutically acceptable salt thereof.

125. The compound of any one of claims 117 to 123, wherein the structure of Formula Y has the structure of Formula Z: ##STR00946## or a pharmaceutically acceptable salt thereof.

126. The compound of any one of claims 117 to 125, wherein u1 is 2.

127. The compound of claim 126, wherein the structure of Formula Z has the structure of Formula AA0: ##STR00947## or a pharmaceutically acceptable salt thereof.

128. The compound of any one of claims 117 to 125, wherein u1 is 1.

129. The compound of claim 128, wherein the structure of Formula Z has the structure of Formula AB: ##STR00948## or a pharmaceutically acceptable salt thereof.

130. The compound of any one of claims 117 to 125, wherein u1 is 3.

131. The compound of claim 130, wherein the structure of Formula Z has the structure of Formula AC: ##STR00949## or a pharmaceutically acceptable salt thereof.

132. The compound of any one of claims 117 to 131, wherein J.sup.A is absent.

133. The compound of any one of claims 117 to 131, wherein J.sup.A is optionally substituted C.sub.1-C.sub.6 alkyl.

134. The compound of claim 133, wherein J.sup.A is ##STR00950##

135. The compound of claim 132, wherein the structure of Formula AA0 has the structure of Formula AA0: ##STR00951## or a pharmaceutically acceptable salt thereof.

136. The compound of any one of claims 117 to 135, wherein v1 is 0, 1, 2, or 3.

137. The compound of claim 136, wherein v1 is 0.

138. The compound of claim 137, wherein the structure of Formula AA has the structure of Formula AA1: ##STR00952## or a pharmaceutically acceptable salt thereof.

139. The compound of any one of claims 117 to 138, wherein R.sup.A5 is H or optionally substituted C.sub.1-C.sub.6 alkyl.

140. The compound of claim 139, wherein R.sup.A5 is H.

141. The compound of claim 139, wherein R.sup.A5 is methyl.

142. The compound of any one of claims 117 to 138, wherein R.sup.A5 is optionally substituted C.sub.1-C.sub.6 heteroalkyl.

143. The compound of claim 142, wherein R.sup.A5 is ##STR00953##

144. The compound of claim 135, wherein the structure of Formula AA has the structure of Formula AA1: ##STR00954## or a pharmaceutically acceptable salt thereof.

145. The compound of claim 129, wherein the structure of Formula AB has the structure of Formula AB1: ##STR00955## or a pharmaceutically acceptable salt thereof.

146. The compound of claim 131, wherein the structure of Formula AC has the structure of Formula AC1: ##STR00956## or a pharmaceutically acceptable salt thereof.

147. The compound of any one of claims 117 to 146, wherein J is absent.

148. The compound of claim 147, wherein the structure of Formula AA1 has the structure of Formula AA2: ##STR00957## or a pharmaceutically acceptable salt thereof.

149. The compound of any one of claims 117 to 146, wherein J is optionally substituted C.sub.3-C.sub.10 carbocyclylene or optionally substituted C.sub.6-C.sub.10 arylene.

150. The compound of claim 149, wherein the structure of Formula AA has the structure of Formula AA4: ##STR00958## or a pharmaceutically acceptable salt thereof.

151. The compound of any one of claims 117 to 146, wherein J is optionally substituted C.sub.2-C.sub.9 heterocyclylene or optionally substituted C.sub.2-C.sub.9 heteroarylene.

152. The compound of claim 151, wherein the structure of Formula AA has the structure of Formula AA3: ##STR00959## or a pharmaceutically acceptable salt thereof.

153. The compound of claim 151, wherein the structure of Formula AA has the structure of Formula A: ##STR00960## wherein in Y.sup.1 is ##STR00961## R.sup.A5 is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; R.sup.A6 is H or optionally substituted C.sub.1-C.sub.6 alkyl; and R.sup.A7 is H or optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.A6 and R.sup.A7, together with the carbon atom to which each is bound, combine to form optionally substituted C.sub.3-C.sub.6carbocyclyl or optionally substituted C.sub.2-C.sub.5 heterocyclyl; or R.sup.A6 and R.sup.A7, together with the carbon atom to which each is bound, combine to form optionally substituted C.sub.3-C.sub.6carbocyclyl or optionally substituted C.sub.2-C.sub.5 heterocyclyl; R.sup.A8 is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, independently, H, A.sup.2, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, and/or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR00962## and ##STR00963## is optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR00964## is substituted with A.sup.2, or a pharmaceutically acceptable salt thereof.

154. The compound of claim 153, each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, independently, H, A.sup.2, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, and/or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR00965## and ##STR00966## is optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR00967## is substituted with A.sup.2, or a pharmaceutically acceptable salt thereof.

155. The compound of claim 154, wherein each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, H, A.sup.2, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, hydroxyl, optionally substituted amino; or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR00968## and ##STR00969## is optionally substituted C.sub.2-C.sub.9 heterocyclyl, which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR00970## is substituted with A.sup.2.

156. The compound of claim 155, wherein each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, independently, H, ##STR00971## or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR00972## and ##STR00973## is optionally substituted C.sub.2-C.sub.9 heterocyclyl, which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR00974## is substituted with A.sup.2.

157. The compound of any one of claims 153 to 156, wherein Y.sup.1 is ##STR00975##

158. The compound of claim 157, wherein Y.sup.1 is ##STR00976##

159. The compound of claim 157, wherein Y.sup.1 is ##STR00977##

160. The compound of claim 159, wherein Y.sup.1 is ##STR00978##

161. The compound of claim 160, wherein Y.sup.1 is ##STR00979##

162. The compound of any one of claims 153 to 161, wherein the structure of Formula A has the structure of Formula A1: ##STR00980## or a pharmaceutically acceptable salt thereof.

163. The compound of any one of claims 153 to 160, wherein the structure of Formula A has the structure of Formula A2: ##STR00981## or a pharmaceutically acceptable salt thereof.

164. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A3: ##STR00982## or a pharmaceutically acceptable salt thereof.

165. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A4: ##STR00983## or a pharmaceutically acceptable salt thereof.

166. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A5: ##STR00984## or a pharmaceutically acceptable salt thereof.

167. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A6: ##STR00985## or a pharmaceutically acceptable salt thereof.

168. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A7: ##STR00986## or a pharmaceutically acceptable salt thereof.

169. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A8: ##STR00987## or a pharmaceutically acceptable salt thereof.

170. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A9: ##STR00988## or a pharmaceutically acceptable salt thereof.

171. The compound of any one of claims 153 to 163, wherein the structure of Formula A has the structure of Formula A10: ##STR00989## or a pharmaceutically acceptable salt thereof.

172. The compound of any one of claims 152 to 171, wherein the structure of Formula A is ##STR00990## ##STR00991## or derivative or analog thereof.

173. The compound of claim 172, wherein the structure of Formula A is ##STR00992##

174. The compound of claim 173, wherein the structure of Formula A is ##STR00993## or derivative or analog thereof.

175. The compound of any one of claims 153 to 171, wherein ##STR00994## is ##STR00995## wherein R.sup.A9 is H, A.sup.2, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl.

176. The compound of claim 175, wherein the structure of Formula A is ##STR00996##

177. The compound of claim 176, wherein R.sup.A9 is H.

178. The compound of claim 176, wherein R.sup.A9 is A.sup.2.

179. The compound of claim 178, wherein the structure of Formula A is ##STR00997##

180. The compound of claim 151, wherein the structure of Formula AA has the structure of Formula B: ##STR00998## wherein R.sup.A5 is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, independently, H, A.sup.2, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, and/or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR00999## and ##STR01000## is optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, or C.sub.2-C.sub.9 heterocyclyl, any of which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR01001## is substituted with A.sup.2, or a pharmaceutically acceptable salt thereof.

181. The compound of claim 180, wherein each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, H, A.sup.2, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted —O—C.sub.3-C.sub.6 carbocyclyl, hydroxyl, optionally substituted amino; or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR01002## and ##STR01003## is optionally substituted C.sub.2-C.sub.9 heterocyclyl, which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR01004## is substituted with A.sup.2.

182. The compound of claim 181, wherein each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is, independently, H, A.sup.2, F, ##STR01005## or R.sup.A1 and R.sup.A2, R.sup.A2 and R.sup.A3, or R.sup.A3 and R.sup.A4, together with the carbon atoms to which each is attached, combine to form ##STR01006## and ##STR01007## is optionally substituted C.sub.2-C.sub.9 heterocyclyl, which is optionally substituted with A.sup.2, wherein one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is A.sup.2, or ##STR01008## is substituted with A.sup.2.

183. The compound of any one of claims 180 to 182, wherein the structure of Formula B has the structure of Formula B1: ##STR01009## or a pharmaceutically acceptable salt thereof.

184. The compound of any one of claims 180 to 182, wherein the structure of Formula B has the structure of Formula B2: ##STR01010## or a pharmaceutically acceptable salt thereof.

185. The compound of any one of claims 180 to 182, wherein the structure of Formula B has the structure of Formula B3: ##STR01011## or a pharmaceutically acceptable salt thereof.

186. The compound of any one of claims 180 to 182, wherein the structure of Formula B has the structure of Formula B4: ##STR01012## or a pharmaceutically acceptable salt thereof.

187. The compound of any one of claims 180 to 182, wherein the structure of Formula B is ##STR01013##

188. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula C: ##STR01014## wherein R.sup.B1 is H, A.sup.2, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; R.sup.B2 is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; R.sup.B3 is A.sup.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.1-C.sub.6 alkyl C.sub.6-C.sub.10 aryl; R.sup.B4 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.1-C.sub.6 alkyl C.sub.6-C.sub.10 aryl; R.sup.B5 is H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each R.sup.B6 is, independently, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and each of R.sup.B7 and R.sup.B8 is, independently, H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.6-C.sub.10 aryl, wherein one of R.sup.B1 and R.sup.B3 is A.sup.2, or a pharmaceutically acceptable salt thereof.

189. The compound of claim 188, wherein the structure of Formula C is ##STR01015## or derivative or analog thereof.

190. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula D: ##STR01016## wherein A.sup.2 is a bond between B and the linker; each of R.sup.C1, R.sup.C2, and R.sup.C7 is, independently, H, optionally substituted C.sub.1-C.sub.6 alkyl, or optionally substituted C.sub.1-C.sub.6 heteroalkyl; R.sup.C3 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.1-C.sub.6 alkyl C.sub.6-C.sub.10 aryl; R.sup.C5 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.1-C.sub.6 alkyl C.sub.6-C.sub.10 aryl; v3 is 0, 1, 2, 3, or 4; each R.sup.C8 is, independently, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; v4 is 0, 1, 2, 3, or 4; and each R.sup.C9 is, independently, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

191. The compound of claim 190, wherein the structure of Formula D is ##STR01017## or derivative or analog thereof.

192. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula E: ##STR01018## wherein A.sup.2 is a bond between B and the linker; each of R.sup.C10 and R.sup.C11 is, independently, H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.10 carbocyclyl, or optionally substituted C.sub.1-C.sub.6 alkyl C.sub.6-C.sub.10 aryl; v5 is 0, 1, 2, 3, or 4; each R.sup.C12 is, independently, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; v6 is 0, 1, 2, 3, or 4; and each R.sup.21 is, independently, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

193. The compound of claim 192, wherein the structure of Formula E is ##STR01019## or derivative or analog thereof.

194. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula FA: ##STR01020## wherein ##STR01021## or a bicyclic moiety which is substituted with A.sup.2 and substituted with one or more groups independently selected from H, R.sup.FF1, and oxo; is a single bond or a double bond; u2 is 0, 1, 2, or 3; A.sup.2 is a bond between the degrader and the linker; Y.sup.Fa is CR.sup.FbR.sup.Fc, C═O, C═S, C═CH.sub.2, SO.sub.2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl).sub.2, P(O)alkyl, P(O)OH, P(O)NH.sub.2; Y.sup.Fb is NH, NR.sup.FF1, CH.sub.2, CHR.sup.FF1, C(R.sup.FF1).sub.2, O, or S; Y.sup.Fc is CR.sup.FdR.sup.Fe, C═O, C═S, C═CH.sub.2, SO.sub.2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl).sub.2, P(O)alkyl, P(O)OH, P(O)NH2; each of R.sup.Fb, R.sup.Fc, R.sup.Fd, and R.sup.Fe is, independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl.sub.2; or R.sup.Fb and R.sup.Fc, together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; or R.sup.Fd and R.sup.Fe, together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; and or R.sup.Fd and R.sup.Fb, together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; each of Y.sup.Fd and Y.sup.Ff is, independently, CH.sub.2, CHR.sup.FF2, C(R.sup.FF2).sub.2, C(O), N, NH, NR.sup.FF3, O, S, or S(O); Y.sup.Fe is a bond or a divalent moiety attached to Y.sup.Fd and Y.sup.Ff that contains 1 to 5 contiguous carbon atoms that form a 3 to 3-membered ring, wherein 1; 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen, or sulfur atom; wherein one of the ring atoms is substituted with A.sup.2 and the others are substituted with one or more groups independently selected from H and R.sup.FF1; and wherein the contiguous atoms of Y.sup.Fe can be attached through a single or double bond; each R.sup.FF1 is, independently, H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl; each R.sup.FF2 is, independently, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including alkyl)(aliphatic including alkyl), —NHSO.sub.2alkyl, —N(alkyl)SO.sub.2alkyl, —NHSO.sub.2aryl, —N(alkyl)SO.sub.2aryl, —NHSO.sub.2alkenyl, —N(alkyl)SO.sub.2alkenyl, —NHSO.sub.2alkynyl, —N(alkyl)SO.sub.2alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and R.sup.FF3 is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, wherein if Y.sup.Fd or Y.sup.Ff is substituted with A.sup.2, then Y.sup.Fe is a bond, or a pharmaceutically acceptable salt thereof.

195. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula FB: ##STR01022## wherein ##STR01023## or a bicyclic moiety which is substituted with A.sup.2 and substituted with one or more groups independently selected from H, R.sup.FF1, and oxo; A.sup.2 is a bond between the degrader and the linker; Y.sup.Fa is CR.sup.FbR.sup.Fc, C═O, C═S, C═CH.sub.2, SO.sub.2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl).sub.2, P(O)alkyl, P(O)OH, P(O)NH.sub.2; each of Y.sup.Fb and Y.sup.Fg is, independently, NH, NR.sup.FF1, CH.sub.2, CHR.sup.FF1, C(R.sup.FF1).sub.2, O, or S; Y.sup.Fc is CR.sup.FdR.sup.Fe, C═O, C═S, C═CH.sub.2, SO.sub.2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl).sub.2, P(O)alkyl, P(O)OH, P(O)NH.sub.2; each of R.sup.Fb, R.sup.Fc, R.sup.Fd, R.sup.Fe, R.sup.Ff, and R.sup.Fg is, independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl.sub.2; or R.sup.Fb and R.sub.Fc, together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; or R.sup.Fd and R.sup.Fe, together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; or R.sup.Ff and R.sup.Fg, together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; or R.sup.Fd and R.sup.Fb, together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; or R.sup.Fd and R.sup.Ff, together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; or R.sup.Fb and R.sup.Fg, together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; each of Y.sup.Fd and Y.sup.Ff is, independently, CH.sub.2, CHR.sup.FF2, C(R.sup.FF2).sub.2, C(O), N, NH, NR.sup.FF3, O, S, or S(O); Y.sup.Fe is a bond or a divalent moiety attached to Y.sup.Fd and Y.sup.Ff that contains 1 to 5 contiguous carbon atoms that form a 3 to 8-membered ring, wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen, or sulfur atom; wherein one of the ring atoms is substituted with A.sup.2 and the others are substituted with one or more groups independently selected from H and R.sup.FF1; and wherein the contiguous atoms of Y.sup.Fe can be attached through a single or double bond; each R.sup.FF1 is, independently, H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl; each R.sup.FF2 is, independently, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including alkyl)(aliphatic including alkyl), —NHSO.sub.2alkyl, —N(alkyl)SO.sub.2alkyl, —NHSO.sub.2aryl, —N(alkyl)SO.sub.2aryl, —NHSO.sub.2alkenyl, —N(alkyl)SO.sub.2alkenyl, —NHSO.sub.2alkynyl, —N(alkyl)SO.sub.2alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and R.sup.FF3 is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, wherein if Y.sup.Fd or Y.sup.Ff is substituted with A.sup.2, then Y.sup.Fe is a bond, or a pharmaceutically acceptable salt thereof.

196. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula F1: ##STR01024## wherein A.sup.2 is a bond between the degrader and the linker; and R.sup.F1 is absent or O, or a pharmaceutically acceptable salt thereof.

197. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula F2: ##STR01025## wherein A.sup.2 is a bond between the degrader and the linker; and R.sup.F1 is absent or O, or a pharmaceutically acceptable salt thereof.

198. The compound of any one of claims 2 to 114, wherein the degradation moiety comprises the structure of Formula G: ##STR01026## wherein A.sup.2 is a bond between the degrader and the linker; and R.sup.F1 is absent or O, or a pharmaceutically acceptable salt thereof.

199. The compound of any one of claims 2 to 198, wherein the linker has the structure of Formula IV:
A.sup.1-(B.sup.1).sub.f—(C.sup.1).sub.g—(B.sup.2).sub.h-(D)-(B.sup.3).sub.i—(C.sup.2).sub.j—(B.sup.4).sub.k-A.sup.2   Formula IV wherein A.sup.1 is a bond between the linker and A; A.sup.2 is a bond between B and the linker; each of B.sup.1, B.sup.2, B.sup.3, and B.sup.4 is, independently, optionally substituted C.sub.1-C.sub.2 alkyl, optionally substituted C.sub.1-C.sub.3 heteroalkyl, O, S, S(O).sub.2, or NR.sup.N; each R.sup.N is, independently, H, optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.2-4 alkenyl, optionally substituted C.sub.2-4 alkynyl, optionally substituted C.sub.2-6 heterocyclyl, optionally substituted C.sub.6-12 aryl, or optionally substituted C.sub.1-7 heteroalkyl; each of C.sup.1 and C.sup.2 is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.2-10 alkenyl, optionally substituted C.sub.2-10 alkynyl, optionally substituted C.sub.2-6 heterocyclyl, optionally substituted C.sub.6-12 aryl, optionally substituted C.sub.2-C.sub.10 polyethylene glycol, or optionally substituted C.sub.1-10 heteroalkyl, or a chemical bond linking A.sup.1-(B.sup.1).sub.f—(C.sup.1).sub.g—(B.sup.2).sub.h— to —(B.sup.3).sub.i—(C.sup.2).sub.j—(B.sup.4).sub.k-A.sup.2.

200. The method of claim 199, wherein each of B.sup.1, B.sup.2, B.sup.3, and B.sup.4 is, independently, optionally substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4 heteroalkyl, or NR.sup.N.

201. The method of claim 198 or 199, wherein each R.sub.N is, independently, H or optionally substituted C.sub.1-C.sub.4 alkyl.

202. The method of any one of claims 198 to 201, wherein each R.sup.N is, independently, H or methyl.

203. The compound of any one of claims 199 to 202, wherein each of B.sup.1 and B.sup.4 is, independently, ##STR01027##

204. The compound of claim 203 wherein B.sup.1 is ##STR01028##

205. The compound of any one of claims 199 to 204, wherein each of C.sup.1 and C.sup.2 is, independently, ##STR01029##

206. The compound of claim 205, wherein C.sup.1 is ##STR01030##

207. The compound of any one of claims 199 to 204, wherein B.sup.2 is NR.sup.N.

208. The compound of any one of claims 199 to 204, wherein B.sup.2 is optionally substituted C.sub.1-C.sub.4 alkyl.

209. The compound of any one of claims 199 to 208, wherein f is 0.

210. The compound of any one of claims 199 to 208, wherein f is 1.

211. The compound of any one of claims 199 to 210, wherein g is 1.

212. The compound of any one of claims 199 to 211, wherein h is 0.

213. The compound of any one of claims 199 to 211, wherein h is 1.

214. The compound of any one of claims 199 to 213, wherein i is 0.

215. The compound of any one of claims 199 to 214, wherein j is 0.

216. The compound of any one of claims 199 to 215, wherein k is 0.

217. The compound of any one of claims 199 to 216, wherein the linker has the structure of ##STR01031## wherein x is 1, 2, 3, 4, 5, 6, 7, or 8; y is 1, 2, 3, or 4; R.sup.x is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; R.sup.y is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; and W is O or NR.sup.w, wherein R.sup.w is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl.

218. The compound of any one of claims 199 to 217, wherein the linker has the structure of: ##STR01032## ##STR01033## ##STR01034##

219. The compound of any one of claims 199 to 218, wherein the linker has the structure of ##STR01035##

220. The compound of any one of claims 2 to 198, wherein the linker has the structure of Formula V:
A.sup.1-(E.sup.1)-(F.sup.1)—(C.sup.3).sub.m-(E.sup.3).sub.n-(F.sup.2).sub.o1—(F.sup.3).sub.o2-(E.sup.2).sub.p-A.sup.2,   Formula V wherein A.sup.1 is a bond between the linker and A; A.sup.2 is a bond between B and the linker; each of m, n, o1, o2, and p is, independently, 0 or 1; each of E.sup.1 and E.sup.2 is, independently, O, S, NR.sup.N, optionally substituted C.sub.1-10 alkylene, optionally substituted C.sub.2-10 alkenylene, optionally substituted C.sub.2-10 alkynylene, optionally substituted C.sub.2-C.sub.10 polyethylene glycol, or optionally substituted C.sub.1-10 heteroalkylene; E.sup.3 is optionally substituted C.sub.1-C.sub.6 alkylene, optionally substituted C.sub.1-C.sub.6 heteroalkylene, O, S, or NR.sup.N; each R.sup.N is, independently, H, optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.2-4 alkenyl, optionally substituted C.sub.2-4 alkynyl, optionally substituted C.sub.2-6 heterocyclyl, optionally substituted C.sub.6-12 aryl, or optionally substituted C.sub.1-7 heteroalkyl; C.sup.3 is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and each of F.sup.1, F.sup.2, and F.sup.3 is, independently, optionally substituted C.sub.3-C.sub.10 carbocyclylene, optionally substituted C.sub.2-10 heterocyclylene, optionally substituted C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene.

221. The compound of claim 220, wherein the linker has the structure of Formula Va:
A.sup.1-(E.sup.1)-(F.sup.1)—(C.sup.3).sub.m-(E.sup.2).sub.p-A.sup.2.   Formula Va

222. The compound of claim 220, wherein the linker has the structure of Formula Vb:
A.sup.1-(E.sup.1)-(F.sup.1)-(E.sup.2).sub.p-A.sup.2.   Formula Vb

223. The compound of claim 220, wherein the linker has the structure of Formula Vc:
A.sup.1-(E.sup.1)-(F.sup.1)-A.sup.2.   Formula Vc

224. The compound of claim 220, wherein the linker has the structure of Formula Vd:
A.sup.1-(E.sup.1)-(F.sup.1)—(C.sup.3).sub.m—(F.sup.2).sub.o1-A.sup.2.   Formula Vd

225. The compound of claim 220, wherein the linker has the structure of Formula Ve:
A.sup.1-(E.sup.1)-(F.sup.1)-(E.sup.3).sub.n-(F.sup.2).sub.o1-(E.sup.2).sub.p-A.sup.2.   Formula Ve

226. The compound of claim 220, wherein the linker has the structure of Formula Vf:
A.sup.1-(E.sup.1)-(F.sup.1)—(C.sup.3).sub.m-(E.sup.3).sub.n-(F.sup.2).sub.o1-(E.sup.2).sub.p-A.sup.2.   Formula Vf

227. The compound of claim 220, wherein the linker has the structure of Formula Vg:
A.sup.1-(E.sup.1)-(F.sup.1)-(E.sup.3).sub.n-(F.sup.2).sub.o1-A.sup.2,   Formula Vg

228. The compound of any one of claims 220 to 27, wherein each of E.sup.1 and E.sup.2 is, independently, NR.sup.N, optionally substituted C.sub.1-10 alkylene, optionally substituted C.sub.2-C.sub.10 polyethylene glycolene, or optionally substituted C.sub.1-10 heteroalkylene.

229. The compound of any one of claims 220 to 228, wherein E.sup.3 is optionally substituted C.sub.1-C.sub.6 alkylene, O, S, or NR.sup.N.

230. The compound of claim 229, wherein E.sup.3 is optionally substituted C.sub.1-C.sub.6 alkylene.

231. The compound of claim 229, wherein E.sup.3 is optionally substituted C.sub.1-C.sub.3 alkylene.

232. The compound of claim 229, wherein E.sup.3 is ##STR01036## wherein a is 0, 1, 2, 3, 4, or 5.

233. The compound of claim 229, wherein E.sup.3 is ##STR01037##

234. The compound of claim 229, wherein E.sup.3 is O.

235. The compound of any one of claims 220 to 234, wherein each R.sup.N is, independently, H or optionally substituted C.sub.1-4 alkyl.

236. The compound of claim 235, wherein each R.sup.N is, independently, H or methyl.

237. The compound of any one of claims 220 to 236, wherein E.sup.1 is ##STR01038## wherein a is 0, 1, 2, 3, 4, or 5.

238. The compound of claim 237, wherein E.sup.1 is ##STR01039##

239. The compound of claim 238, wherein E.sup.1 is ##STR01040##

240. The compound of any one of claims 220 to 239, wherein E.sup.1 is ##STR01041## ##STR01042## wherein b is 0, 1, 2, 3, 4, 5, or 6; R.sup.a is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; R.sup.b is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; and R.sup.c is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl.

241. The compound of claim 240, wherein E.sup.1 is ##STR01043##

242. The compound of claim 241, wherein E.sup.1 is ##STR01044##

243. The compound of claim 240, wherein E.sup.1 is ##STR01045##

244. The compound of claim 243, wherein E.sup.1 is ##STR01046##

245. The compound of any one of claims 240 to 244, wherein R.sup.a is H or methyl.

246. The compound of claim 245, wherein R.sup.a is H.

247. The compound of claim 245, wherein R.sup.a is methyl.

248. The compound of any one of claims 220 to 247, wherein E.sup.2 is O, NR.sup.w, ##STR01047## wherein c is 0, 1, 2, 3, 4, 5, 6, 7, or 8; d is 0, 1, 2, or 3; e is 0, 1, 2, 3, 4, 5, or 6; f is 0, 1, 2, 3, or 4; R.sup.d is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; R.sup.e is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; R.sup.f is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; R.sup.g is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl; and W is O or NR.sup.w, wherein R.sup.w is H or optionally substituted C.sub.1-C.sub.6 alkyl.

249. The compound of claim 248, wherein E.sup.2 is O, ##STR01048##

250. The compound of any one of claims 220 to 249, wherein each of F.sup.1, F.sup.2, or F.sup.3 is, independently, optionally substituted C.sub.3-C.sub.10 carbocyclylene.

251. The compound of claim 250, wherein the C.sub.3-C.sub.10 carbocyclylene is monocyclic.

252. The compound of claim 250, wherein the C.sub.3-C.sub.10 carbocyclylene is polycyclic.

253. The compound of claim 252, wherein the C.sub.3-C.sub.10 carbocyclylene is fused.

254. The compound of claim 252, wherein the C.sub.3-C.sub.10 carbocyclylene is spirocyclic.

255. The compound of claim 252, wherein the C.sub.3-C.sub.10 carbocyclylene is bridged.

256. The compound of claim 255, wherein the C.sub.3-C.sub.10 carbocyclylene is ##STR01049##

257. The compound of claim 256, wherein the C.sub.3-C.sub.10 carbocyclylene is ##STR01050##

258. The compound of any one of claims 220 to 249, wherein each of F.sup.1, F.sup.2, or F.sup.3 is, independently, optionally substituted C.sub.2-C.sub.6 heterocyclylene.

259. The compound of claim 258, wherein the C.sub.2-C.sub.6 heterocyclylene is monocyclic.

260. The compound of claim 259, wherein the C.sub.2-C.sub.6 heterocyclylene is ##STR01051## ##STR01052## wherein q1 is 0, 1, 2, 3, or 4; q2 is 0, 1, 2, 3, 4, 5, or 6; q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each R.sup.h is, independently, .sup.2H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, OR.sup.i2, or NR.sup.i3R.sup.i4; or two R.sup.h groups, together with the carbon atom to which each is attached, combine to form optionally substituted C.sub.3-C.sub.10 carbocyclyl or optionally substituted C.sub.2-C.sub.9 heterocyclyl; or two R.sup.h groups, together with the carbon atoms to which each is attached, combine to form optionally substituted C.sub.3-C.sub.10 carbocyclyl or optionally substituted C.sub.2-C.sub.9 heterocyclyl; R.sup.i1 is H or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.i2 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.6 carbocyclyl;

261. The compound of claim 260, wherein the C.sub.2-C.sub.9 heterocyclylene is ##STR01053## ##STR01054##

262. The compound of claim 260 or 261, wherein each R.sup.h is, independently, .sup.2H, halogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, OR.sup.i2, or NR.sup.i3R.sup.i4.

263. The compound of claim 262, wherein each R.sup.h is, independently, .sup.2H, F, methyl, ##STR01055##

264. The compound of claim 263, wherein each R.sup.h is, independently, F, methyl, or NR.sup.i3R.sup.i4.

265. The compound of any one of claims 260 to 264, wherein q1 is 0, 1, or 2.

266. The compound of any one of claims 260 to 265, wherein q2 is 0, 1, or 2.

267. The compound of any one of claims 260 to 264, wherein q3 is 0, 1, or 2.

268. The compound of any one of claims 260 to 267, wherein the C.sub.2-C.sub.9 heterocyclylene is ##STR01056## ##STR01057## ##STR01058## ##STR01059##

269. The compound of claim 268, wherein the C.sub.2-C.sub.9 heterocyclylene is ##STR01060## ##STR01061##

270. The compound of claim 269, wherein the C.sub.2-C.sub.9 heterocyclylene is ##STR01062##

271. The compound of any one of claims 260 to 270, wherein F.sup.1 is ##STR01063##

272. The compound of any one of claims 260 to 271, wherein F.sup.2 is ##STR01064##

273. The compound of any one of claims 260 to 271, wherein F.sup.3 is ##STR01065##

274. The compound of claim 258, wherein the C.sub.2-C.sub.6 heterocyclylene is polycyclic.

275. The compound of claim 274, wherein the C.sub.2-C.sub.6 heterocyclylene is bicyclic.

276. The compound of claim 274 or 275, wherein the C.sub.2-C.sub.6 heterocyclylene is bridged.

277. The compound of claim 276, wherein the C.sub.2-C.sub.6 heterocyclylene is ##STR01066##

278. The compound of claim 274 or 275, wherein the C.sub.2-C.sub.6 heterocyclylene is fused.

279. The compound of claim 278, wherein the C.sub.2-C.sub.9 heterocyclylene is ##STR01067## ##STR01068##

280. The compound of claim 279, wherein F.sup.1 is ##STR01069##

281. The compound of claim 279 or 280, wherein F.sup.2 is ##STR01070##

282. The compound of claim 274 or 275, wherein the C.sub.2-C.sub.6 heterocyclylene is spirocyclic.

283. The compound of claim 282, wherein the C.sub.2-C.sub.6 heterocyclylene is ##STR01071## ##STR01072## ##STR01073##

284. The compound of claim 283, wherein F.sup.1 is ##STR01074##

285. The compound of claim 283 or 284, wherein F.sup.2 is ##STR01075##

286. The compound of any one of claims 283 to 288, wherein F.sup.3 is ##STR01076##

287. The compound of any one of claims 258 to 286 wherein the C.sub.2-C.sub.9 heterocyclylene comprises a quaternary amine.

288. The compound of any one of claims 220 to 249, wherein each of F.sup.1, F.sup.2, or F.sup.3 is, independently, optionally substituted C.sub.6-C.sub.10 arylene.

289. The compound of claim 288, wherein the C.sub.6-C.sub.10 arylene is ##STR01077##

290. The compound of any one of claims 220 to 249, wherein each of F.sup.1, F.sup.2, or F.sup.3 is, independently, optionally substituted C.sub.2-C.sub.9 heteroarylene.

291. The compound of claim 290, wherein the C.sub.2-C.sub.9 heteroarylene is ##STR01078## ##STR01079##

292. The compound of claim 291, wherein F.sup.2 is ##STR01080##

293. The compound of claim 292, wherein F.sup.2 is ##STR01081##

294. The compound of any one of claims 220 to 293, C.sup.3 is ##STR01082##

295. The compound of claim 294, wherein C.sup.3 is ##STR01083##

296. The compound of any one of claims 220 to 295, wherein m is 1.

297. The compound of any one of claims 220 to 295, wherein m is 0.

298. The compound of any one of claims 220 to 297, wherein p is 1.

299. The compound of any one of claims 220 to 297, wherein p is 0.

300. The compound of any one of claims 220 to 299, wherein o1 is 1.

301. The compound of any one of claims 220 to 299, wherein o1 is 0.

302. The compound of any one of claims 220 to 301, wherein o2 is 1.

303. The compound of any one of claims 220 to 301, wherein o2 is 0.

304. The compound of any one of claims 220 to 303, wherein n is 1.

305. The compound of any one of claims 220 to 303, wherein n is 0.

306. The compound of any one of claims 220 to 305, wherein the linker has the structure of ##STR01084## ##STR01085## ##STR01086## ##STR01087## ##STR01088## ##STR01089## ##STR01090## ##STR01091## ##STR01092##

307. The compound of any one of claims 220 to 305, wherein the linker has the structure of ##STR01093## ##STR01094## ##STR01095## ##STR01096## ##STR01097## ##STR01098## ##STR01099## ##STR01100## ##STR01101## ##STR01102## ##STR01103## ##STR01104## ##STR01105## ##STR01106## ##STR01107##

308. The compound of any one of claims 220 to 305, wherein the linker has the structure of: ##STR01108## ##STR01109## ##STR01110## ##STR01111## ##STR01112##

309. The compound of any one of claims 2 to 198, wherein the linker is optionally substituted C.sub.3-C.sub.10 carbocyclylene, optionally substituted C.sub.2-10 heterocyclylene, optionally substituted C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene.

310. The compound of claim 309, wherein the linker is optionally substituted C.sub.2-10 heterocyclylene

311. The compound of claim 310, wherein the linker has the structure of ##STR01113##

312. The compound of claim 311, wherein the linker has the structure of ##STR01114##

313. The compound of any one of claims 2 to 198, wherein the linker is absent.

314. The compound of claim 1, wherein the compound has the structure of any one of compounds B1-B6 in Table 1, or a pharmaceutically acceptable salt thereof.

315. The compound of any one of claims 2 to 313, wherein the compound has the structure of any one of compounds D1-D15 in Table 2A, or a pharmaceutically acceptable salt thereof.

316. The compound of any one of claims 2 to 313, wherein the compound has the structure of any one of compounds D16-D90 in Table 2B, or a pharmaceutically acceptable salt thereof.

317. The compound of any one of claims 2 to 313, wherein the compound has the structure of any one of compounds D91-D220 in Table 2C, or a pharmaceutically acceptable salt thereof.

318. A pharmaceutical composition comprising the compound of any one of claims 1 to 317 and a pharmaceutically acceptable excipient.

319. A method of inhibiting the level of BRD9 in a cell, the method involving contacting the cell with an effective amount of a compound of any one of claims 1 to 317, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

320. A method of inhibiting the activity of BRD9 in a cell, the method involving contacting the cell with an effective amount of a compound of any one of claims 1 to 317, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

321. The method of claim 319 or 320, wherein the cell is a cancer cell.

322. The method of claim 321, wherein the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma, non-small cell lung cancer, stomach cancer, or breast cancer.

323. The method of claim 322, wherein the cancer is a sarcoma.

324. The method of claim 323, wherein the sarcoma is a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma.

325. The method of claim 324, wherein the sarcoma is synovial sarcoma.

326. A method of treating a BAF complex-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of a compound of any one of claims 1 to 317, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

327. A method of treating an SS18-SSX fusion protein-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of a compound of any one of claims 1 to 317, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

328. A method of treating a BRD9-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of a compound of any one of claims 1 to 315, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

329. The method of any one of claims 326 to 328, wherein the disorder is cancer.

330. A method of treating a cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 317, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

331. The method of claim 329 or 330, wherein the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma, non-small cell lung cancer, stomach cancer, or breast cancer.

332. The method of claim 331, wherein the cancer is a sarcoma.

333. The method of claim 332, wherein the sarcoma is a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma.

334. The method of claim 333, wherein the sarcoma is synovial sarcoma.

335. The method of any one of claims 326 to 328, wherein the disorder is infection.

336. A method of treating infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 317, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 318.

337. The method of claim 335 or 336, wherein the infection is a viral infection.

338. The method of claim 337, wherein the viral infection is an infection with a virus of the Retroviridae family, Hepadnaviridae family, Flaviviridae family, Adenoviridae family, Herpesviridae family, Papillomaviridae family, Parvoviridae family, Polyomaviridae family, Paramyxoviridae family, or Togaviridae family.

339. The method of claim 337 or 338, wherein the viral infection is Coffin Siris, Neurofibromatosis, or Multiple Meningioma.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0795] FIG. 1 is a series of graphs illustrating the effect of specific guide RNA (sgRNA) targeting of the BRD9 BAF complex subunit on synovial sarcoma cell growth. The Y-axis indicated the dropout ratio. The X-axis indicates the nucleotide position of the BRD9 gene. The grey box indicates the range of the negative control sgRNAs in the screen. The SYO1 cell line carries SS18-SSX2 fusion protein. The breakpoint joining the N-terminal region of SS18 to the C-terminal region of SSX2 are indicated by the black lines in their respective panel. The linear protein sequence is show with BRD9 PFAM domains annotated from the PFAM database.

[0796] FIG. 2 is an image illustrating dose dependent depletion of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrader.

[0797] FIG. 3 is an image illustrating sustained suppression of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrader over 72 hours.

[0798] FIG. 4 is an image illustrating sustained suppression of BRD9 levels in two cell lines (293T and SYO1) in the presence of a BRD9 degrader over 5 days.

[0799] FIG. 5 is an image illustrating sustained suppression of BRD9 levels in synovial sarcoma cell lines (SYO1 and Yamato) in the presence of a BRD9 degrader over 7 days compared to the levels in cells treated with CRISPR reagents.

[0800] FIG. 6 is an image illustrating the effect on cell growth of six cell lines (SYO1, Yamato, A549, HS-SY-II, ASKA, and 293T) in the presence of a BRD9 degrader and a BRD9 inhibitor.

[0801] FIG. 7 is an image illustrating the effect on cell growth of two cell lines (SYO1 and G401) in the presence of a BRD9 degrader.

[0802] FIG. 8 is an image illustrating the effect on cell growth of three synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presence of a BRD9 degrader, BRD9 binder and E3 ligase binder.

[0803] FIG. 9 is an image illustrating the effect on cell growth of three non-synovial sarcoma cell lines (RD, HCT116, and Calu6) in the presence of a BRD9 degrader, BRD9 binder and E3 ligase binder.

[0804] FIG. 10 is a graph illustrating the percentage of SYO1 in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, or Compound 1 at 1 μM for 8 or 13 days.

[0805] FIG. 11 is a series of contour plots illustrating the percentage of SYO1 cells in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for 8 days. Numerical values corresponding to each contour plot are found in the table below.

[0806] FIG. 12 is a series of contour plots illustrating the percentage of SYO1 cells in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for 13 days. Numerical values corresponding to each contour plot are found in the table below.

[0807] FIG. 13 is a series of contour plots illustrating the percentage of early- and late-apoptotic SYO1 cells following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for 8 days. Numerical values corresponding to each contour plot are found in the table below.

[0808] FIG. 14 is a graph illustrating the proteins present in BAF complexes including the SS18-SSX fusion protein.

DETAILED DESCRIPTION

[0809] The present disclosure features compositions and methods useful for the treatment of BAF-related disorders (e.g., cancer and infection). The disclosure further features compositions and methods useful for inhibition of the level and/or activity of BRD9, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof.

Compounds

[0810] Compounds described herein reduce the level of an activity related to BRD9, or a related downstream effect, or reduce the level of BRD9 in a cell or subject. Exemplary compounds described herein have the structure according to Formula I or Formula II.

[0811] Formula I is:

##STR00729##

[0812] where

[0813] R.sup.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.10 carbocyclyl;

[0814] Z.sup.1 is CR.sup.2 or N;

[0815] R.sup.2 is H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl;

##STR00730##

[0816] X.sup.1 is CR.sup.X1 or N;

[0817] X.sup.2 is O or S;

[0818] R.sup.X1 is H or optionally substituted C.sub.1-C.sub.6 alkyl;

[0819] R.sup.3 is H, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted amino, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; and

[0820] G is optionally substituted C.sub.3-C.sub.10 carbocyclyl, C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl, or a pharmaceutically acceptable salt thereof.

[0821] Formula II is:

A-L-B   Formula II,

[0822] where

[0823] L is a linker;

[0824] B is a degradation moiety; and

[0825] A has the structure of Formula III:

##STR00731##

[0826] where

[0827] R.sup.1 is, independently, H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted C.sub.3-C.sub.10 carbocyclyl;

[0828] Z.sup.1 is CR.sup.2 or N;

[0829] R.sup.2 is H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl;

##STR00732##

[0830] X.sup.1 is CR.sup.X1 or N;

[0831] X.sup.2 is O or S;

[0832] R.sup.X1 is H or optionally substituted C.sub.1-C.sub.6 alkyl;

[0833] R.sup.3 is H,

##STR00733##

cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted amino, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.10 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; and

[0834] R.sup.3′ is absent, optionally substituted C.sub.1-C.sub.6 alkylene, optionally substituted C.sub.2-C.sub.9 heteroarylene, or optionally substituted C.sub.1-C.sub.6 heteroalkylene;

[0835] G is

##STR00734##

optionally substituted C.sub.3-C.sub.10 carbocyclyl, C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl;

[0836] G′ is optionally substituted C.sub.3-C.sub.10 carbocyclylene, C.sub.2-C.sub.9 heterocyclylene, optionally substituted C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene; and

[0837] A.sup.1 is a bond between A and the linker,

[0838] where G is

##STR00735##

or a pharmaceutically acceptable salt thereof.

[0839] In some embodiments, the compound has the structure of any one of compounds B1-B10 in Table 1, or a pharmaceutically acceptable salt thereof.

[0840] In some embodiments, the compound has the structure of any one of compounds D1-D15 in Table 2A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D16-D90 in Table 2B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D91-D220 in Table 2C, or a pharmaceutically acceptable salt thereof.

[0841] Other embodiments, as well as exemplary methods for the synthesis of production of these compounds, are described herein.

Pharmaceutical Uses

[0842] The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and/or activity of a BAF complex, e.g., by inhibiting the activity or level of the BRD9 protein in a cell within the BAF complex in a mammal.

[0843] An aspect of the present invention relates to methods of treating disorders related to BRD9 such as cancer in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject.

[0844] Treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.

[0845] Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

[0846] Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2×, 10×, or 50×).

[0847] Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0848] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

Combination Therapies

[0849] A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect.

[0850] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammalI and calicheamicin omegalI (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0851] In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAM PATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-l-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates.

[0852] The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.

[0853] The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab/YERVOY® or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/Ig fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof.

[0854] In some embodiments, the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No. 20060121005.

[0855] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.

Pharmaceutical Compositions

[0856] The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0857] The compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0858] A compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound described herein may also be administered parenterally. Solutions of a compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.

[0859] The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

Dosages

[0860] The dosage of the compounds described herein, and/or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0861] Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-100 mg/kg (e.g., 0.1-50 mg/kg (e.g., 0.25-25 mg/kg)). In exemplary, non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).

Kits

[0862] The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.

EXAMPLES

Example 1—High Density Tiling sgRNA Screen Against Human BAF Complex Subunits in Synovial Sarcoma Cell Line SYO1

[0863] The following example shows that BRD9 sgRNA inhibits cell growth in synovial sarcoma cells.

[0864] Procedure: To perform high density sgRNA tiling screen, an sgRNA library against BAF complex subunits was custom synthesized at Cellecta (Mountain View, Calif.). Sequences of DNA encoding the BRD9-targeting sgRNAs used in this screen are listed in Table 3. Negative and positive control sgRNA were included in the library. Negative controls consisted of 200 sgRNAs that do not target human genome. The positive controls are sgRNAs targeting essential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1, PCNA, POLR2L, RPL9, and SF3A3). DNA sequences encoding all positive and negative control sgRNAs are listed in Table 4. Procedures for virus production, cell infection, and performing the sgRNA screen were previously described (Tsherniak et al, Cell 170:564-576 (2017); Munoz et al, Cancer Discovery 6:900-913 (2016)). For each sgRNA, 50 counts were added to the sequencing counts and for each time point the resulting counts were normalized to the total number of counts. The log 2 of the ratio between the counts (defined as dropout ratio) at day 24 and day 1 post-infection was calculated. For negative control sgRNAs, the 2.5 and 97.5 percentile of the log 2 dropout ratio of all non-targeting sgRNAs was calculated and considered as background (grey box in the graph). Protein domains were obtained from PFAM regions defined for the UNIPROT identifier: Q9H8M2.

[0865] Results: As shown in FIG. 1, targeted inhibition of the GBAF complex component BRD9 by sgRNA resulted in growth inhibition of the SYO1 synovial sarcoma cell line. sgRNAs against other components of the BAF complexes resulted in increased proliferation of cells, inhibition of cell growth, or had no effect on SYO1 cells. These data show that targeting various subunits of the GBAF complex represents a therapeutic strategy for the treatment of synovial sarcoma.

TABLE-US-00005 TABLE 3 BRD9 sgRNA Library SEQ ID NO Nucleic Acid Sequence 203 CAAGAAGCACAAGAAGCACA 204 CTTGTGCTTCTTGCCCATGG 205 CTTCTTGTGCTTCTTGCCCA 206 ACAAGAAGCACAAGGCCGAG 207 CTCGTAGGACGAGCGCCACT 208 CGAGTGGCGCTCGTCCTACG 209 GAGTGGCGCTCGTCCTACGA 210 AGGCTTCTCCAGGGGCTTGT 211 AGATTATGCCGACAAGCCCC 212 ACCTTCAGGACTAGCTTTAG 213 AGCTTTAGAGGCTTCTCCAG 214 CTAGCTTTAGAGGCTTCTCC 215 TAGCTTTAGAGGCTTCTCCA 216 CTAAAGCTAGTCCTGAAGGT 217 GCCTCTAAAGCTAGTCCTGA 218 CTTCACTTCCTCCGACCTTC 219 AAGCTAGTCCTGAAGGTCGG 220 AGTGAAGTGACTGAACTCTC 221 GTGACTGAACTCTCAGGATC 222 ATAGTAACTGGAGTCGTGGC 223 CATCATAGTAACTGGAGTCG 224 TGACCTGTCATCATAGTAAC 225 ACTCCAGTTACTATGATGAC 226 CTTTGTGCCTCTCTCGCTCA 227 GGTCAGACCATGAGCGAGAG 228 GAAGAAGAAGAAGTCCGAGA 229 GTCCAGATGCTTCTCCTTCT 230 GTCCGAGAAGGAGAAGCATC 231 GGAGAAGCATCTGGACGATG 232 TGAGGAAAGAAGGAAGCGAA 233 ATCTGGACGATGAGGAAAGA 234 AGAAGAAGCGGAAGCGAGAG 235 GAAGAAGCGGAAGCGAGAGA 236 CCGCCCAGGAAGAGAAGAAG 237 AGAGAGGGAGCACTGTGACA 238 AGGGAGCACTGTGACACGGA 239 GAGGGAGCACTGTGACACGG 240 GCACTGTGACACGGAGGGAG 241 GAGGCTGACGACTTTGATCC 242 AGGCTGACGACTTTGATCCT 243 TCCACCTCCACCTTCTTCCC 244 CGACTTTGATCCTGGGAAGA 245 CTTTGATCCTGGGAAGAAGG 246 TGATCCTGGGAAGAAGGTGG 247 TCCTGGGAAGAAGGTGGAGG 248 CGGACTGGCCGATCTGGGGG 249 ACGCTCGGACTGGCCGATCT 250 AGGTGGAGCCGCCCCCAGAT 251 CGCTCGGACTGGCCGATCTG 252 GCTCGGACTGGCCGATCTGG 253 CACGCTCGGACTGGCCGATC 254 TGTGTCCGGCACGCTCGGAC 255 CTGGCTGTGTCCGGCACGCT 256 ATCGGCCAGTCCGAGCGTGC 257 CACCCTTGCCTGGCTGTGTC 258 CGAGCGTGCCGGACACAGCC 259 TGTTCCAGGAGTTGCTGAAT 260 CACACCTATTCAGCAACTCC 261 GCTGGCGGAGGAAGTGTTCC 262 TTTACCTCTGAAGCTGGCGG 263 CCCCGGTTTACCTCTGAAGC 264 ACTTCCTCCGCCAGCTTCAG 265 CAGGAAAAGCAAAAAATCCA 266 GCTTTCAGAAAAGATCCCCA 267 AGGAAAAGCAAAAAATCCAT 268 GGAAAAGCAAAAAATCCATG 269 GGAGCAATTGCATCCGTGAC 270 GTCACGGATGCAATTGCTCC 271 TTTATTATCATTGAATATCC 272 AATGATAATAAAACATCCCA 273 ATAAAACATCCCATGGATTT 274 TTCATGGTGCCAAAATCCAT 275 TTTCATGGTGCCAAAATCCA 276 TAATGAATACAAGTCAGTTA 277 CAAGTCAGTTACGGAATTTA 278 ATAATGCAATGACATACAAT 279 AACTTGTAGTACACGGTATC 280 CTTCGCCAACTTGTAGTACA 281 AGATACCGTGTACTACAAGT 282 GCGAAGAAGATCCTTCACGC 283 TCATCTTAAAGCCTGCGTGA 284 TTCTCAGCAGGCAGCTCTTT 285 CAATGAAGATACAGCTGTTG 286 ACTGGTACAACTTCAGGGAC 287 CTTGTACTGGTACAACTTCA 288 ACTTGTACTGGTACAACTTC 289 TTGGCAGTTTCTACTTGTAC 290 TACCTGATAACTTCTCTACT 291 AGCCGAGTAGAGAAGTTATC 292 AGCTGCATGTTTGAGCCTGA 293 GCTGCATGTTTGAGCCTGAA 294 AAGCTGCAGGCATTCCCTTC 295 GGTACTGTCCGTCAAGCTGC 296 AGGGAATGCCTGCAGCTTGA 297 CTTGACGGACAGTACCGCAG 298 CGCCAGCACGTGCTCCTCTG 299 TACCGCAGAGGAGCACGTGC 300 AGAGGAGCACGTGCTGGCGC 301 GGAGCACGTGCTGGCGCTGG 302 AGCACGCAGCTGACGAAGCT 303 GCACGCAGCTGACGAAGCTC 304 CAGCTGACGAAGCTCGGGAC 305 AAGCTCGGGACAGGATCAAC 306 CCTTGCCGCCTGGGAGGAAC 307 AGGATCAACCGGTTCCTCCC 308 ATCAACCGGTTCCTCCCAGG 309 GCACTACCTTGCCGCCTGGG 310 AGAGCACTACCTTGCCGCCT 311 CCGGTTCCTCCCAGGCGGCA 312 TCCTCTTCAGATAGCCCATC 313 ATGGGCTATCTGAAGAGGAA 314 GGGCTATCTGAAGAGGAACG 315 TGGGCTATCTGAAGAGGAAC 316 TATCTGAAGAGGAACGGGGA 317 ATCTGAAGAGGAACGGGGAC 318 TGTTGACCACGCTGTAGAGC 319 GCTCTACAGCGTGGTCAACA 320 CGGGAGCCTGCTCTACAGCG 321 CGTGGTCAACACGGCCGAGC 322 CCCACCATCAGCGTCCGGCT 323 ACGGCCGAGCCGGACGCTGA 324 GGGCACCCACCATCAGCGTC 325 GCCGAGCCGGACGCTGATGG 326 CCATGTCCGTGTTGCAGAGG 327 CCGAGCCGGACGCTGATGGT 328 CGAGCTCAAGTCCACCGGGT 329 GCGAGCTCAAGTCCACCGGG 330 AGAGCGAGCTCAAGTCCACC 331 GAGAGCGAGCTCAAGTCCAC 332 GAAGCCTGGGAGTAGCTTAC 333 CTCTCCAGTAAGCTACTCCC 334 AGCCCAGCGTGGTGAAGCCT 335 AAGCCCAGCGTGGTGAAGCC 336 ACTCCCAGGCTTCACCACGC 337 CTCCCAGGCTTCACCACGCT 338 CTCGTCTTTGAAGCCCAGCG 339 CACTGGAGAGAAAGGTGACT 340 GCACTGGAGAGAAAGGTGAC 341 AGTAGTGGCACTGGAGAGAA 342 CGAAAGCGCAGTAGTGGCAC 343 CTGCATCGAAAGCGCAGTAG 344 ATGCAGAATAATTCAGTATT 345 AGTATTTGGCGACTTGAAGT 346 CGACTTGAAGTCGGACGAGA 347 GAGCTGCTCTACTCAGCCTA 348 CACGCCTGTCTCATCTCCGT 349 TCAGCCTACGGAGATGAGAC 350 CAGGCGTGCAGTGTGCGCTG 351 CCGCGGCCCCTCTAGCCTGC 352 CATCCTTCACAAACTCCTGC 353 TAGCCTGCAGGAGTTTGTGA 354 CAGGAGTTTGTGAAGGATGC 355 AGGAGTTTGTGAAGGATGCT 356 TGGGAGCTACAGCAAGAAAG 357 GAGCTACAGCAAGAAAGTGG 358 GAAAGTGGTGGACGACCTCC 359 CGCCTGTGATCTGGTCCAGG 360 CTCCGCCTGTGATCTGGTCC 361 GACCTCCTGGACCAGATCAC 362 CTCCTGGACCAGATCACAGG 363 GCTGGAAGAGCGTCCTAGAG 364 TGCAGCCCACCTGCTTCAGC 365 GACGCTCTTCCAGCTGAAGC 366 CTCTTCCAGCTGAAGCAGGT 367 GCTCTTCCAGCTGAAGCAGG 368 CCTCCAGATGAAGCCAAGGT 369 GCTTCATCTGGAGGCTTCAT 370 GGCTTCATCTGGAGGCTTCA 371 CTTACCTTGGCTTCATCTGG 372 AAACTTACCTTGGCTTCATC 373 GAAGCCTCCAGATGAAGCCA 374 TCCTAGGGTGTCCCCAACCT 375 CCTAGGGTGTCCCCAACCTG 376 GTGTCTGTCTCCACAGGTTG 377 TGTGTCTGTCTCCACAGGTT 378 CCACAGGTTGGGGACACCCT 379 AGAGCTGCTGCTGTCTCCTA 380 CAGAGCTGCTGCTGTCTCCT 381 AGACAGCAGCAGCTCTGTTC 382 ATCCACAGAAACGTCGGGAT 383 GAGATATCCACAGAAACGTC 384 GGAGATATCCACAGAAACGT 385 GTCCTATCCCGACGTTTCTG 386 TCTCCATGCTCAGCTCTCTG 387 CTCACCCAGAGAGCTGAGCA 388 ATCTCCATGCTCAGCTCTCT 389 TATCTCCATGCTCAGCTCTC 390 ATGTCCTGTTTACACAGGGA 391 TTACACAGGGAAGGTGAAGA 392 AGTTCAAATGGCTGTCGTCA 393 TGACGACAGCCATTTGAACT 394 AAGTTCAAATGGCTGTCGTC 395 TCGTCTCATCCAAGTTCAAA 396 TGAGACGACGAAGCTCCTGC 397 GTGCTTCGTGCAGGTCCTGC 398 GCAGGACCTGCACGAAGCAC 399 GCTCCGCCTGTGCTTCGTGC 400 GGACCTGCACGAAGCACAGG 401 CACGAAGCACAGGCGGAGCG 402 AGGCGGAGCGCGGCGGCTCT 403 AGGGAGCTGAGGTTGGACGA 404 GTTGGACAGGGAGCTGAGGT 405 AGGCGTTGGACAGGGAGCTG 406 CCCTCTCGGAGGCGTTGGAC 407 CCTCTCGGAGGCGTTGGACA 408 CTGGTCCCTCTCGGAGGCGT 409 CCCTGTCCAACGCCTCCGAG 410 CCTGTCCAACGCCTCCGAGA 411 GTGGTGCTGGTCCCTCTCGG 412 CAGGTGGTGCTGGTCCCTCT 413 GCATCTCACCCAGGTGGTGC 414 CGAGAGGGACCAGCACCACC 415 GAGAGGGACCAGCACCACCT 416 GTGGGGGCATCTCACCCAGG 417 CCCCGACACTCAGGCGAGAA 418 TCCCCGACACTCAGGCGAGA 419 AGCCCTTCTCGCCTGAGTGT 420 CTGGCTGCTCCCCGACACTC 421 CCCTTCTCGCCTGAGTGTCG 422 GCCCTTCTCGCCTGAGTGTC 423 TAGGGGTCGTGGGTGACGTC 424 AAGAAACTCATAGGGGTCGT 425 GAAGAAACTCATAGGGGTCG 426 GAGACTGAAGAAACTCATAG 427 GGAGACTGAAGAAACTCATA 428 TGGAGACTGAAGAAACTCAT 429 TCTTCAGTCTCCAGAGCCTG 430 TTGGCAGAGGCCGCAGGCTC 431 TAGGTCTTGGCAGAGGCCGC 432 CTAGAGTTAGGTCTTGGCAG 433 GGTGGTCTAGAGTTAGGTCT

TABLE-US-00006 TABLE 4 Control sgRNA Library SEQ ID NO. gRNA Label Gene Nucleic Acid Sequence 434 1|sg_Non_Targeting_Human_0001| Non_Targeting_Human GTAGCGAACGTGTCCGGCGT Non_Targeting_Human 435 1|sg_Non_Targeting_Human_0002| Non_Targeting_Human GACCGGAACGATCTCGCGTA Non_Targeting_Human 436 1|sg_Non_Targeting_Human_0003| Non_Targeting_Human GGCAGTCGTTCGGTTGATAT Non_Targeting_Human 437 1|sg_Non_Targeting_Human_0004| Non_Targeting_Human GCTTGAGCACATACGCGAAT Non_Targeting_Human 438 1|sg_Non_Targeting_Human_0005| Non_Targeting_Human GTGGTAGAATAACGTATTAC Non_Targeting_Human 439 1|sg_Non_Targeting_Human_0006| Non_Targeting_Human GTCATACATGGATAAGGCTA Non_Targeting_Human 440 1|sg_Non_Targeting_Human_0007| Non_Targeting_Human GATACACGAAGCATCACTAG Non_Targeting_Human 441 1|sg_Non_Targeting_Human_0008| Non_Targeting_Human GAACGTTGGCACTACTTCAC Non_Targeting_Human 442 1|sg_Non_Targeting_Human_0009| Non_Targeting_Human GATCCATGTAATGCGTTCGA Non_Targeting_Human 443 1|sg_Non_Targeting_Human_0010| Non_Targeting_Human GTCGTGAAGTGCATTCGATC Non_Targeting_Human 444 1|sg_Non_Targeting_Human_0011| Non_Targeting_Human GTTCGACTCGCGTGACCGTA Non_Targeting_Human 445 1|sg_Non_Targeting_Human_0012| Non_Targeting_Human GAATCTACCGCAGCGGTTCG Non_Targeting_Human 446 1|sg_Non_Targeting_Human_0013| Non_Targeting_Human GAAGTGACGTCGATTCGATA Non_Targeting_Human 447 1|sg_Non_Targeting_Human_0014| Non_Targeting_Human GCGGTGTATGACAACCGCCG Non_Targeting_Human 448 1|sg_Non_Targeting_Human_0015| Non_Targeting_Human GTACCGCGCCTGAAGTTCGC Non_Targeting_Human 449 1|sg_Non_Targeting_Human_0016| Non_Targeting_Human GCAGCTCGTGTGTCGTACTC Non_Targeting_Human 450 1|sg_Non_Targeting_Human_0017| Non_Targeting_Human GCGCCTTAAGAGTACTCATC Non_Targeting_Human 451 1|sg_Non_Targeting_Human_0018| Non_Targeting_Human GAGTGTCGTCGTTGCTCCTA Non_Targeting_Human 452 1|sg_Non_Targeting_Human_0019| Non_Targeting_Human GCAGCTCGACCTCAAGCCGT Non_Targeting_Human 453 1|sg_Non_Targeting_Human_0020| Non_Targeting_Human GTATCCTGACCTACGCGCTG Non_Targeting_Human 454 1|sg_Non_Targeting_Human_0021| Non_Targeting Human GTGTATCTCAGCACGCTAAC Non_Targeting_Human 455 1|sg_Non_Targeting_Human_0022| Non_Targeting_Human GTCGTCATACAACGGCAACG Non_Targeting_Human 456 1|sg_Non_Targeting_Human_0023| Non_Targeting_Human GTCGTGCGCTTCCGGCGGTA Non_Targeting_Human 457 1|sg_Non_Targeting_Human_0024| Non_Targeting_Human GCGGTCCTCAGTAAGCGCGT Non_Targeting_Human 458 1|sg_Non_Targeting_Human_0025| Non_Targeting_Human GCTCTGCTGCGGAAGGATTC Non_Targeting_Human 459 1|sg_Non_Targeting_Human_0026| Non_Targeting_Human GCATGGAGGAGCGTCGCAGA Non_Targeting_Human 460 1|sg_Non_Targeting_Human_0027| Non_Targeting_Human GTAGCGCGCGTAGGAGTGGC Non_Targeting_Human 461 1|sg_Non_Targeting_Human_0028| Non_Targeting_Human GATCACCTGCATTCGTACAC Non_Targeting_Human 462 1|sg_Non_Targeting_Human_0029| Non_Targeting_Human GCACACCTAGATATCGAATG Non_Targeting_Human 463 1|sg_Non_Targeting_Human_0030| Non_Targeting_Human GTTGATCAACGCGCTTCGCG Non_Targeting_Human 464 1|sg_Non_Targeting_Human_0031| Non_Targeting_Human GCGTCTCACTCACTCCATCG Non_Targeting_Human 465 1|sg_Non_Targeting_Human_0032| Non_Targeting_Human GCCGACCAACGTCAGCGGTA Non_Targeting_Human 466 1|sg_Non_Targeting_Human_0033| Non_Targeting_Human GGATACGGTGCGTCAATCTA Non_Targeting_Human 467 1|sg_Non_Targeting_Human_0034| Non_Targeting_Human GAATCCAGTGGCGGCGACAA Non_Targeting_Human 468 1|sg_Non_Targeting_Human_0035| Non_Targeting_Human GCACTGTCAGTGCAACGATA Non_Targeting_Human 469 1|sg_Non_Targeting_Human_0036| Non_Targeting_Human GCGATCCTCAAGTATGCTCA Non_Targeting_Human 470 1|sg_Non_Targeting_Human_0037| Non_Targeting_Human GCTAATATCGACACGGCCGC Non_Targeting_Human 471 1|sg_Non_Targeting_Human_0038| Non_Targeting_Human GGAGATGCATCGAAGTCGAT Non_Targeting_Human 472 1|sg_Non_Targeting_Human_0039| Non_Targeting_Human GGATGCACTCCATCTCGTCT Non_Targeting_Human 473 1|sg_Non_Targeting_Human_0040| Non_Targeting_Human GTGCCGAGTAATAACGCGAG Non_Targeting_Human 474 1|sg_Non_Targeting_Human_0041| Non_Targeting_Human GAGATTCCGATGTAACGTAC Non_Targeting_Human 475 1|sg_Non_Targeting_Human_0042| Non_Targeting_Human GTCGTCACGAGCAGGATTGC Non_Targeting_Human 476 1|sg_Non_Targeting_Human_0043| Non_Targeting_Human GCGTTAGTCACTTAGCTCGA Non_Targeting_Human 477 1|sg_Non_Targeting_Human_0044| Non_Targeting_Human GTTCACACGGTGTCGGATAG Non_Targeting_Human 478 1|sg_Non_Targeting_Human_0045| Non_Targeting_Human GGATAGGTGACCTTAGTACG Non_Targeting_Human 479 1|sg_Non_Targeting_Human_0046| Non_Targeting_Human GTATGAGTCAAGCTAATGCG Non_Targeting_Human 480 1|sg_Non_Targeting_Human_0047| Non_Targeting_Human GCAACTATTGGAATACGTGA Non_Targeting_Human 481 1|sg_Non_Targeting_Human_0048| Non_Targeting_Human GTTACCTTCGCTCGTCTATA Non_Targeting_Human 482 1|sg_Non_Targeting_Human_0049| Non_Targeting_Human GTACCGAGCACCACAGGCCG Non_Targeting_Human 483 1|sg_Non_Targeting_Human_0050| Non_Targeting_Human GTCAGCCATCGGATAGAGAT Non_Targeting_Human 484 1|sg_Non_Targeting_Human_0051| Non_Targeting_Human GTACGGCACTCCTAGCCGCT Non_Targeting_Human 485 1|sg_Non_Targeting_Human_0052| Non_Targeting_Human GGTCCTGTCGTATGCTTGCA Non_Targeting_Human 486 1|sg_Non_Targeting_Human_0053| Non_Targeting_Human GCCGCAATATATGCGGTAAG Non_Targeting_Human 487 1|sg_Non_Targeting_Human_0054| Non_Targeting_Human GCGCACGTATAATCCTGCGT Non_Targeting_Human 488 1|sg_Non_Targeting_Human_0055| Non_Targeting_Human GTGCACAACACGATCCACGA Non_Targeting_Human 489 1|sg_Non_Targeting_Human_0056| Non_Targeting_Human GCACAATGTTGACGTAAGTG Non_Targeting_Human 490 1|sg_Non_Targeting_Human_0057| Non_Targeting_Human GTAAGATGCTGCTCACCGTG Non_Targeting_Human 491 1|sg_Non_Targeting_Human_0058| Non_Targeting_Human GTCGGTGATCCAACGTATCG Non_Targeting_Human 492 1|sg_Non_Targeting_Human_0059| Non_Targeting_Human GAGCTAGTAGGACGCAAGAC Non_Targeting_Human 493 1|sg_Non_Targeting_Human_0060| Non_Targeting_Human GTACGTGGAAGCTTGTGGCC Non_Targeting_Human 494 1|sg_Non_Targeting_Human_0061| Non_Targeting_Human GAGAACTGCCAGTTCTCGAT Non_Targeting_Human 495 1|sg_Non_Targeting_Human_0062| Non_Targeting_Human GCCATTCGGCGCGGCACTTC Non_Targeting_Human 496 1|sg_Non_Targeting_Human_0063| Non_Targeting_Human GCACACGACCAATCCGCTTC Non_Targeting_Human 497 1|sg_Non_Targeting_Human_0064| Non_Targeting_Human GAGGTGATCGATTAAGTACA Non_Targeting_Human 498 1|sg_Non_Targeting_Human_0065| Non_Targeting_Human GTCACTCGCAGACGCCTAAC Non_Targeting_Human 499 1|sg_Non_Targeting_Human_0066| Non Targeting_Human GCGCTACGGAATCATACGTT Non_Targeting_Human 500 1|sg_Non_Targeting_Human_0067| Non_Targeting_Human GGTAGGACCTCACGGCGCGC Non_Targeting_Human 501 1|sg_Non_Targeting_Human_0068| Non_Targeting_Human GAACTGCATCTTGTTGTAGT Non_Targeting_Human 502 1|sg_Non_Targeting_Human_0069| Non_Targeting_Human GATCCTGATCCGGCGGCGCG Non_Targeting_Human 503 1|sg_Non_Targeting_Human_0070| Non_Targeting_Human GGTATGCGCGATCCTGAGTT Non_Targeting_Human 504 1|sg_Non_Targeting_Human_0071| Non_Targeting_Human GCGGAGCTAGAGAGCGGTCA Non_Targeting_Human 505 1|sg_Non_Targeting_Human_0072| Non_Targeting_Human GAATGGCAATTACGGCTGAT Non_Targeting_Human 506 1|sg_Non_Targeting_Human_0073| Non_Targeting_Human GTATGGTGAGTAGTCGCTTG Non_Targeting_Human 507 1|sg_Non_Targeting_Human_0074| Non_Targeting_Human GTGTAATTGCGTCTAGTCGG Non_Targeting_Human 508 1|sg_Non_Targeting_Human_0075| Non_Targeting_Human GGTCCTGGCGAGGAGCCTTG Non_Targeting_Human 509 1|sg_Non_Targeting_Human_0076| Non_Targeting_Human GAAGATAAGTCGCTGTCTCG Non_Targeting_Human 510 1|sg_Non_Targeting_Human_0077| Non_Targeting_Human GTCGGCGTTCTGTTGTGACT Non_Targeting_Human 511 1|sg_Non_Targeting_Human_0078| Non_Targeting_Human GAGGCAAGCCGTTAGGTGTA Non_Targeting_Human 512 1|sg_Non_Targeting_Human_0079| Non_Targeting_Human GCGGATCCAGATCTCATTCG Non_Targeting_Human 513 1|sg_Non_Targeting_Human_0080| Non_Targeting_Human GGAACATAGGAGCACGTAGT Non_Targeting_Human 514 1|sg_Non_Targeting_Human_0081| Non_Targeting_Human GTCATCATTATGGCGTAAGG Non_Targeting_Human 515 1|sg_Non_Targeting_Human_0082| Non_Targeting_Human GCGACTAGCGCCATGAGCGG Non_Targeting_Human 516 1|sg_Non_Targeting_Human_0083| Non_Targeting_Human GGCGAAGTTCGACATGACAC Non_Targeting_Human 517 1|sg_Non_Targeting_Human_0084| Non_Targeting_Human GCTGTCGTGTGGAGGCTATG Non_Targeting_Human 518 1|sg_Non_Targeting_Human_0085| Non_Targeting_Human GCGGAGAGCATTGACCTCAT Non_Targeting_Human 519 1|sg_Non_Targeting_Human_0086| Non_Targeting_Human GACTAATGGACCAAGTCAGT Non_Targeting_Human 520 1|sg_Non_Targeting_Human_0087| Non_Targeting_Human GCGGATTAGAGGTAATGCGG Non_Targeting_Human 521 1|sg_Non_Targeting_Human_0088| Non_Targeting_Human GCCGACGGCAATCAGTACGC Non_Targeting_Human 522 1|sg_Non_Targeting_Human_0089| Non_Targeting_Human GTAACCTCTCGAGCGATAGA Non_Targeting_Human 523 1|sg_Non_Targeting_Human_0090| Non_Targeting_Human GACTTGTATGTGGCTTACGG Non_Targeting_Human 524 1|sg_Non_Targeting_Human_0091| Non_Targeting_Human GTCACTGTGGTCGAACATGT Non_Targeting_Human 525 1|sg_Non_Targeting_Human_0092| Non_Targeting_Human GTACTCCAATCCGCGATGAC Non_Targeting_Human 526 1|sg_Non_Targeting_Human_0093| Non_Targeting_Human GCGTTGGCACGATGTTACGG Non_Targeting_Human 527 1|sg_Non_Targeting_Human_0094| Non_Targeting_Human GAACCAGCCGGCTAGTATGA Non_Targeting_Human 528 1|sg_Non_Targeting_Human_0095| Non_Targeting_Human GTATACTAGCTAACCACACG Non_Targeting_Human 529 1|sg_Non_Targeting_Human_0096| Non_Targeting_Human GAATCGGAATAGTTGATTCG Non_Targeting_Human 530 1|sg_Non_Targeting_Human_0097| Non_Targeting_Human GAGCACTTGCATGAGGCGGT Non_Targeting_Human 531 1|sg_Non_Targeting_Human_0098| Non Targeting_Human GAACGGCGATGAAGCCAGCC Non_Targeting_Human 532 1|sg_Non_Targeting_Human_0099| Non_Targeting_Human GCAACCGAGATGAGAGGTTC Non_Targeting_Human 533 1|sg_Non_Targeting_Human_0100| Non_Targeting_Human GCAAGATCAATATGCGTGAT Non_Targeting_Human 534 1|sg_Non_Targeting_Human_GA_0101| Non_Targeting_Human ACGGAGGCTAAGCGTCGCAA Non_Targeting_Human 535 1|sg_Non_Targeting_Human_GA_0102| Non_Targeting_Human CGCTTCCGCGGCCCGTTCAA Non_Targeting_Human 536 1|sg_Non_Targeting_Human_GA_0103| Non_Targeting_Human ATCGTTTCCGCTTAACGGCG Non_Targeting_Human 537 1|sg_Non_Targeting_Human_GA_0104| Non_Targeting_Human GTAGGCGCGCCGCTCTCTAC Non_Targeting_Human 538 1|sg_Non_Targeting_Human_GA_0105| Non_Targeting_Human CCATATCGGGGCGAGACATG Non_Targeting_Human 539 1|sg_Non_Targeting_Human_GA_0106| Non_Targeting_Human TACTAACGCCGCTCCTACAG Non_Targeting_Human 540 1|sg_Non_Targeting_Human_GA_0107| Non_Targeting Human TGAGGATCATGTCGAGCGCC Non_Targeting_Human 541 1|sg_Non_Targeting_Human_GA_0108| Non_Targeting Human GGGCCCGCATAGGATATCGC Non_Targeting_Human 542 1|sg_Non_Targeting_Human_GA_0109| Non_Targeting_Human TAGACAACCGCGGAGAATGC Non_Targeting_Human 543 1|sg_Non Targeting_Human_GA_0110| Non_Targeting_Human ACGGGCGGCTATCGCTGACT Non_Targeting_Human 544 1|sg_Non_Targeting_Human_GA_0111| Non_Targeting_Human CGCGGAAATTTTACCGACGA Non_Targeting_Human 545 1|sg_Non_Targeting_Human_GA_0112| Non_Targeting_Human CTTACAATCGTCGGTCCAAT Non_Targeting_Human 546 1|sg_Non_Targeting_Human_GA_0113| Non_Targeting_Human GCGTGCGTCCCGGGTTACCC Non_Targeting_Human 547 1|sg_Non_Targeting_Human_GA_0114| Non_Targeting_Human CGGAGTAACAAGCGGACGGA Non_Targeting_Human 548 1|sg_Non_Targeting_Human_GA_0115| Non_Targeting_Human CGAGTGTTATACGCACCGTT Non_Targeting_Human 549 1|sg_Non_Targeting_Human_GA_0116| Non_Targeting_Human CGACTAACCGGAAACTTTTT Non_Targeting_Human 550 1|sg_Non_Targeting_Human_GA_0117| Non_Targeting_Human CAACGGGTTCTCCCGGCTAC Non_Targeting_Human 551 1|sg_Non_Targeting_Human_GA_0118| Non_Targeting_Human CAGGAGTCGCCGATACGCGT Non_Targeting_Human 552 1|sg_Non_Targeting_Human_GA_0119| Non_Targeting_Human TTCACGTCGTCTCGCGACCA Non_Targeting_Human 553 1|sg_Non_Targeting_Human_GA_0120| Non_Targeting_Human GTGTCGGATTCCGCCGCTTA Non_Targeting_Human 554 1|sg_Non_Targeting_Human_GA_0121| Non_Targeting_Human CACGAACTCACACCGCGCGA Non_Targeting_Human 555 1|sg_Non_Targeting_Human_GA_0122| Non_Targeting_Human CGCTAGTACGCTCCTCTATA Non_Targeting_Human 556 1|sg_Non_Targeting_Human_GA_0123| Non_Targeting_Human TCGCGCTTGGGTTATACGCT Non_Targeting_Human 557 1|sg_Non_Targeting_Human_GA_0124| Non_Targeting_Human CTATCTCGAGTGGTAATGCG Non_Targeting_Human 558 1|sg_Non_Targeting_Human_GA_0125| Non_Targeting_Human AATCGACTCGAACTTCGTGT Non_Targeting_Human 559 1|sg_Non_Targeting_Human_GA_0126| Non Targeting_Human CCCGATGGACTATACCGAAC Non_Targeting_Human 560 1|sg_Non Targeting_Human_GA_0127| Non_Targeting_Human ACGTTCGAGTACGACCAGCT Non_Targeting_Human 561 1|sg_Non_Targeting_Human_GA_0128| Non_Targeting Human CGCGACGACTCAACCTAGTC Non_Targeting_Human 562 1|sg_Non_Targeting_Human GA_0129| Non_Targeting Human GGTCACCGATCGAGAGCTAG Non_Targeting_Human 563 1|sg_Non_Targeting_Human_GA_0130| Non_Targeting_Human CTCAACCGACCGTATGGTCA Non_Targeting_Human 564 1|sg_Non_Targeting_Human_GA_0131| Non_Targeting_Human CGTATTCGACTCTCAACGCG Non_Targeting_Human 565 1|sg_Non_Targeting_Human_GA_0132| Non_Targeting_Human CTAGCCGCCCAGATCGAGCC Non_Targeting_Human 566 1|sg_Non_Targeting_Human_GA_0133| Non_Targeting_Human GAATCGACCGACACTAATGT Non_Targeting_Human 567 1|sg_Non_Targeting_Human_GA_0134| Non Targeting_Human ACTTCAGTTCGGCGTAGTCA Non_Targeting_Human 568 1|sg_Non_Targeting_Human_GA_0135| Non_Targeting_Human GTGCGATGTCGCTTCAACGT Non_Targeting_Human 569 1|sg_Non_Targeting_Human_GA_0136| Non_Targeting_Human CGCCTAATTTCCGGATCAAT Non_Targeting Human 570 1|sg_Non_Targeting_Human_GA_0137| Non_Targeting_Human CGTGGCCGGAACCGTCATAG Non_Targeting_Human 571 1|sg_Non_Targeting_Human_GA_0138| Non_Targeting_Human ACCCTCCGAATCGTAACGGA Non_Targeting_Human 572 1|sg_Non_Targeting_Human_GA_0139| Non_Targeting_Human AAACGGTACGACAGCGTGTG Non_Targeting_Human 573 1|sg_Non_Targeting_Human_GA_0140| Non_Targeting_Human ACATAGTCGACGGCTCGATT Non_Targeting_Human 574 1|sg_Non_Targeting_Human_GA_0141| Non_Targeting_Human GATGGCGCTTCAGTCGTCGG Non_Targeting_Human 575 1|sg_Non_Targeting_Human_GA_0142| Non_Targeting_Human ATAATCCGGAAACGCTCGAC Non_Targeting_Human 576 1|sg_Non_Targeting_Human_GA_0143| Non Targeting_Human CGCCGGGCTGACAATTAACG Non_Targeting_Human 577 1|sg_Non_Targeting_Human_GA_0144| Non_Targeting_Human CGTCGCCATATGCCGGTGGC Non_Targeting_Human 578 1|sg_Non_Targeting_Human_GA_0145| Non_Targeting_Human CGGGCCTATAACACCATCGA Non_Targeting_Human 579 1|sg_Non_Targeting_Human_GA_0146| Non_Targeting_Human CGCCGTTCCGAGATACTTGA Non_Targeting_Human 580 1|sg_Non_Targeting_Human_GA_0147| Non_Targeting_Human CGGGACGTCGCGAAAATGTA Non_Targeting_Human 581 1|sg_Non_Targeting_Human_GA_0148| Non_Targeting_Human TCGGCATACGGGACACACGC Non_Targeting_Human 582 1|sg Non_Targeting_Human_GA_0149| Non_Targeting_Human AGCTCCATCGCCGCGATAAT Non_Targeting_Human 583 1|sg_Non_Targeting_Human_GA_0150| Non_Targeting_Human ATCGTATCATCAGCTAGCGC Non_Targeting_Human 584 1|sg_Non_Targeting_Human_GA_0151| Non_Targeting_Human TCGATCGAGGTTGCATTCGG Non_Targeting_Human 585 1|sg_Non_Targeting_Human_GA_0152| Non_Targeting Human CTCGACAGTTCGTCCCGAGC Non_Targeting_Human 586 1|sg_Non_Targeting_Human_GA_0153| Non_Targeting_Human CGGTAGTATTAATCGCTGAC Non_Targeting_Human 587 1|sg_Non_Targeting_Human_GA_0154| Non_Targeting_Human TGAACGCGTGTTTCCTTGCA Non_Targeting_Human 588 1|sg_Non_Targeting_Human_GA_0155| Non_Targeting_Human CGACGCTAGGTAACGTAGAG Non_Targeting_Human 589 1|sg_Non_Targeting_Human_GA_0156| Non_Targeting_Human CATTGTTGAGCGGGCGCGCT Non_Targeting_Human 590 1|sg_Non_Targeting_Human_GA_0157| Non_Targeting_Human CCGCTATTGAAACCGCCCAC Non_Targeting_Human 591 1|sg_Non_Targeting_Human_GA_0158| Non_Targeting_Human AGACACGTCACCGGTCAAAA Non_Targeting_Human 592 1|sg_Non_Targeting_Human_GA_0159| Non Targeting Human TTTACGATCTAGCGGCGTAG Non_Targeting_Human 593 1|sg_Non_Targeting_Human_GA_0160| Non_Targeting_Human TTCGCACGATTGCACCTTGG Non_Targeting_Human 594 1|sg_Non_Targeting_Human_GA_0161| Non_Targeting_Human GGTTAGAGACTAGGCGCGCG Non_Targeting_Human 595 1|sg_Non_Targeting_Human_GA_0162| Non_Targeting_Human CCTCCGTGCTAACGCGGACG Non_Targeting_Human 596 1|sg_Non_Targeting_Human_GA_0163| Non_Targeting_Human TTATCGCGTAGTGCTGACGT Non_Targeting_Human 597 1|sg_Non_Targeting_Human_GA_0164| Non_Targeting_Human TACGCTTGCGTTTAGCGTCC Non_Targeting_Human 598 1|sg_Non_Targeting_Human_GA_0165| Non_Targeting_Human CGCGGCCCACGCGTCATCGC Non_Targeting_Human 599 1|sg_Non_Targeting_Human_GA_0166| Non_Targeting_Human AGCTCGCCATGTCGGTTCTC Non_Targeting_Human 600 1|sg_Non_Targeting_Human_GA_0167| Non_Targeting_Human AACTAGCCCGAGCAGCTTCG Non_Targeting_Human 601 1|sg_Non_Targeting_Human_GA_0168| Non_Targeting_Human CGCAAGGTGTCGGTAACCCT Non_Targeting_Human 602 1|sg_Non_Targeting_Human_GA_0169| Non_Targeting_Human CTTCGACGCCATCGTGCTCA Non_Targeting_Human 603 1|sg_Non_Targeting_Human_GA_0170| Non_Targeting_Human TCCTGGATACCGCGTGGTTA Non_Targeting_Human 604 1|sg_Non_Targeting_Human_GA_0171| Non_Targeting_Human ATAGCCGCCGCTCATTACTT Non_Targeting_Human 605 1|sg_Non_Targeting_Human_GA_0172| Non_Targeting_Human GTCGTCCGGGATTACAAAAT Non_Targeting_Human 606 1|sg Non_Targeting_Human_GA_0173| Non_Targeting_Human TAATGCTGCACACGCCGAAT Non_Targeting_Human 607 1|sg_Non_Targeting_Human_GA_0174| Non_Targeting_Human TATCGCTTCCGATTAGTCCG Non_Targeting_Human 608 1|sg_Non_Targeting_Human_GA_0175| Non_Targeting_Human GTACCATACCGCGTACCCTT Non_Targeting_Human 609 1|sg_Non_Targeting_Human_GA_0176| Non_Targeting_Human TAAGATCCGCGGGTGGCAAC Non_Targeting_Human 610 1|sg_Non_Targeting_Human_GA_0177| Non_Targeting_Human GTAGACGTCGTGAGCTTCAC Non_Targeting_Human 611 1|sg_Non_Targeting_Human_GA_0178| Non_Targeting_Human TCGCGGACATAGGGCTCTAA Non_Targeting_Human 612 1|sg_Non_Targeting_Human_GA_0179| Non_Targeting_Human AGCGCAGATAGCGCGTATCA Non_Targeting_Human 613 1|sg_Non_Targeting_Human_GA_0180| Non_Targeting_Human GTTCGCTTCGTAACGAGGAA Non_Targeting_Human 614 1|sg_Non_Targeting_Human_GA_0181| Non_Targeting_Human GACCCCCGATAACTTTTGAC Non_Targeting_Human 615 1|sg_Non_Targeting_Human_GA_0182| Non_Targeting_Human ACGTCCATACTGTCGGCTAC Non_Targeting_Human 616 1|sg_Non_Targeting_Human_GA_0183| Non_Targeting_Human GTACCATTGCCGGCTCCCTA Non_Targeting_Human 617 1|sg_Non_Targeting_Human_GA_0184| Non_Targeting_Human TGGTTCCGTAGGTCGGTATA Non_Targeting_Human 618 1|sg_Non_Targeting_Human_GA_0185| Non_Targeting_Human TCTGGCTTGACACGACCGTT Non_Targeting_Human 619 1|sg_Non_Targeting_Human_GA_0186| Non_Targeting_Human CGCTAGGTCCGGTAAGTGCG Non_Targeting_Human 620 1|sg_Non_Targeting_Human_GA_0187| Non_Targeting_Human AGCACGTAATGTCCGTGGAT Non_Targeting_Human 621 1|sg_Non_Targeting_Human_GA_0188| Non_Targeting_Human AAGGCGCGCGAATGTGGCAG Non_Targeting_Human 622 1|sg_Non_Targeting_Human_GA_0189| Non_Targeting_Human ACTGCGGAGCGCCCAATATC Non_Targeting_Human 623 1|sg_Non_Targeting_Human_GA_0190| Non_Targeting_Human CGTCGAGTGCTCGAACTCCA Non_Targeting_Human 624 1|sg_Non_Targeting_Human_GA_0191| Non_Targeting_Human TCGCAGCGGCGTGGGATCGG Non_Targeting_Human 625 1|sg_Non_Targeting_Human_GA_0192| Non_Targeting_Human ATCTGTCCTAATTCGGATCG Non_Targeting_Human 626 1|sg_Non_Targeting_Human_GA_0193| Non_Targeting_Human TGCGGCGTAATGCTTGAAAG Non_Targeting_Human 627 1|sg_Non_Targeting_Human_GA_0194| Non_Targeting_Human CGAACTTAATCCCGTGGCAA Non_Targeting_Human 628 1|sg_Non_Targeting_Human_GA_0195| Non_Targeting Human GCCGTGTTGCTGGATACGCC Non_Targeting_Human 629 1|sg_Non_Targeting_Human_GA_0196| Non_Targeting_Human TACCCTCCGGATACGGACTG Non_Targeting_Human 630 1|sg_Non_Targeting_Human_GA_0197| Non_Targeting_Human CCGTTGGACTATGGCGGGTC Non_Targeting_Human 631 1|sg_Non_Targeting_Human_GA_0198| Non_Targeting_Human GTACGGGGCGATCATCCACA Non_Targeting_Human 632 1|sg_Non_Targeting_Human_GA_0199| Non_Targeting_Human AAGAGTAGTAGACGCCCGGG Non_Targeting_Human 633 1|sg_Non_Targeting_Human_GA_0200| Non_Targeting_Human AAGAGCGAATCGATTTCGTG Non_Targeting_Human 634 3|sg_hCDC16_CC_1|CDC16 CDC16 TCAACACCAGTGCCTGACGG 635 3|sg_hCDC16_CC_2|CDC16 CDC16 AAAGTAGCTTCACTCTCTCG 636 3|sg_hCDC16_CC_3|CDC16 CDC16 GAGCCAACCAATAGATGTCC 637 3|sg_hCDC16_CC_4|CDC16 CDC16 GCGCCGCCATGAACCTAGAG 638 3|sg_hGTF2B_CC_1|GTF2B GTF2B ACAAAGGTTGGAACAGAACC 639 3|sg_hGTF2B_CC 2|GTF2B GTF2B GGTGACCGGGTTATTGATGT 640 3|sg_hGTF2B_CC_3|GTF2B GTF2B TTAGTGGAGGACTACAGAGC 641 3|sg_hGTF2B_CC_4|GTF2B GTF2B ACATATAGCCCGTAAAGCTG 642 3|sg_hHSPA5_CC_1|HSPA5 HSPA5 CGTTGGCGATGATCTCCACG 643 3|sg_hHSPA5_CC_2|HSPA5 HSPA5 TGGCCTTTTCTACCTCGCGC 644 3|sg_hHSPA5_CC_3|HSPA5 HSPA5 AATGGAGATACTCATCTGGG 645 3|sg_hHSPA5_CC_4|HSPA5 HSPA5 GAAGCCCGTCCAGAAAGTGT 646 3|sg_hHSPA9_CC_1|HSPA9 HSPA9 CAATCTGAGGAACTCCACGA 647 3|sg_hHSPA9_CC_2|HSPA9 HSPA9 AGGCTGCGGCGCCCACGAGA 648 3|sg_hHSPA9_CC_3|HSPA9 HSPA9 ACTTTGACCAGGCCTTGCTA 649 3|sg_hHSPA9_CC_4|HSPA9 HSPA9 ACCTTCCATAACTGCCACGC 650 3|sg_hPAFAH1B1_CC_1|PAFAH1B1 PAFAH1B1 CGAGGCGTACATACCCAAGG 651 3|sg hPAFAH1B1_CC_2|PAFAH1B1 PAFAH1B1 ATGGTACGGCCAAATCAAGA 652 3|sg hPAFAH1B1_CC_3|PAFAH1B1 PAFAH1B1 TCTTGTAATCCCATACGCGT 653 3|sg_hPAFAH1B1_CC_4|PAFAH1B1 PAFAH1B1 ATTCACAGGACACAGAGAAT 654 3|sg_hPCNA_CC_1|PCNA PCNA CCAGGGCTCCATCCTCAAGA 655 3|sg_hPCNA_CC_2|PCNA PCNA TGAGCTGCACCAAAGAGACG 656 3|sg_hPCNA_CC_3|PCNA PCNA ATGTCTGCAGATGTACCCCT 657 3|sg_hPCNA_CC_4|PCNA PCNA CGAAGATAACGCGGATACCT 658 3|sg_hPOLR2L_CC_1|POLR2L POLR2L GCTGCAGGCCGAGTACACCG 659 3|sg_hPOLR2L_CC_2|POLR2L POLR2L ACAAGTGGGAGGCTTACCTG 660 3|sg_hPOLR2L_CC_3|POLR2L POLR2L GCAGCGTACAGGGATGATCA 661 3|sg_hPOLR2L_CC_4|POLR2L POLR2L GCAGTAGCGCTTCAGGCCCA 662 3|sg_hRPL9_CC_1|RPL9 RPL9 CAAATGGTGGGGTAACAGAA 663 3|sg_hRPL9_CC_2|RPL9 RPL9 GAAAGGAACTGGCTACCGTT 664 3|sg_hRPL9_CC_3|RPL9 RPL9 AGGGCTTCCGTTACAAGATG 665 3|sg_hRPL9_CC_4|RPL9 RPL9 GAACAAGCAACACCTAAAAG 666 3|sg_hSF3A3_CC_1|SF3A3 SF3A3 TGAGGAGAAGGAACGGCTCA 667 3|sg_hSF3A3_CC_2|SF3A3 SF3A3 GGAAGAATGCAGAGTATAAG 668 3|sg_hSF3A3_CC_3|SF3A3 SF3A3 GGAATTTGAGGAACTCCTGA 669 3|sg_hSF3A3_CC_4|SF3A3 SF3A3 GCTCACCGGCCATCCAGGAA 670 3|sg_hSF3B3_CC_1|SF3B3 SF3B3 ACTGGCCAGGAACGATGCGA 671 3|sg_hSF3B3_CC_2|SF3B3 SF3B3 GCAGCTCCAAGATCTTCCCA 672 3|sg_hSF3B3_CC_3|SF3B3 SF3B3 GAATGAGTACACAGAACGGA 673 3|sg_hSF3B3_CC_4|SF3B3 SF3B3 GGAGCAGGACAAGGTCGGGG

Example 2—BRD9 Degrader Depletes BRD9 Protein

[0866] The following example demonstrates the depletion of the BRD9 protein in synovial sarcoma cells treated with a BRD9 degrader.

[0867] Procedure: Cells were treated with DMSO or the BRD9 degrader, Compound 1 (also known as dBRD9, see Remillard et al, Angew. Chem. Int. Ed. Engl. 56(21):5738-5743 (2017); see structure of compound 1 below), for indicated doses and timepoints.

##STR00736##

[0868] Whole cell extracts were fractionated by SDS-PAGE and transferred to a polyvinylidene difluoride membrane using a transfer apparatus according to the manufacturer's protocols (Bio-Rad). After incubation with 5% nonfat milk in TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween 20) for 60 min, the membrane was incubated with antibodies against BRD9 (1:1,000, Bethyl laboratory A303-781A), GAPDH (1:5,000, Cell Signaling Technology), and/or MBP (1:1,000, BioRad) overnight at 4° C. Membranes were washed three times for 10 minutes and incubated with anti-mouse or anti-rabbit antibodies conjugated with either horseradish peroxidase (HRP, FIGS. 2-3) or IRDye (FIG. 4, 1:20,000, LI-COR) for at least 1 h. Blots were washed with TBST three times and developed with either the ECL system according to the manufacturer's protocols (FIGS. 2-3) or scanned on an Odyssey CLx Imaging system (FIG. 4).

[0869] Results: Treatment of SYO1 synovial sarcoma cells with the BRD9 degrader Compound 1 results in dose dependent (FIG. 2) and time dependent (FIG. 3) depletion of BRD9 in the cells. Further, as shown in FIG. 4, the depletion of BRD9 by Compound 1 is replicated in a non-synovial sarcoma cell line (293T) and may be sustained for at least 5 days.

Example 3—Inhibition of Growth of Synovial Cell Lines by BRD9 Inhibitors and BRD9 Degraders

[0870] The following example demonstrates that BRD9 degraders and inhibitors selectively inhibit growth of synovial sarcoma cells.

[0871] Procedures:

[0872] Cells were treated with DMSO or the BRD9 degrader, Compound 1, at indicated concentrations, and proliferation was monitored from day 7 to day 14 by measuring confluency over time using an IncuCyte live cell analysis system (FIG. 5). Growth medium and compounds were refreshed every 3-4 days.

[0873] Cells were seeded into 12-well plates and treated with DMSO, 1 μM BRD9 inhibitor, Compound 2 (also known as BI-7273, see Martin et al, J Med Chem. 59(10):4462-4475 (2016); see structure of compound 2 below), or 1 μM BRD9 degrader, Compound 1.

##STR00737##

[0874] The number of cells was optimized for each cell line. Growth medium and compounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T and HS-SY-II cells were fixed and stained at day 11. ASKA cells were fixed and stained at day 23. Staining was done by incubation with crystal violet solution (0.5 g Crystal Violet, 27 ml 37% Formaldehyde, 100 mL 10×PBS, 10 mL Methanol, 863 dH2O to 1 L) for 30 minutes followed by 3× washes with water and drying the plates for at least 24h at room temperature. Subsequently plates were scanned on an Odyssey CLx Imaging system (FIG. 6).

[0875] Cells were seeded into 96-well ultra low cluster plate (Costar, #7007) in 200 μL complete media and treated at day 2 with DMSO, Staurosporin, or BRD9 degrader, Compound 1, at indicated doses (FIG. 7). Media and compounds were changed every 5 d and cell colonies were imaged at day 14.

[0876] Results: As shown in FIGS. 5, 6, and 7, treatment of synovial sarcoma cell lines (SYO1, Yamato, HS-SY-II, and ASKA) with a BRD9 inhibitor, Compound 2, or a BRD9 degrader, Compound 1, results in inhibition of the growth of the cells, but does not result in inhibition of the growth of non-synovial control cancer cell lines (293T, A549, G401).

Example 4—Selective Inhibition of Growth of Synovial Cell Lines by BRD9 Degraders and BRD9 Binders

[0877] The following example demonstrates that BRD9 degraders and binders selectively inhibit growth of synovial sarcoma cells.

[0878] Procedure: Cells were seeded into 6-well or 12-well plates and were treated daily with a BRD9 degrader (Compound 1), a bromo-domain BRD9 binder (Compound 2), E3 ligase binder (lenalidomide), DMSO, or staurosporin (positive control for cell killing), at indicated concentrations. The number of cells was optimized for each cell line. Growth media was refreshed every 5 days. By day 14, medium was removed, cells were washed with PBS, and stained using 500 μL of 0.005% (w/v) crystal violet solution in 25% (v/v) methanol for at least 1 hour at room temperature. Subsequently plates were scanned on an Odyssey CLx Imaging system.

[0879] Results: As shown in FIGS. 8 and 9, treatment of synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) with Compound 1 or Compound 2 resulted in inhibition of the growth of the cells, but did not result in inhibition of the growth of non-synovial control cancer cell lines (RD, HCT116, and Calu6). Overall, Compound 1 showed most significant growth inhibition in all synovial cell lines.

Example 5—Inhibition of Cell Growth in Synovial Sarcoma Cells

[0880] The following example shows that BRD9 degraders inhibit cell growth and induce apoptosis in synovial sarcoma cells.

[0881] Procedure: SYO1 cells were treated for 8 or 13 days with DMSO, a BRD9 degrader (Compound 1) at 200 nM or 1 μM, or an E3 ligase binder (lenalidomide) at 200 nM. Compounds were refreshed every 5 days. Cell cycle analysis was performed using the Click-iT™ Plus EdU Flow Cytometry Assay (Invitrogen). The apoptosis assay was performed using the Annexin V-FITC Apoptosis Detection Kit (Sigma A9210). Assays were performed according to the manufacturer's protocol.

[0882] Results: As shown in FIGS. 10-13, treatment with Compound 1 for 8 or 13 days resulted in reduced numbers of cells in the S-phase of the cell cycle as compared to DMSO and lenalidomide. Treatment with Compound 1 for 8 days also resulted in increased numbers of early- and late-apoptotic cells as compared to DMSO controls.

Example 6—Composition for SS18-SSX1-BAF

[0883] The following example shows the identification of BRD9 as a component of SS18-SSX containing BAF complexes.

[0884] Procedure: A stable 293T cell line expressing HA-SS18SSX1 was generated using lentiviral integration. SS18-SSX1 containing BAF complexes were subject to affinity purification and subsequent mass spectrometry analysis revealed SS18-SSX1 interacting proteins.

[0885] Results: As shown in FIG. 14, BAF complexes including the SS18-SSX fusion protein also included BRD9. More than 5 unique peptides were identified for ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69 peptides), SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides), SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22 peptides), DPF1 Isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B (6 peptides).

Example 7—Preparation of N-(1,1-dioxo-1λ6,2-thiazinan-4-yl)-5-methyl-4-oxo-7-[3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-carboximidamide (Compound B1)

[0886] ##STR00738##

Step 1: Preparation of 4-amino-1λ6,2-thiazinane-1,1-dione (i-1)

[0887] ##STR00739##

[0888] 4-(benzylamino)-1λ6,2-thiazinane-1,1-dione (200.00 mg, 0.832 mmol, 1.00 equiv) and Pd/C (199.27 mg, 1.873 mmol, 2.25 equiv) in MeOH (10.00 mL) were stirred under an atmosphere of hydrogen at balloon and room temperature for 3 hours. The solid was filtered out, and the filtrate was concentrated under reduced pressure to afford 4-amino-1λ6,2-thiazinane-1,1-dione (120 mg, 96%) as a brown solid. This material was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H]+=151.

Step 2: Preparation of 4-amino-1λ6,2-thiazinane-1,1-dione Hydrochloride (i-2)

[0889] ##STR00740##

[0890] 4-amino-1λ6,2-thiazinane-1,1-dione (110.00 mg, 0.732 mmol, 1.00 equiv) was added a solution of HCl in 1,4-dioxane (4 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford 4-amino-1λ6,2-thiazinane-1,1-dione hydrochloride (131 mg, 96%) as a brown solid. This material was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H]+=151.

Step 3: Preparation of N-(1,1-dioxo-1λ6,2-thiazinan-4-yl)-5-methyl-4-oxo-7-[3-(trifluoromethyl)phen yl]thieno[3,2-c]pyridine-2-carboximidamide (Compound B1)

[0891] ##STR00741##

[0892] To a solution of 5-methyl-4-oxo-7-[3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-carbonitrile (50.00 mg, 0.150 mmol, 1.00 equiv) in MeOH (1.00 mL) was added NaOMe (8.08 mg, 0.150 mmol, 1 equiv), and the resulting mixture was stirred at 75° C. for 3 hours. Then 4-amino-1λ6,2-thiazinane-1,1-dione hydrochloride (33.50 mg, 0.179 mmol, 1.2 equiv) was added to the reaction mixture. After stirring at 75° C. for 16 hours, the crude product was purified by flash C18-flash chromatography, elution gradient 0 to 50% MeCN in water (containing 0.1% NH.sub.4HCO.sub.3). Pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (conditions: XBridge Prep OBD 018 Column, 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 35 B to 50 B in 12 minutes; 254/220 nm; R.sub.T (retention time): 8.62 minutes). Fractions containing the desired compound were evaporated to dryness to afford N-(1,1-dioxo-1λ6,2-thiazinan-4-yl)-5-methyl-4-oxo-7-[3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-carboximidamide (5.8 mg, 7.9%) as a white solid. LCMS (ESI) m/z: [M+H]+=485.20.

Example 8—Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-[3H-imidazo[4,5-c]pyridin-2-yl]-5-methylthieno[3,2-c]pyridin-4-one (Compound B2)

[0893] ##STR00742##

Step 1: Preparation of 5-methyl-4-oxothieno[3,2-c]pyridine-2-carbaldehyde (i-6)

[0894] ##STR00743##

[0895] To a solution of 2-bromo-5-methylthieno[3,2-c]pyridin-4-one (2.00 g, 8.193 mmol, 1.00 equiv) in THF (20.00 mL) was added n-BuLi (1.05 g, 16.386 mmol, 2.00 equiv) in dropwise at −78° C. under nitrogen atmosphere, the resulting mixture was stirred at −78° C. for 30 minutes, then DMF (5.99 g, 81.930 mmol, 10.00 equiv) was added to the reaction mixture. The reaction was warmed to room temperature naturally. The reaction was quenched by the addition of sat. NH.sub.4Cl (aq.) (30 mL) at 0° C., and extracted with EtOAc (ethyl acetate) (50 mL×4). The organic layer was washed with water (50 mL) and brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in petroleum ether (PE). Pure fractions were evaporated to dryness to afford 5-methyl-4-oxothieno[3,2-c]pyridine-2-carbaldehyde (658 mg, 42%) as a brown solid. LCMS (ESI) m/z: [M+H].sup.+=194.

Step 2: Preparation of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carbaldehyde (i-7)

[0896] ##STR00744##

[0897] To a solution of 5-methyl-4-oxothieno[3,2-c]pyridine-2-carbaldehyde (600.00 mg, 3.105 mmol, 1.00 equiv) in THF (10.00 mL) was added NBS (663.23 mg, 3.726 mmol, 1.20 equiv), the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed with water (3×30 mL) and saturated brine (1×30 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carbaldehyde (510 mg, 60%) as a brown solid. LCMS (ESI) m/z: [M+H].sup.+=272.

Step 3: Preparation of 7-bromo-2-[3H-imidazo[4,5-c]pyridin-2-yl]-5-methylthieno[3,2-c]pyridin-4-one (i-9)

[0898] ##STR00745##

[0899] To a solution of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carbaldehyde (300.00 mg, 1.102 mmol, 1.00 equiv) and 3,4-diaminopyridine (120.31 mg, 1.102 mmol, 1 equiv) in DMF (5.00 mL) was added Na.sub.2S.sub.2O.sub.5 (628.75 mg, 3.307 mmol, 3 equiv), the resulting mixture was stirred at 120° C. for 16 hours. The solvent was removed under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-bromo-2-[3H-imidazo[4,5-c]pyridin-2-yl]-5-methylthieno[3,2-c]pyridin-4-one (165 mg, 41%) as a brown solid. LCMS (ESI) m/z: [M+H].sup.+=361.

Step 4: Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-[3H-imidazo[4,5-c]pyridin-2-yl]-5-methylthieno[3,2-c]pyridin-4-one (Compound 82)

[0900] ##STR00746##

[0901] To a solution of 7-bromo-2-[3H-imidazo[4,5-c]pyridin-2-yl]-5-methylthieno[3,2-c]pyridin-4-one (60.00 mg, 0.166 mmol, 1.00 equiv), 4-[(dimethylamino)methyl]-3,5-dimethoxyphenylboronic acid (47.65 mg, 0.199 mmol, 1.20 equiv) and 052003 (108.24 mg, 0.332 mmol, 2.00 equiv) in DMF (1.00 mL) and H.sub.2O (0.25 mL) was added Pd(dppf)Cl.sub.2 (12.15 mg, 0.017 mmol, 0.10 equiv), the resulting mixture was stirred at 100° C. for 1 hour under a nitrogen atmosphere. The mixture was concentrated, the crude product was purified by reverse phase flash with the following conditions to afford crude product: column, 018 silica gel; mobile phase, MeCN in water, 5% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.05% TFA, trifluoroacetic acid); Mobile Phase B: ACN (acetonitrile); Flow rate: 25 mL/minute; Gradient: 8% B to 8% B in 2 minutes; 254/220 nm; R.sub.T (retention time): 13.87 minutes) to afford 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-[3H-imidazo[4,5-c]pyridin-2-yl]-5-methylthieno[3,2-c]pyridin-4-one (3 mg, 3.8%) as a yellow solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 9.19 (s, 1H), 8.55 (d, J=6.5 Hz, 1H), 8.46 (s, 1H), 8.10 (d, J=6.5 Hz, 1H), 7.93 (s, 1H), 7.11 (s, 2H), 4.44 (s, 2H), 4.05 (s, 6H), 3.75 (s, 3H), 2.94 (s, 6H). LCMS (ESI) m/z: [M+H].sup.+=476.30.

Example 9—Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl)-1-methylpiperidine-4-carboxamide (Compound B3)

[0902] ##STR00747##

Step 1: Preparation of 2-bromo-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (i-11)

[0903] ##STR00748##

[0904] To a solution of 2-bromo-5-methylthieno[3,2-c]pyridin-4-one (1.50 g, 6.145 mmol, 1.00 equiv) in DMF (5.00 mL) was added NCS (0.90 mg, 0.007 mmol, 1.1 equiv) at 25° C. The resulting solution was stirred at 70° C. for 3 hours. The resulting mixture was concentrated. The residue was purified by chromatography on silica gel eluted with petroleum ether/EtOAc (2/1) to afford 2-bromo-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (1.6 g, 94%) as a brown solid. LCMS (ESI) m/z: [M+H]+=278

Step 2: Preparation of 7-chloro-2-[(diphenylmethylidene)amino]-5-methylthieno[3,2-c]pyridin-4-one (i-12)

[0905] ##STR00749##

[0906] To a solution of 2-bromo-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (1.6 g, 5.744 mmol, 1.00 equiv) and benzophenone imine (1093.09 mg, 6.032 mmol, 1.05 equiv) in dioxane (15 mL) was added Xantphos (332.37 mg, 0.574 mmol, 0.1 equiv), sodium tert-butoxide (1656.09 mg, 17.232 mmol, 3 equiv), and Pd.sub.2(dba).sub.3 (262.99 mg, 0.288 mmol, 0.05 equiv) at 25° C. The resulting solution was stirred for 2 hours at 80° C. The resulting mixture was concentrated. The residue was purified by chromatography on silica gel eluted with petroleum ether/EtOAc (5:1) to afford 7-chloro-2-[(diphenylmethylidene)amino]-5-methylthieno[3,2-c]pyridin-4-one (1.6 g, 74%) as a dark yellow solid. LCMS (ESI) m/z: [M+H]+=379.

Step 3: Preparation of 2-amino-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (i-13)

[0907] ##STR00750##

[0908] To a solution of 7-chloro-2-[(diphenylmethylidene)amino]-5-methylthieno[3,2-c]pyridin-4-one (1.60 g, 4.223 mmol, 1.00 equiv) in THF (10.00 mL) was added HCl (5.00 mL) at 25° C. The resulting solution was stirred at 25° C. for 2 hours. The solvent was removed under reduced pressure. This resulted in 1.5 g (crude) of 2-amino-7-chloro-5-methylthieno [3,2-c]pyridin-4-one as a dark brown solid. The product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=215.

Step 4: Preparation of N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-1-methylpiperidine-4-carboxamide (i-14)

[0909] ##STR00751##

[0910] To a solution of 1-methylpiperidine-4-carboxylic acid (80.04 mg, 0.559 mmol, 1.20 equiv) and HATU (354.25 mg, 0.932 mmol, 2.00 equiv) in DMF (1.00 mL) was added 2-amino-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (100.00 mg, 0.466 mmol, 1.00 equiv) and DIEA (180.62 mg, 1.397 mmol, 3.00 equiv), the resulting solution was stirred at 25 degree for 2 hours. The resulting mixture was concentrated. The residue was applied onto a silica gel column with CH.sub.2Cl.sub.2/MeOH (20:1). This resulted in (80 mg, 51%) of N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-1-methylpiperidine-4-carboxamide as a yellow solid. LCMS (ESI) m/z: [M+H]+=340.10

Step 5: Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl)-1-methylpiperidine-4-carboxamide (Compound 83

[0911] ##STR00752##

[0912] To a solution of N-[7-chloro-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl]-1-methylpiperidine-4-carboxamide (60.00 mg, 0.177 mmol, 1.00 equiv) and [4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (50.65 mg, 0.212 mmol, 1.20 equiv) in H.sub.2O (1.00 mL) and dioxane (3.00 mL) was added 052003 (172.57 mg, 0.530 mmol, 3.00 equiv) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (12.92 mg, 0.018 mmol, 0.10 equiv). The resulting solution was stirred at 80° C. for 2 hours (under N.sub.2 atmosphere). The crude product was purified by preparative HPLC (conditions: XSelect CSH Prep C18 OBD Column, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R.sub.T: 7.12 minutes). Fractions containing the desired compound were evaporated to dryness to afford N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl)-1-methylpiperidine-4-carboxamide (32 mg, 36%) as a white solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 1H), 7.23 (s, 1H), 7.06 (s, 2H), 4.42 (s, 2H), 4.02 (s, 6H), 3.75 (s, 3H), 3.64 (d, J=12.6 Hz, 2H), 3.16-3.06 (m, 2H), 2.92 (d, J=1.0 Hz, 9H), 2.82-2.71 (m, 1H), 2.21 (d, J=14.5 Hz, 2H), 2.10-1.94 (m, 2H). LCMS (ESI) m/z: [M+H]+=499.30.

Example 10—Preparation of N-(7-[4-[(Dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl)-4-methylmorpholine-2-carboxamide Formic Acid (Compound B4 Formic Acid)

[0913] ##STR00753##

Step 1: Preparation of tert-butyl 2-([7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]carbamoyl l)morpholine-4-carboxylate (i-15)

[0914] ##STR00754##

[0915] To a solution of 2-amino-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (507.00 mg, 2.362 mmol, 1.00 equiv) and 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (710.00 mg, 3.070 mmol, 1.3 equiv)) in DMF (6 mL) was added HATU (1796.03 mg, 4.724 mmol, 2 equiv) and DIEA (1220.97 mg, 9.447 mmol, 4 equiv) at 25° C. The resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated. The residue was purified by chromatography on silica gel eluted with petroleum ether/EtOAc (2:1) to afford tert-butyl2-([7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]carbamoyl)morpholine-4-carboxylate (820 mg, 81%) as a brown solid. LCMS (ESI) m/z: [M+H]+=428.

Step 2: Preparation of N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]morpholine-2-carboxamide (i-16)

[0916] ##STR00755##

[0917] To a solution of tert-butyl 2-([7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]carbamoyl)morpholine-4-carboxylate (800.00 mg, 1.870 mmol, 1.00 equiv) in DCM (6.00 mL) was added TFA (2.00 mL) at 25° C. The resulting solution was stirred at 25° C. for 2 hours. The solvent was removed under reduced pressure. This resulted in 1 g (crude) of N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]morpholine-2-carboxamide as a dark brown solid. The product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=328.

Step 3: Preparation of N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-4-methylmorpholine-2-carboxamide (i-17)

[0918] ##STR00756##

[0919] To a solution of N-[7-chloro-5-methyl-4-oxothie[3,2-c]pyridin-2-yl]morpholine-2-carboxamide (1.00 g, 3.051 mmol, 1.00 equiv) in HCHO (4.00 mL) and MeOH (10.00 mL) was added NaBH.sub.3CN (0.38 g, 0.006 mmol, 2 equiv) and CH.sub.3COOH (0.50 mL, 8.726 mmol, 2.86 equiv) at 25° C. The resulting solution was stirred at 25° C. for 4 hours. The resulting mixture was concentrated. The residue was purified by chromatography on silica gel eluted with petroleum ether/EtOAc (1:1) to afford N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-4-methylmorpholine-2-carboxamide (284 mg, 27%) as a brown solid. LCMS (ESI) m/z: [M+H]+=342.

Step 4: Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl)-4-methylmorpholine-2-carboxamide Formic Acid (Compound 84 Formic Acid)

[0920] ##STR00757##

[0921] To a solution of N-[7-chloro-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl]-4-methylmorpholine-2-carboxamide (100 mg, 0.293 mmol, 1.00 equiv) and [4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (104.92 mg, 0.439 mmol, 1.5 equiv) in H.sub.2O (1 mL) and dioxane (4 mL) was added 052003 (190.64 mg, 0.585 mmol, 2 equiv) and XPhos palladium(II) biphenyl-2-amine chloride (23.02 mg, 0.029 mmol, 0.10 equiv) at 25° C. The resulting solution was stirred at 90° C. for 12 hours. The crude product was purified by Prep-HPLC (conditions: Sun Fire Prep 018 OBD Column 19×150 mm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 3% B to 3% B in 2 minutes; 254/220 nm; R.sub.T: 7.5 minutes) to afford N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-2-yl)-4-methylmorpholine-2-carboxamide; formic acid (31.7 mg, 20%) as a light brown solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 7.67 (s, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.06 (d, J=1.1 Hz, 2H), 4.41 (s, 2H), 4.27 (dd, J=10.3, 2.8 Hz, 1H), 4.14-4.01 (m, 1H), 4.02 (s, 6H), 3.79 (td, J=11.4, 2.5 Hz, 1H), 3.74 (s, 3H), 3.12 (d, J=11.7 Hz, 1H), 2.91 (s, 6H), 2.77 (d, J=11.9 Hz, 1H), 2.38 (s, 3H), 2.28 (t, J=11.6 Hz, 1H), 2.17 (t, J=10.9 Hz, 1H). LCMS (ESI) m/z: [M+H]+=501.35.

Example 11—Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-N-(6-oxopiperidin-3-yl)-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (Compound B5)

[0922] ##STR00758##

Step 1: Preparation of Methyl 5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (i-18)

[0923] ##STR00759##

[0924] To a mixture of 2-bromo-5-methylthieno[3,2-c]pyridin-4-one (2.44 g, 9.996 mmol, 1.00 equiv) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.82 g, 1.00 mmol, 0.100 equiv) in MeOH (20.00 mL) was added TEA (2.78 mL, 27.460 mmol, 2.00 equiv). The resulting mixture was stirred at 100° C. for 16 hours under CO atmosphere (50 atm). Then the mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in petroleum ether to give methyl 5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (1.81 g, 81%) as a yellow solid. LCMS (ESI) m/z: [M+H].sup.+=224.

Step 2: Preparation of Methyl 7-bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (i-19)

[0925] ##STR00760##

[0926] To a stirred mixture of methyl 5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylate (1.80 g, 8.063 mmol, 1.00 equiv) in) DMF (30 mL) was added NBS (1.58 g, 8.869 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The mixture was then diluted with water (100 mL) and extracted with EtOAc (300 mL×3). The organic layers were combined and dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to give methyl 7-bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (2.43 g, crude) as a yellow solid. This material was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H].sup.+=302.

Step 3: Preparation of 7-bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylic Acid (i-20)

[0927] ##STR00761##

[0928] Into a sealed tube was added methyl 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylate (2.43 g, 8.05 mmol, 1.00 equiv) and concentrated hydrochloric acid (40 mL). The mixture was stirred for 4 hours at 90° C. The resulting mixture was concentrated to give 7-bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylic acid (2.20 g, 95%) as a brown solid. This material was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H].sup.+=288.

Step 4: Preparation of 7-bromo-5-methyl-4-oxo-N-(6-oxopiperidin-3-yl)thieno[3,2-c]pyridine-2-carboxamide (i-21)

[0929] ##STR00762##

[0930] To a solution of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylic acid (50.00 mg, 0.174 mmol, 1.00 equiv) and HATU (131.97 mg, 0.347 mmol, 2.00 equiv) in DMF (1.00 mL) was added 5-aminopiperidin-2-one (21.79 mg, 0.191 mmol, 1.10 equiv) and DIEA (67.29 mg, 0.521 mmol, 3.00 equiv). The resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated. The residue was applied onto a silica gel column with CH.sub.2Cl.sub.2/MeOH (20:1) to afford 7-bromo-5-methyl-4-oxo-N-(6-oxopiperidin-3-yl)thieno[3,2-c]pyridine-2-carboxamide (42 mg, 63%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=386.01.

Step 5: Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-N-(6-oxopiperidin-3-yl)-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (Compound 85)

[0931] ##STR00763##

[0932] To a solution of 7-bromo-5-methyl-4-oxo-N-(6-oxopiperidin-3-yl)-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (30.00 mg, 0.078 mmol, 1.00 equiv) and [4-[(dimethylamino)methyl]-3,5-dimethoxy phenyl]boronic acid (22.40 mg, 0.094 mmol, 1.20 equiv) in H.sub.2O (1.00 mL) and dioxane (3.00 mL) was added Cs.sub.2CO.sub.3 (76.31 mg, 0.234 mmol, 3.00 equiv) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6.38 mg, 0.008 mmol, 0.10 equiv). The resulting solution was stirred at 80° C. for 2 hours (under N.sub.2 atmosphere). The crude product was purified by preparative HPLC (conditions: XSelect CSH Prep 018 OBD Column, 5 μm, 19150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R.sub.T: 7.12 minutes). Fractions containing the desired compound were evaporated to dryness to afford 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-N-(6-oxopiperidin-3-yl)-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (28 mg, 72%) as a white solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H, FA), 8.28 (s, 1H), 7.86 (s, 1H), 7.06 (s, 2H), 4.37 (s, 2H), 4.37-4.30 (m, 1H), 4.02 (s, 6H), 3.75 (s, 3H), 3.58 (dd, J=12.0, 4.9 Hz, 1H), 3.30-3.26 (m, 1H), 2.88 (s, 6H), 2.55-2.47 (m, 2H), 2.19-2.01 (m, 2H). LCMS (ESI) m/z: [M+H]+=499.35.

Example 12—Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (Compound B6)

[0933] ##STR00764##

Step 1: Preparation of 7-bromo-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide (i-22)

[0934] ##STR00765##

[0935] To a solution of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylic acid (50.00 mg, 0.174 mmol, 1.00 equiv) and HATU (131.97 mg, 0.347 mmol, 2.00 equiv) in DMF (1.00 mL) was added 1-methylpiperidin-4-amine (21.80 mg, 0.191 mmol, 1.10 equiv) and DIEA (67.29 mg, 0.521 mmol, 3.00 equiv). The resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated. The residue was applied onto a silica gel column with CH.sub.2Cl.sub.2/MeOH (20:1). This resulted in (45 mg, 68%) of 7-bromo-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide as a yellow solid. LCMS (ESI) m/z: [M+H]+=384.01.

Step 2: Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (Compound 86)

[0936] ##STR00766##

[0937] To a solution of 7-bromo-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (30.00 mg, 0.078 mmol, 1.00 equiv) and [4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (22.40 mg, 0.094 mmol, 1.20 equiv) in H.sub.2O (1.00 mL) and dioxane (3.00 mL) was added Cs.sub.2CO.sub.3 (76.31 mg, 0.234 mmol, 3.00 equiv) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6.38 mg, 0.008 mmol, 0.10 equiv). The resulting solution was stirred at 80° C. for 2 hours (under N2 atmosphere). The crude product was purified by preparative HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R.sub.T: 7.12 minutes). Fractions containing the desired compound were evaporated to dryness to afford 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboxamide (21 mg, 54%) as a white solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H, FA), 8.26 (s, 1H), 7.86 (s, 1H), 7.07 (s, 2H), 4.40 (s, 2H), 4.02 (s, 7H), 3.75 (s, 3H), 3.27 (d, J=11.2 Hz, 2H), 2.90 (s, 6H), 2.79-2.67 (m, 2H), 2.62 (s, 3H), 2.12 (d, J=13.4 Hz, 2H), 1.94-1.79 (m, 2H). LCMS (ESI) m/z: [M+H]+=499.25.

Example 13—Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-2-(4-methylpiperazine-1-carbonyl)-4H,5H-thieno[3,2-c]pyridin-4-one (Compound B7)

[0938] ##STR00767##

Step 1: Preparation of 7-bromo-5-methyl-2-(4-methylpiperazine-1-carbonyl)thieno[3,2-c]pyridin-4-one (i-23)

[0939] ##STR00768##

[0940] To a solution of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylic acid (150.00 mg, 0.521 mmol, 1.00 equiv), HATU (296.93 mg, 0.781 mmol, 1.50 equiv) and DIEA (134.57 mg, 1.041 mmol, 2.00 equiv) in DMF (10.00 mL). The resulting mixture was stirred for 10 minutes at 25° C. Then 1-methylpiperazine (62.58 mg, 0.625 mmol, 1.20 equiv) was added to the reaction mixture. The resulting solution was stirred for 2 hours at 25° C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 80 mg (42%) of 7-bromo-5-methyl-2-(4-methylpiperazine-1-carbonyl)thieno[3,2-c]pyridin-4-one as a yellow solid.

Step 2: Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-2-(4-methylpiperazine-1-carbonyl)-4H,5H-thieno[3,2-c]pyridin-4-one (Compound 87)

[0941] ##STR00769##

[0942] To a solution of 7-bromo-5-methyl-2-(4-methylpiperazine-1-carbonyl)-4H,5H-thieno[3,2-c]pyridin-4-one (100.00 mg, 0.270 mmol, 1.00 equiv) and 052003 (263.99 mg, 0.810 mmol, 3.00 equiv) in 1,4-dioxane (5.00 mL) was added [4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (64.57 mg, 0.270 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (22.06 mg, 0.027 mmol, 0.10 equiv), and H.sub.2O (1.00 mL). The resulting solution was stirred for 2 hours at 80° C. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC (conditions: 2 #SHIMADZU (HPLC-01); SunFire 018 OBD Prep Column, 19 mm×250 mm; mobile phase: Water (0.1% FA, formic acid) and ACN (hold 5% Phase B in 2 minutes, up to 12% in 10 minutes); UV Detector). This resulted in 5.3 mg (4.1%) of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-2-(4-methylpiperazine-1-carbonyl)-4H,5H-thieno[3,2-c]pyridin-4-one as a brown semi-solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 2H, FA), 7.93 (s, 1H), 7.87 (s, 1H), 7.06 (s, 2H), 4.41 (s, 2H), 4.01 (s, 6H), 3.97-3.85 (m, 4H), 3.75 (s, 3H), 2.91 (s, 6H), 2.75-2.64 (m, 4H), 2.45 (s, 3H); LCMS (ESI) m/z: [M+H]+=485.20.

Example 14—Preparation of 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)acetic Acid Trifluoroacetic Acid (Compound B8 Trifluoroacetic Acid)

[0943] ##STR00770##

Step 1 Preparation of 5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (i-24)

[0944] ##STR00771##

[0945] To a solution of 2-bromo-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (500.00 mg, 2.048 mmol, 1.00 equiv) and Zn(CN).sub.2 (529.22 mg, 4.506 mmol, 2.20 equiv) in DMF (20.00 mL) was added Pd(dppf)Cl.sub.2 (149.87 mg, 0.205 mmol, 0.10 equiv). The resulting mixture was stirred at 120° C. for 16 hours under N.sub.2 atmosphere. Fifteen identical reactions were set up in 15 sealed tubes in parallel. The reaction mixtures were combined and diluted with EA (500 mL). The resulting mixture was washed with water (3×300 mL) and saturated brine (300 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (4.4 g, 75%) as a black solid.

Step 2: Preparation of 7-bromo-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (i-25)

[0946] ##STR00772##

[0947] To a solution of 5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (4.40 g, 23.131 mmol, 1.00 equiv) in THF (50.00 mL) was added NBS (6.18 g, 34.697 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA (400 mL). The resulting mixture was washed with water (3×200 mL) and saturated brine (300 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (3.5 g, 56%) as a brown solid.

Step 3: Preparation of 7-bromo-N-(1,1-dioxo-1λ6-thian-4-yl)-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboximidamide (i-26)

[0948] ##STR00773##

[0949] To a solution of 7-bromo-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (3 g, 11.147 mmol, 1.00 equiv) in MeOH (45.00 mL, 11.451 mmol, 99.70 equiv) was added MeONa (2.00 g, 11.147 mmol, 1 equiv) solution in MeOH (30% by weight). The reaction mixture was heated to 75° C. for 3 hours. Then 4-amino-1λ6-thiane-1,1-dione hydrochloride (2.48 g, 0.013 mmol, 1.2 equiv) was added at 75° C., and the reaction mixture was stirred for a further 16 hours. The volatile components were removed in vacuo, and the resulting solid was suspended in MeOH (50 mL), filtered under reduced pressure, and washed with MeOH (20 mL) to afford 7-bromo-N-(1,1-dioxo-1λ6-thian-4-yl)-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboximidamide (3.0 g, 64%) as a brown solid.

Step 4: Preparation of Ethyl 2-(4-bromo-2-methoxyphenoxy)acetate (i-27)

[0950] ##STR00774##

[0951] To a solution of 4-bromo-2-methoxyphenol (5 g, 24.626 mmol, 1 equiv) and K2003 (6.81 g, 49.253 mmol, 2 equiv) in acetone (50 mL) was added ethyl 2-bromoacetate (4.94 g, 29.580 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA (500 mL), The resulting mixture was washed with water (3×300 mL) and saturated brine (300 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ethyl 2-(4-bromo-2-methoxyphenoxy)acetate (4 g, 56%) as a yellow oil.

Step 5: Preparation of Ethyl 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (i-28)

[0952] ##STR00775##

[0953] To a solution of ethyl 2-(4-bromo-2-methoxyphenoxy)acetate (6 g, 20.752 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.32 g, 24.903 mmol, 1.2 equiv) in solvent dioxane (120 mL) was added KOAc (4.07 g, 41.505 mmol, 2 equiv) and Pd(dppf)Cl.sub.2 (1.52 g, 2.075 mmol, 0.1 equiv). The resulting solution was stirred at 90° C. for 1 hour (under N2 atmosphere). The resulting mixture was washed with water (3×300 mL). The organic phase was concentrated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ethyl 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (6.9 g, 98%) as a yellow oil.

Step 6: Preparation of ethyl 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)acetate (i-29)

[0954] ##STR00776##

[0955] To a solution of 7-bromo-N-(1,1-dioxo-1λ6-thian-4-yl)-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboximidamide (1.00 g, 2.391 mmol, 1.00 equiv), ethyl 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (0.88 g, 2.630 mmol, 1.10 equiv), and K3PO4 (1.01 g, 4.781 mmol, 2.00 equiv) in water (2.00 mL) and DMF (20.00 mL) was added Pd(dppf)Cl.sub.2 (0.17 g, 0.239 mmol, 0.10 equiv). The resulting mixture was stirred at 75° C. for 1 hour. The reaction mixture was diluted with EA (500 mL). The resulting mixture was washed with water (3×300 mL) and saturated brine (300 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)acetate (860 mg, 66%) as a brown solid.

Step 7: Preparation of 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)acetic Acid Trifluoroacetic Acid (Compound B8 Trifluoroacetic Acid)

[0956] ##STR00777##

[0957] To a solution of ethyl 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)acetate (560 mg, 1.023 mmol, 1.00 equiv) in MeOH (25.00 mL) and H.sub.2O (2.50 mL) was added LiOH.H.sub.2O (429.48 mg, 10.226 mmol, 10.00 equiv). The resulting mixture was stirred at room temperature for 5 hours. The mixture was acidified to pH 2 with 1 N HCl (aq.). The crude product was purified by HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5% B to 22% B in 8 minutes; 254 nm; R.sub.T: 5.68 minutes). Fractions containing the desired compound were evaporated to dryness to afford 2-(4-[2-[N-(1,1-dioxo-11A6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)acetic acid trifluoroacetic acid (330 mg, 49%) as a yellow solid. LCMS (ES, m/z): 520.20. .sup.1H NMR (400 MHz, DMSO-d6) δ9.73 (d, J=8.1 Hz, 1H), 9.65 (s, 1H), 9.34 (s, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.25-7.12 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 4.76 (s, 2H), 4.01 (d, J=8.9 Hz, 1H), 3.87 (s, 3H), 3.63 (s, 3H), 3.30-3.15 (m, 4H). 2.28-2.15 (m, 4H).

Example 15—Preparation of 7-(3,4-dimethoxyphenyl)-2-(1H-imidazol-2-yl)-5-methyl-4H,5H-thieno[3,2-c]pyridine-4-one (Compound B9)

[0958] ##STR00778##

Step 1: Preparation of 7-bromo-2-(1H-imidazol-2-yl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (i-30)

[0959] ##STR00779##

[0960] To a solution of 7-bromo-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carbonitrile (50.00 mg, 0.186 mmol, 1.00 equiv) and NaOMe (100.37 mg, 1.858 mmol, 10.00 equiv) in MeOH (1.00 mL) was stirred for 3 hours at room temperature. To the above mixture was added AcOH (446.28 mg, 7.432 mmol, 40.00 equiv) and HCl (1.50 mL, 49.368 mmol, 265.72 equiv) at room temperature. The resulting mixture was stirred for additional 16 hours at 75° C. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with water (3×30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 5:1) to afford 7-bromo-2-(1H-imidazol-2-yl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (30 mg, 52%) as a white solid. LCMS (ES, m/z): 310.0.

Step 2: Preparation of 7-(3,4-dimethoxyphenyl)-2-(1H-imidazol-2-yl)-5-methyl-4H,5H-thieno[3,2-c]pyridine-4-one (Compound 89)

[0961] ##STR00780##

[0962] To a solution of 7-bromo-2-(1H-imidazol-2-yl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (30.00 mg, 0.097 mmol, 1.00 equiv) and (3,4-dimethoxyphenyl)boronic acid (17.60 mg, 0.097 mmol, 1 equiv) in dioxane (1.50 mL) and H.sub.2O (0.50 mL) was added Cs.sub.2CO.sub.3 (63.03 mg, 0.193 mmol, 2.00 equiv) and XPhos-Pd-G3 (16.37 mg, 0.019 mmol, 0.2 equiv). The resulting solution was stirred at 80° C. for 1 hour (under N.sub.2 atmosphere). The crude product was purified by preparative HPLC (conditions: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 25% B to 33% B in 8 minutes; 254 nm; R.sub.T: 6.77 minutes). Fractions containing the desired compound were evaporated to dryness to afford 7-(3,4-dimethoxyphenyl)-2-(1H-imidazol-2-yl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (10.8 mg, 30%) as a white solid. LCMS (ES, m/z): 368.1. .sup.1H-NMR (400 MHz, CD.sub.3OD) δ 7.96 (s, 1H), 7.62 (s, 1H), 7.26 (m, J=2.1 Hz, 1H), 7.24 (m, J=8.1, 2.2 Hz, 1H), 7.17 (s, 2H), 7.11 (m, J=8.1 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.74 (s, 3H).

Example 16—Preparation of 7-(3,4-dimethoxyphenyl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (Compound B10)

[0963] ##STR00781##

Step 1: Preparation of 7-bromothieno[3,2-c]pyridin-4(5H)-one (i-32)

[0964] ##STR00782##

[0965] A solution of 4H,5H-thieno[3,2-c]pyridin-4-one (1 g, 6.615 mmol, 1 equiv) and NBS (1.41 g, 7.938 mmol, 1.2 equiv) in DMF (10 mL) was stirred for 16 hours at room temperature. The resulting solution was diluted with of EtOAc. The resulting mixture was washed with water (3×50 mL). The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). Fractions containing the desired compound were evaporated to dryness to afford 7-bromo-4H,5H-thieno[3,2-c]pyridin-4-one (440.0 mg, 29%) as a purple solid. LCMS (ES, m/z): 230.0.

Step 2: Preparation of 7-bromo-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (i-33)

[0966] ##STR00783##

[0967] To a solution of 7-bromo-4H,5H-thieno[3,2-c]pyridin-4-one (200.00 mg, 0.869 mmol, 1.00 equiv) and Cs.sub.2CO.sub.3 (849.67 mg, 2.608 mmol, 3 equiv) in THF (10.00 mL) was added MeI (246.76 mg, 1.739 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (hexane/EtOAc 5:1) to afford 7-bromo-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (200 mg, 94%) as a brown solid. LCMS (ES, m/z): 244.0.

Step 3: Preparation of 7-(3,4-dimethoxyphenyl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (Compound B10)

[0968] ##STR00784##

[0969] To a solution of 7-bromo-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (100.00 mg, 0.410 mmol, 1.00 equiv) and (3,4-dimethoxyphenyl)boronic acid (74.55 mg, 0.410 mmol, 1 equiv) in solvent H.sub.2O (1.00 mL) and dioxane (3.00 mL) was added 052003 (266.95 mg, 0.819 mmol, 2 equiv) and XPhos-Pd-G3 (69.35 mg, 0.082 mmol, 0.2 equiv). The resulting solution was stirred at 80° C. for 1 hour (under N.sub.2 atmosphere). The crude product was purified by preparative HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R.sub.T: 7.12 minutes). Fractions containing the desired compound were evaporated to dryness to afford 7-(3,4-dimethoxyphenyl)-5-methyl-4H,5H-thieno[3,2-c]pyridin-4-one (60.1 mg, 48%) as a white solid. LCMS (ES, m/z): 302. .sup.1H NMR (400 MHz, DMSO) δ 7.72 (s, 1H), 7.66 (d, J=5.4 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 7.22-7.15 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 3.83 (d, J=6.4 Hz, 6H), 3.60 (s, 3H).

Example 17—Preparation of Intermediates

Preparation of Ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]-acetate (i-35)

[0970] ##STR00785##

Step 1: Preparation of Ethyl 2-[4-bromo-2-(trifluoromethyl)phenoxy]acetate (i-34)

[0971] ##STR00786##

[0972] To a solution of 4-bromo-2-(trifluoromethyl)phenol (5 g, 20.746 mmol, 1 equiv) and K.sub.2CO.sub.3 (5.73 g, 41.493 mmol, 2 equiv) in acetone (50 mL) was added ethyl 2-bromoacetate (5.20 g, 31.119 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The solid was then filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford ethyl 2-[4-bromo-2-(trifluoromethyl)phenoxy] acetate (6.5 g, 96%) as a white solid. LCMS (ESI) m/z: [M+H]+=327.

Step 2: Preparation of Ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]-acetate (i-35)

[0973] ##STR00787##

[0974] To a solution of ethyl 2-[4-bromo-2-(trifluoromethyl)phenoxy]acetate (1 g, 3.057 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (931.6 mg, 3.669 mmol, 1.2 equiv) in dioxane (10 mL) was added KOAc (0.60 g, 6.114 mmol, 2.00 equiv) and Pd(dppf)Cl.sub.2 (223.7 mg, 0.306 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at 90° C. under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]acetate (800 mg, 70%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=375.

Preparation of Tert-Butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate (i-37)

[0975] ##STR00788##

Step 1: Preparation of Tert-Butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)amino)octyl)carbamate (i-36)

[0976] ##STR00789##

[0977] To a solution of 3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (200 mg, 0.773 mmol, 1 equiv) and tert-butyl N-(8-oxooctyl)carbamate (225.31 mg, 0.927 mmol, 1.2 equiv) in MeOH (10 mL) was added NaBH.sub.3CN (145.41 mg, 2.319 mmol, 3 equiv) and AcOH (0.5 mL). The resulting solution was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-ihydro-1H-isoindol-4-yl]amino]octyl)carbamate (202 mg, 62%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=487.

Step 2: Preparation of tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate (i-37)

[0978] ##STR00790##

[0979] To a solution of tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate (100 mg, 0.310 mmol, 1 equiv) in DCM (5.0 ml) was added TFA (2.0 ml). The resulting solution was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (conditions: column, 018 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm). This resulted in 3-[4-[(8-aminooctyl)amino]-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (103 mg, 87%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=387.

Preparation of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentanal (i-39)

[0980] ##STR00791##

Step 1: Preparation of 4-(4-(1,3-dioxolan-2-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i-38)

[0981] ##STR00792##

[0982] To a stirred mixture of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (400 mg, 1.459 mmol, 1.00 equiv) and 2-(4-bromobutyl)-1,3-dioxolane (274.5 mg, 1.313 mmol, 0.90 equiv) in DMF (4.00 mL) was added Cs.sub.2CO.sub.3 (950.5 mg, 2.917 mmol, 2.00 equiv) at 60° C. under nitrogen atmosphere. The resulting mixture was stirred for 5 hours. The resulting mixture was filtered with acetonitrile (200 mL), concentrated, and purified by Prep-TLC (PE/EtOAc (1:1)) to afford 4-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (81 mg, 13%) as a colorless oil. LCMS (ESI) m/z: [M+H].sup.+=403.

Step 2: Preparation of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentanal (i-39)

[0983] ##STR00793##

[0984] To a stirred mixture of 4-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (46.0 mg, 0.114 mmol, 1.00 equiv) in H.sub.2O (3.0 mL) was added 4 M HCl in dioxane (3 mL) dropwise at room temperature under nitrogen atmosphere. After 3 hours, saturated NaHCO.sub.3 solution (50 mL) was added to the mixture. The mixture was then extracted with EtOAc (100 mL×3), and the combined organic layers were concentrated to give 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanal (35 mg, 70%) as a light yellow semi-solid. LCMS (ESI) m/z: [M+H].sub.+=359.

Preparation of tert-butyl 4-([7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]carbamoyl)piperidine-1-carboxylate (i-40)

[0985] ##STR00794##

[0986] To a solution of 2-amino-7-chloro-5-methylthieno[3,2-c]pyridin-4-one (300.0 mg, 1.397 mmol, 1.00 equiv)v) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (416.5 mg, 1.817 mmol, 1.3 equiv) in solvent DMF (4 mL) was added DIEA (722.5 mg, 5.590 mmol, 4 equiv) and HATU (1062.7 mg, 2.795 mmol, 2 equiv). The resulting solution was stirred at 25° C. for 2 hours. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by chromatography on silica gel eluted with DCM/MeOH (from 20:1 to 10:1) to give tert-butyl 4-([7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]carbamoyl)piperidine-1-carboxylate (360 mg, 61%) as a brown solid. LCMS (ESI) m/z: [M+H]+=426.

[0987] The following compounds (intermediates i-41, i-42, and i-43) were prepared in a similar manner as described in the preparation of intermediate i-40.

TABLE-US-00007 Compound (Intermediate No.) Structure Analytical Data tert-butyl 3-([7-chloro-5-methyl-4-oxothieno[3,2- c]pyridin-2-yl]carbamoyl)piperidine-1- carboxylate (i-41) [00795] 340 mg (57%) as a yellow oil; LCMS (ESI) m/z: [M + H].sup.+ = 426.12 7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2- yl]-1-methylpiperidine-4-carboxamide (i-42) [00796] 80 mg (51%) as a yellow solid; LCMS (ESI) m/z: [M + H]+ = 340 tert-butyl 4-(7-bromo-5-methyl-4-oxo-4,5- dihydrothieno[3,2-c]pyridine-2- carboxamido)piperidine-1-carboxylate (i-42) [00797] 154 mg (31%) as a yellow solid; LCMS (ESI) m/z: [M + H].sup.+ = 470

Preparation of tert-butyl 2-[([2,6-dimethoxy-4-[5-methyl-2-(1-methylpiperidine-4-amido)-4-oxothieno[3,2-c]pyridin-7-yl]phenyl]methyl)(methyl)amino]acetate (i-44)

[0988] ##STR00798##

[0989] To a solution of N-[7-chloro-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-1-methylpiperidine-4-carboxamide (50.0 mg, 0.147 mmol, 1.00 equiv) and 4-([[2-(tert-butoxy)-2-oxoethyl](methyl)amino]methyl)-3,5-dimethoxyphenylboronic acid (59.9 mg, 0.177 mmol, 1.20 equiv) in solvent dioxane (1.50 mL) and H.sub.2O (0.50 mL) was added Pd(dppf)Cl.sub.2*CH.sub.2Cl.sub.2 (8.5 mg, 0.015 mmol, 0.10 equiv) and 052003 (95.9 mg, 0.294 mmol, 2.00 equiv), and the resulting solution was stirred at 90° C. for 3 hours. The reaction mixture was then diluted with 10 mL of water and extracted ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with CH.sub.2Cl.sub.2/MeOH (20:1). This resulted in tert-butyl 2-[([2,6-dimethoxy-4-[5-methyl-2-(1-methylpiperidine-4-amido)-4-oxothieno[3,2-c]pyridin-7-yl]phenyl]methyl)(methyl)amino]acetate (40 mg, 45%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=599.

[0990] The following compounds (intermediates i-45, i-46, and i-47) were prepared in a similar manner as described in the preparation of intermediate i-44.

TABLE-US-00008 Compound (Intermediate No.) Structure Analytical Data tert-butyl 4-[(7-[4-[(dimethylamino)methyl]-3,5- dimethoxyphenyl]-5-methyl-4-oxothieno[3,2- c]pyridin-2-yl)carbamoyl]piperidine-1- carboxylate (i-45) [00799] 168 mg (34%) as a brown solid; LCMS (ESI) m/z: [M + H]+ = 585 tert-butyl 3-[(7-[4-[(dimethylamino)methyl]-3,5- dimethoxyphenyl]-5-methyl-4-oxothieno[3,2- c]pyridin-2-yl)carbamoyl]piperidine-1- carboxylate (i-46) [00800] 260 mg (63%) as a red oil; LCMS (ESI) m/z: [M + H]+ = 585.27 tert-butyl 4-(7-(4-((dimethylamino)methyl)-3,5- dimethoxyphenyl)-5-methyl-4-oxo-4,5- dihydrothieno[3,2-c]pyridine-2- carboxamido)piperidine-1-carboxylate (i-47) [00801] 122 mg (62%) as a brown solid; LCMS (ESI) m/z: [M + H].sup.+ = 585

Preparation of ethyl 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)acetate (i-48)

[0991] ##STR00802##

[0992] To a solution of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl) phenoxy]acetate (100 mg, 0.267 mmol, 1 equiv) and 7-bromo-N-(1,1-dioxo-1λ6-thian-4-yl)-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridine-2-carboximidamide (111.8 mg, 0.267 mmol, 1 equiv) in DMF (3 mL) and H.sub.2O (0.3 mL) was added K3PO4 (113.46 mg, 0.535 mmol, 2 equiv) and Pd(dppf)Cl.sub.2 (39.1 mg, 0.053 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for 1 hour at 75° C. under nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with CH.sub.2Cl.sub.2/MeOH (5:1) to afford ethyl 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy) acetate (97 mg, 62%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=586.

Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-4-carboxamide (i-49)

[0993] ##STR00803##

[0994] To a solution of tert-butyl 4-[(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)carbamoyl]piperidine-1-carboxylate (168.0 mg, 0.287 mmol, 1.00 equiv) in

[0995] DCM (9.00 mL) was added TFA (3.00 mL, 13.463 mmol, 262.41 equiv), and the resulting solution was stirred at 25° C. for 2 hours. The solvent was removed to afford N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-4-carboxamide (180 mg, crude) as a brown solid that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=485.

[0996] The following compounds (intermediates i-50 and i-51) were prepared in a similar manner as described in the preparation of intermediate i-49.

TABLE-US-00009 Compound (Intermediate No.) Structure Analytical Data N-(7-[4-[(dimethylamino)methyl]-3,5- dimethoxyphenyl]-5-methyl-4- oxothieno[3,2-c]pyridin-2-yl)piperidine-3- carboxamide (i-50) [00804] 160 mg (88%) as a red oil; LCMS (ESI) m/z: [M + H].sup.+ = 485.21 N-(7-[4-[(dimethylamino)methyl]-3,5- dimethoxyphenyl]-5-methyl-4- oxothieno[3,2-c]pyridin-2-yl)piperidine-4- carboxamide (i-51) [00805] 180 mg (crude) as a brown solid (used directly without further purification); LCMS (ESI) m/z: [M + H]+ = 485

Preparation of [([2,6-dimethoxy-4-[5-methyl-2-(1-methylpiperidine-4-amido)-4-oxothieno[3,2-c]pyridin-7-yl]phenyl]methyl)(methyl)amino]acetic Acid (i-52)

[0997] ##STR00806##

[0998] To a solution of tert-butyl 2-[([2,6-dimethoxy-4-[5-methyl-2-(1-methylpiperidine-4-amido)-4-oxothieno[3,2-c]pyridin-7-yl]phenyl]methyl)(methyl)amino]acetate (40.0 mg, 0.067 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (2.00 mL), and the resulting solution was stirred at 25° C. for 1 hour. The resulting mixture was concentrated to afford [([2,6-dimethoxy-4-[5-methyl-2-(1-methylpiperidine-4-amido)-4-oxothieno[3,2-c]pyridin-7-yl]phenyl]methyl)(methyl)amino]acetic acid (50 mg, crude) as a yellow solid that was used directly without further purification.

Preparation of 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)acetic Acid (i-53)

[0999] ##STR00807##

[1000] A solution of ethyl 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)acetate (90 mg, 0.154 mmol, 1 equiv) and LiOH.H.sub.2O (64.49 mg, 1.537 mmol, 10 equiv) in MeOH (2 mL) and H.sub.2O (0.5 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum and afforded 2-(4-[2-[N-(1,1-dioxo-1A6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)acetic acid (80 mg, 93%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=558.

Preparation of tert-butyl 4-[7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-amido]-3,3-difluoro piperidine-1-carboxylate (i-55)

[1001] ##STR00808##

[1002] To a solution of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylic acid (200.0 mg, 0.694 mmol, 1.00 equiv) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (213.2 mg, 0.902 mmol, 1.3 equiv) in DMF (4 mL) was added DIEA (448.57 mg, 3.471 mmol, 5 equiv) and HATU (527.8 mg, 1.388 mmol, 2 equiv), and the resulting solution was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (30 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by chromatography on silica gel eluted with DCM/MeOH (from 30:1 to 20:1) to give tert-butyl 4-[7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-amido]-3,3-difluoropiperidine-1-carboxylate (100 mg, 28.45%) as a brown yellow solid. LCMS (ESI) m/z: [M+H]+=506.

Preparation of Tert-Butyl 4-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-amido)-3,3-difluoropiperidine-1-carboxylate (i-57)

[1003] ##STR00809##

[1004] To a solution of tert-butyl 4-[7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-amido]-3,3-difluoropiperidine-1-carboxylate (90.0 mg, 0.178 mmol, 1.00 equiv) and 4-[(dimethylamino)methyl]-3,5-dimethoxyphenylboronic acid (63.7 mg, 0.267 mmol, 1.5 equiv) in dioxane (4 mL) and H.sub.2O (0.4 mL) was added 052003 (115.8 mg, 0.355 mmol, 2 equiv) and RuPhos Palladacycle Gen.4 (15.1 mg, 0.018 mmol, 0.1 equiv). The resulting solution was stirred at room temperature for 2 hours (under N.sub.2 atmosphere). The mixture was diluted with EtOAc (20 mL) and washed with water (30 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by chromatography on silica gel eluted with DCM/MeOH (from 20:1 to 10:1) to give tert-butyl 4-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-amido)-3,3-difluoropiperidine-1-carboxylate (66 mg, 59.82%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=621.

Preparation of N-(3,3-difluoropiperidin-4-yl)-7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide (i-58)

[1005] ##STR00810##

[1006] To a solution of tert-butyl 4-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-amido)-3,3-difluoropiperidine-1-carboxylate (66.0 mg, 0.106 mmol, 1.00 equiv) in DCM (9.00 mL) was added TFA (3 mL, 40.389 mmol, 379.85 equiv). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford N-(3,3-difluoropiperidin-4-yl)-7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide (66 mg, crude) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=521.

Preparation of 7-bromo-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide (i-59)

[1007] ##STR00811##

[1008] To a stirred mixture of 7-bromo-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxylic acid (200.00 mg, 0.694 mmol, 1.00 equiv) and 1-methylpiperidin-4-amine (118.90 mg, 1.041 mmol, 1.50 equiv) in DMF (2.00 mL) was added HATU (527.88 mg, 1.388 mmol, 2 equiv) at 0° C. After 10 minutes, DIEA (358.86 mg, 2.777 mmol, 4.00 equiv) was added, and the reaction mixture was stirred for 10 minutes at 0° C. The mixture was allowed to stirred one hour at room temperature. The resulting mixture was extracted with the mixture of DCM and isopropanol (3:1; 3×100 mL), concentrated, and purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford 7-bromo-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide (232 mg, 82.10%) as a yellow solid. LCMS (ESI) m/z: [M+H].sup.+=384.

Preparation of 7-(4-formyl-3,5-dimethoxyphenyl)-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide (i-60)

[1009] ##STR00812##

[1010] To a stirred mixture of 7-bromo-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide (232.00 mg, 0.604 mmol, 1.00 equiv) and 4-formyl-3,5-dimethoxyphenylboronic acid (190.16 mg, 0.906 mmol, 1.50 equiv) in dioxane (4.00 mL) and H.sub.2O (0.80 mL) was added Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (49.30 mg, 0.060 mmol, 0.10 equiv) and Cs.sub.2CO.sub.3 (590.10 mg, 1.811 mmol, 3.00 equiv). The mixture was allowed to stir at 80° C. under nitrogen atmosphere for 3 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford 7-(4-formyl-3,5-dimethoxyphenyl)-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide (131 mg, 43.67%) as a yellow solid. LCMS (ESI) m/z: [M+H].sup.+=470.

Preparation of tert-butyl 2-[[(2,6-dimethoxy-4-[5-methyl-2-[(1-methylpiperidin-4-yl)carbamoyl]-4-oxothieno[3,2-c]pyridin-7-yl]phenyl)methyl]methyl)amino]acetate (i-61)

[1011] ##STR00813##

[1012] To a stirred mixture of 7-(4-formyl-3,5-dimethoxyphenyl)-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide (131.00 mg, 0.279 mmol, 1.00 equiv) and tert-butyl 2-(methylamino)acetate hydrochloride (60.82 mg, 0.335 mmol, 1.20 equiv) in MeOH (1.50 mL) was added TEA (84.69 mg, 0.837 mmol, 3.00 equiv) at room temperature. After 30 minutes, NaBH.sub.3CN (52.60 mg, 0.837 mmol, 3.00 equiv) was added at room temperature. After 3 hours, the reaction mixture was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford tert-butyl 2-[[(2,6-dimethoxy-4-[5-methyl-2-[(1-methylpiperidin-4-yl)carbamoyl]-4-oxothieno[3,2-c]pyridin-7-yl]phenyl)methyl] (methyl)amino]acetate (84 mg, 50.28%) as a yellow solid. LCMS (ESI) m/z: [M+H].sup.+=599.

Preparation of [[(2,6-dimethoxy-4-[5-methyl-2-[(1-methylpiperidin-4-yl)carbamoyl]-4-oxothieno[3,2-c]pyridin-7-yl]phenyl)methyl]methyl)amino] trifluoroacetic Acid (i-62)

[1013] ##STR00814##

[1014] To a stirred mixture of tert-butyl 2-[[(2,6-dimethoxy-4-[5-methyl-2-[(1-methylpiperidin-4-yl)carbamoyl]-4-oxothieno[3,2-c]pyridin-7-yl]phenyl)methyl](methyl)amino]acetate (84.00 mg, 0.140 mmol, 1.00 equiv) in DCM (4.00 mL) was added TFA (1.00 mL) dropwise at room temperature and stirred for one hour at room temperature. The resulting mixture was concentrated under vacuum. This resulted in [[(2,6-dimethoxy-4-[5-methyl-2-[(1-methylpiperidin-4-yl)carbamoyl]-4-oxothieno[3,2-c]pyridin-7yl]phenyl) methyl](methyl) amino] trifluoroacetic acid (101 mg, 96.48%) as a yellow crude solid. LCMS (ESI) m/z: [M+H].sup.+=543.

Example 18—Preparation of N-[7-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-1-methylpiperidine-4-carboxamide Formic Acid (Compound D1 Formic Acid)

[1015] ##STR00815##

[1016] To a solution of [([2,6-dimethoxy-4-[5-methyl-2-(1-methylpiperidine-4-amido)-4-oxothieno[3,2-c]pyridin-7-yl]phenyl]methyl)(methyl)amino]acetic acid (50.0 mg, 0.092 mmol, 1.00 equiv) and HATU (70.1 mg, 0.184 mmol, 2.00 equiv) in DMF (2.00 mL) was added 4-[2-(2-aminoethoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (33.3 mg, 0.092 mmol, 1.00 equiv) and DIEA (35.7 mg, 0.276 mmol, 3.00 equiv). The resulting solution was stirred at 25° C. for 2 hours. The crude product was purified by preparative HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R.sub.T: 7.12 minutes) to afford N-[7-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl]-1-methylpiperidine-4-carboxamide formic acid (7 mg, 8.6%) of as a yellow solid. .sup.1H NMR (300 MHz, Methanol-d4) δ 8.40 (br s, 0.4H, FA), 7.64-7.53 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.20-7.09 (m, 2H), 6.97 (s, 2H), 5.07 (dd, J=12.9, 5.3 Hz, 1H), 4.29 (s, 2H), 4.07-3.90 (m, 8H), 3.73 (s, 4H), 3.63-3.48 (m, 7H), 3.46-3.38 (m, 2H), 3.18-3.02 (m, 2H), 2.91-2.72 (m, 9H), 2.64-2.47 (m, 1H), 2.25-1.98 (m, 5H). LCMS (ESI) m/z: [M+H]+=886.80.

[1017] The following compound (compound D2) was prepared in a similar manner as described for compound D1.

##STR00816##

[1018] 2-(4-[2-[N-(1,1-dioxo-A6-thian-4-yl) carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-methoxyphenoxy)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamide (14 mg, 16%) as a yellow solid. .sup.1H NMR (300 MHz, Methanol-d4) δ 8.54 (s, 0.4H, FA), 8.21 (s, 1H), 7.74 (s, 1H), 7.34-7.16 (m, 3H), 7.13 (d, J=8.3 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.16 (dd, J=13.3, 5.1 Hz, 1H), 4.59 (d, J=5.2 Hz, 3H), 4.28 (d, J=3.0 Hz, 2H), 3.96 (s, 3H), 3.73 (s, 3H), 3.29-3.10 (m, 4H), 3.03-2.79 (m, 3H), 2.51 (td, J=13.2, 5.0 Hz, 1H), 2.32-2.15 (m, 5H), 1.61 (dd, J=15.5, 7.3 Hz, 4H), 1.36 (s, 8H). LCMS (ESI) m/z: [M+H]+=888.30.

Example 19—Preparation of 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamide (Compound D3)

[1019] ##STR00817##

[1020] To a solution of 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)acetic acid (69 mg, 0.124 mmol, 1 equiv) and DIEA (N,N-diisopropylamine) (48 mg, 0.371 mmol, 3 equiv) in DMF (1 mL) was added PyBOP (96.6 mg, 0.186 mmol, 1.5 equiv) and 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (49.6 mg, 0.124 mmol, 1 equiv). The resulting solution was stirred at room temperature for overnight. Without workup, the crude product (69 mg) was purified by Prep-HPLC (conditions: SunFire Prep 018 OBD Column 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 25% B to 55% B in 8 minutes; 254 nm; R.sub.T: 7.35 minutes) to afford 2-(4-[2-[N-(1,1-dioxo-1λ6-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4H,5H-thieno[3,2-c]pyridin-7-yl]-2-(trifluoromethyl)phenoxy)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamide (30 mg, 25%) as a yellow solid. .sup.1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.23 (s, 1H), 8.14 (s, 0.26H, FA), 7.94-7.78 (m, 4H), 7.62-7.50 (m, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.03 (dd, J=13.8, 7.8 Hz, 2H), 6.51 (t, J=5.9 Hz, 1H), 5.05 (dd, J=12.8, 5.3 Hz, 1H), 4.74 (s, 2H), 3.69 (s, 1H), 3.58 (s, 3H), 3.26 (d, J=6.6 Hz, 2H), 3.20-3.09 (m, 5H), 3.12-2.96 (m, 1H), 2.98-2.79 (m, 1H), 2.61 (s, 1H), 2.03 (s, 4H), 1.79-1.68 (m, 1H), 1.55-1.45 (m, 4H), 1.30 (s, 8H). LCMS (ESI) m/z: [M+H]+=940.50.

Example 20—Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-[3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoyl]piperidine-4-carboxamide Formic Acid (Compound D4)

[1021] ##STR00818##

[1022] To a solution of 3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoic acid (39.4 mg, 0.091 mmol, 1.1 equiv), HOBt (22.3 mg, 0.165 mmol, 2 equiv), and EDCI (31.7 mg, 0.165 mmol, 2 equiv) in DMF (1 mL) was added N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-4-carboxamide (40.0 mg, 0.083 mmol, 1.00 equiv) and DIEA (53.4 mg, 0.413 mmol, 5 equiv), and the resulting solution was stirred at 25° C. for 2 hours. Without any additional work-up, the mixture was purified by Prep-HPLC (conditions: SunFire 018 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate:25 mL/minute; Gradient:11 B to 26 B in 13 minutes; 254 nm) to give N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-[3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoyl]piperidine-4-carboxamide formic acid (22.3 mg, 29%). .sup.1H NMR (400 MHz, Methanol-d4) δ 8.56 (br s, 0.8H, FA), 7.64 (s, 1H), 7.47-7.41 (m, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.03-6.98 (m, 3H), 6.95 (d, J=7.2 Hz, 1H), 5.02 (dd, J=12.7, 5.4 Hz, 1H), 4.59 (d, J=13.3 Hz, 1H), 4.28 (s, 2H), 4.13 (d, J=13.9 Hz, 1H), 3.99 (s, 6H), 3.81-3.66 (m, 9H), 3.65-3.61 (m, 2H), 3.52-3.44 (m, 2H), 3.23-3.14 (m, 1H), 2.88-2.79 (m, 8H), 2.77-2.60 (m, 4H), 2.55-2.46 (m, 1H), 2.11-2.01 (m, 1H), 1.95-1.74 (m, 3H), 1.73-1.60 (m, 1H). LCMS (ESI) m/z: [M+H]+=900.50.

Example 21—Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-[3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoyl]piperidine-3-carboxamide (Compound D5)

[1023] ##STR00819##

[1024] To a stirred solution of 3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy] propanoic acid (53.66 mg, 0.124 mmol, 1.20 equiv) in DMF (1.00 mL) was added HOBT (27.88 mg, 0.206 mmol, 2.00 equiv) and EDCI (39.56 mg, 0.206 mmol, 2.00 equiv) at 25° C. The resulting mixture was stirred for 20 minutes at 25° C. Then N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-3-carboxamide (50.00 mg, 0.103 mmol, 1.00 equiv) and DIEA (40.00 mg, 0.310 mmol, 3.00 equiv) was added to the reaction mixture. The resulting mixture was stirred for 2 hours at room temperature. The crude product was purified by Prep-HPLC (conditions: SunFire 018 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (11% Phase B up to 23% in 18 minutes); Detector, UV) to afford N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-[3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoyl]piperidin e-3-carboxamide (12 mg, 13%) as a green solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.57 (brs, 0.8H, FA), 7.66-7.58 (m, 1H), 7.57-7.25 (m, 1H), 7.19-7.06 (m, 1H), 7.05-6.95 (m, 3H), 6.86-6.76 (m, 1H), 5.04 (dd, J=12.5, 5.4 Hz, 1H), 4.53-4.40 (m, 1H), 4.37-4.24 (m, 0.5H), 4.20 (d, J=7.0 Hz, 2H), 4.03-3.98 (m, 6H), 3.95-3.88 (m, 0.5H), 3.81-3.62 (m, 11H), 3.52-3.48 (m, 1H), 3.45-3.36 (m, 1.5H), 3.21-3.12 (m, 0.5H), 3.06-2.92 (m, 1H), 2.87-2.63 (m, 11H), 2.61-2.53 (m, 1H), 2.25-1.98 (m, 2H), 1.86-1.73 (m, 2H), 1.69-1.46 (m, 1H). LCMS (ESI) m/z: [M+H]+=900.50.

Example 22—Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)piperidine-4-carboxamide Formic Acid (Compound D6 Formic Acid)

[1025] ##STR00820##

[1026] To a solution of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-4-carboxamide (30.0 mg, 0.062 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanal (24.4 mg, 0.068 mmol, 1.10 equiv) in DMF (1.00 mL) was added sodium triacetoxyborohydride (26.2 mg, 0.124 mmol, 2.00 equiv), and the resulting solution was stirred at room temperature for 2 hours. Without any additional work-up, the mixture was purified by Prep-HPLC (conditions: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient:7 B to 19 B in 12 minutes; 254/220 nm) to give N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)piperidine-4-carboxamide; formic acid (4.7 mg, 8.7%). .sup.1H NMR (400 MHz, Methanol-d4) δ 8.55 (br s, 1.1H, FA), 7.67 (s, 1H), 7.63-7.57 (m, 1H), 7.29 (d, J=7.1 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (s, 2H), 5.13 (dd, J=12.9, 5.5 Hz, 1H), 4.38 (s, 2H), 4.02 (s, 6H), 3.85 (t, J=7.0 Hz, 2H), 3.74 (s, 3H), 3.39-3.35 (m, 2H), 2.93-2.87 (m, 8H), 2.78 (s, 2H), 2.71-2.56 (m, 4H), 2.15-2.08 (m, 1H), 2.05-1.92 (m, 4H), 1.77-1.60 (m, 4H), 1.44-1.34 (m, 2H). LCMS (ESI) m/z: [M+H]+=827.50.

[1027] Compound D11 was prepared in a similar manner as described for compound D6.

##STR00821##

[1028] 7-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentyl)piperidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide trifluoroacetic acid (12.8 mg, 26%) as a white solid. .sup.1H NMR (300 MHz, Methanol-d4) δ 8.25 (s, 1H), 7.87 (s, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.06 (s, 2H), 5.16 (dd, J=12.8, 5.4 Hz, 1H), 4.42 (s, 2H), 4.24-4.10 (m, 1H), 4.02 (s, 6H), 3.88 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.69 (s, 2H), 3.25-3.06 (m, 4H), 2.96-2.87 (m, 8H), 2.77-2.60 (m, 1H), 2.31-2.14 (m, 3H), 2.01-1.88 (m, 2H), 1.86-1.62 (m, 4H), 1.51-1.39 (m, 2H). LCMS (ESI) m/z: [M+H].sup.+=827.40.

Example 23—Preparation of (3R) and (3S) N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo thieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)piperidine-3-carboxamide (Compounds D7 and D8)

[1029] ##STR00822##

[1030] To a stirred solution of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-3-carboxamide (50.00 mg, 0.103 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoic acid (46.35 mg, 0.124 mmol, 1.20 equiv) in DMF (1 mL) was added DIEA (26.67 mg, 0.206 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 15 minutes at room temperature. Then HATU (58.84 mg, 0.155 mmol, 1.50 equiv) was added to the reaction mixture. The resulting mixture was stirred for 1 hour at room temperature. The crude products were purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (7% Phase B up to 21% in 12 minutes); Detector, UV).

##STR00823##

[1031] (3R)—N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)piperidine-3-carboxamide (9.7 mg, 11%) as a white semi-solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 7.78-7.61 (m, 2H), 7.42 (dd, J=8.0, 2.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 0.5H), 7.23 (d, J=7.2 Hz, 0.5H), 7.18 (s, 0.5H), 7.06 (s, 0.5H), 7.04 (d, J=2.3 Hz, 2H), 5.10-4.92 (m, 1H), 4.41 (d, J=5.1 Hz, 2H), 4.31-4.18 (m, 3H), 4.14 (d, J=12.6 Hz, 0.5H), 4.03 (d, J=2.8 Hz, 6H), 3.89 (d, J=14.1 Hz, 0.5H), 3.73 (d, J=5.0 Hz, 3H), 3.52-3.43 (m, 1H), 3.26-3.14 (m, 1H), 2.92 (d, J=4.2 Hz, 6H), 2.78-2.55 (m, 6H), 2.13-1.99 (m, 2H), 1.97-1.84 (m, 6H), 1.68-1.47 (m, 1H). LCMS (ESI) m/z: [M+H]+=841.32.

##STR00824##

[1032] (3S)—N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)piperidine-3-carboxamide (11.3 mg, 13%) as a white semi-solid. .sup.1H NMR (300 MHz, Methanol-d4) δ 7.79-7.71 (m, 0.5H), 7.64 (s, 1H), 7.60 (d, J=7.9 Hz, 0.5H), 7.43 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.19 (s, 0.5H), 7.05 (s, 2H), 7.04 (s, 0.5H), 6.92 (s, 0.5H), 5.12-5.08 (m, 0.5H), 4.96-4.92 (m, 0.5H), 4.42 (d, J=4.5 Hz, 2H), 4.35-4.22 (m, 3H), 4.21-4.14 (m, 0.5H), 4.03 (s, 6H), 3.96-3.88 (m, 0.5H), 3.74 (d, J=5.8 Hz, 3H), 3.43-3.40 (m, 1H), 3.24-3.09 (m, 1H), 2.92 (s, 6H), 2.88-2.49 (m, 6H), 2.16-2.00 (m, 2H), 1.99-1.76 (m, 6H), 1.69-1.42 (m, 1H). LCMS (ESI) m/z: [M+H]+=841.32.

Example 24—Preparation of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)piperidine-3-carboxamide (Compound D9)

[1033] ##STR00825##

[1034] A solution of N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)piperidine-3-carboxamide (30.00 mg, 0.062 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanal (26.62 mg, 0.074 mmol, 1.20 equiv) in DMF (1.5 mL) was stirred for 20 minutes at room temperature. Then NaBH.sub.3CN (7.78 mg, 0.124 mmol, 2.00 equiv) was added to the reaction mixture. The resulting mixture was stirred for 2 hours at room temperature. The crude product was purified by Prep-HPLC (conditions: SunFire 018 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (7% Phase B up to 21% in 12 minutes); Detector, UV). This resulted in N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl) piperidine-3-carboxamide (5.2 mg, 10%) as a red semi-solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.45 (brs, 0.2H, FA), 7.66 (d, J=5.8 Hz, 1H), 7.62-7.55 (m, 1H), 7.33-7.12 (m, 3H), 7.04 (d, J=2.0 Hz, 2H), 5.14-5.04 (m, 1H), 4.41 (s, 2H), 4.01 (d, J=5.8 Hz, 6H), 3.86 (d, J=7.5 Hz, 2H), 3.74 (s, 3H), 3.31-3.12 (m, 3H), 3.04-2.95 (m, 3H), 2.91 (s, 6H), 2.89-2.82 (m, 2H), 2.73-2.60 (m, 1H), 2.10-1.93 (m, 3H), 1.90-1.73 (m, 4H), 1.66 (t, J=7.1 Hz, 2H), 1.48-1.38 (m, 2H). LCMS (ESI) m/z: [M+H].sup.+=827.80.

Example 25—Preparation of 7-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentanoyl)piperidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide Formic Acid (Compound D10 Formic Acid)

[1035] ##STR00826##

[1036] Into a stirred mixture of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxo-N-(piperidin-4-yl)thieno[3,2-c]pyridine-2-carboxamide (25.0 mg, 0.052 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoic acid (19.3 mg, 0.052 mmol, 1.00 equiv) in DMF (0.50 mL) was added HATU (49.0 mg, 0.129 mmol, 2.50 equiv) at 0° C. under nitrogen atmosphere. After 10 minutes, to the above mixture was added DIEA (33.3 mg, 0.258 mmol, 5.00 equiv) at 0° C. under nitrogen atmosphere and stirred for 10 minutes. Then the mixture was allowed to stir at room temperature for 2 hours. The crude product was purified by Prep-HPLC (conditions: Sunfire C18 OBD Prep Column, 100A, 5 μm, 19 mm*250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 12% B to 35% B in 15 minutes; 254/220 nm; R.sub.T: 11.34 minutes). This resulted in 7-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentanoyl)piperidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide; formic acid (7.8 mg, 17%) as a white solid. .sup.1H NMR (300 MHz, Methanol-d4) δ 8.56 (br s, 0.9H, FA), 8.23 (s, 1H), 7.84 (s, 1H), 7.83-7.76 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.06 (s, 2H), 5.14-5.05 (m, 1H), 4.61-4.52 (m, 1H), 4.36-4.27 (m, 4H), 4.16-4.05 (m, 2H), 4.01 (s, 6H), 3.74 (s, 3H), 2.85 (s, 7H), 2.81-2.73 (m, 3H), 2.69-2.59 (m, 3H), 2.14-2.06 (m, 1H), 2.04-1.87 (m, 6H), 1.66-1.47 (m, 2H). LCMS (ESI) m/z: [M+H].sup.+=841.50.

[1037] Compound D12 was prepared in a similar manner as described in compound D10.

##STR00827##

[1038] N-(7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridin-2-yl)-1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)piperidine-4 carboxamide formic acid (8.2 mg, 15%) as a light yellow solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.57 (brs, 0.7H, FA), 7.79 (dd, J=8.6, 7.3 Hz, 1H), 7.64 (s, 1H), 7.45 (dd, J=7.6, 3.3 Hz, 2H), 7.20 (d, J=3.1 Hz, 1H), 7.03 (s, 2H), 5.10-5.04 (m, 1H), 4.62-4.56 (m, 1H), 4.32-4.23 (m, 4H), 4.16-4.08 (m, 1H), 4.00 (s, 6H), 3.74 (s, 3H), 3.23-3.15 (m, 1H), 2.79 (s, 6H), 2.76-2.59 (m, 6H), 2.15-2.07 (m, 1H), 1.99-1.84 (m, 7H), 1.81-1.58 (m, 2H). LCMS (ESI) m/z: [M+H]+=841.35.

Example 26—Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)-3,3-difluoropiperidin-4-yl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide Formic Acid (Compound D13 Formic Acid)

[1039] ##STR00828##

[1040] To a solution of N-(3,3-difluoropiperidin-4-yl)-7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide (40.0 mg, 0.077 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanal (30.29 mg, 0.085 mmol, 1.1 equiv) in DMF (1 mL) was added NaBH(AcO).sub.3 (32.6 mg, 0.154 mmol, 2 equiv). The resulting solution was stirred at room temperature for 2 hours. Without any additional work-up, the mixture was purified by Prep-HPLC (conditions: SunFire 018 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate:25 mL/minute; Gradient:13 B to 25 B in 10 minutes; 254 nm) to afford 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)-3,3-difluoropiperidin-4-yl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide formic acid (20.9 mg, 29.78%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.87 (d, J=8.8 Hz, 1H), 8.59 (s, 1H), 8.15 (s, 0.3H, FA), 7.97 (s, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 6.96 (s, 2H), 5.09 (dd, J=12.9, 5.4 Hz, 1H), 4.38-4.20 (m, 3H), 3.88 (s, 6H), 3.79 (s, 2H), 3.63 (s, 3H), 3.15 (s, 1H), 2.96-2.83 (m, 2H), 2.70-2.56 (m, 3H), 2.41 (s, 8H), 2.19 (t, J=11.4 Hz, 1H), 2.08-2.00 (m, 1H), 1.92-1.73 (m, 4H), 1.58-1.43 (m, 4H). LCMS (ESI) m/z: [M+H]+=863.35.

Example 27—Preparation of 7-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4 yl]oxy]ethoxy)ethyl] carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno[3,2-c]pyridine-2-carboxamide Formic Acid (Compound D14 Formic Acid)

[1041] ##STR00829##

[1042] To a stirred mixture of [[(2,6-dimethoxy-4-[5-methyl-2-[(1-methylpiperidin-4-yl)carbamoyl]-4-oxothieno[3,2-c]pyridin-7-yl]phenyl)methyl](methyl)amino]acetic acid (50.00 mg, 0.076 mmol, 1.00 equiv) and 4-[2-(2-aminoethoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetic acid (36.20 mg, 0.076 mmol, 1.00 equiv) in DMF (1.00 mL) was added HATU (72.38 mg, 0.190 mmol, 2.50 equiv) at 0° C. under atmosphere. After 10 minutes, DIEA (49.20 mg, 0.381 mmol, 5.00 equiv) was added at 0° C. under nitrogen atmosphere, and the reaction mixture was then stirred for 10 minutes. Then the mixture was allowed to stir at room temperature for 3 hours. The crude product (0.1% TA) was concentrated, purified by Prep-TLC (DCM/MeOH=10:1) to afford crude product. Then the crude product was purified by Prep-HPLC (conditions: Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm*250 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 12 B to 35 B in 12 minutes; 254 nm; R.sub.T: 11.68 minutes). This resulted in 7-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-5-methyl-N-(1-methylpiperidin-4-yl)-4-oxothieno [3,2-c]pyridine-2-carboxamide formic acid (3.0 mg, 7.96%) as a white solid. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1.0H, FA), 8.21 (s, 1H), 7.78 (s, 1H), 7.64 (dd, J=8.6, 7.2 Hz, 1H), 7.33 (dd, J=7.8, 2.1 Hz, 2H), 6.88 (s, 2H), 5.07 (dd, J=12.7, 5.5 Hz, 1H), 4.32-4.26 (m, 2H), 4.17-4.08 (m, 1H), 4.02 (s, 2H), 3.92 (s, 6H), 3.90-3.86 (m, 2H), 3.73 (s, 3H), 3.69 (t, J=5.2 Hz, 2H), 3.54-3.43 (m, 6H), 3.09 (t, J=12.2 Hz, 2H), 2.91-2.80 (m, 4H), 2.78-2.61 (m, 2H), 2.56 (s, 3H), 2.27-2.18 (m, 2H), 2.14-2.06 (m, 1H), 2.02-1.89 (m, 2H). LCMS (ESI) m/z: [M+H].sup.+=886.20.

Example 28—Preparation of 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentyl)-3,3-difluoropiperidin-4-yl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide Formic Acid (Compound D15 Formic Acid)

[1043] ##STR00830##

[1044] To a solution of N-(3,3-difluoropiperidin-4-yl)-7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide (40.0 mg, 0.077 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (30.3 mg, 0.085 mmol, 1.1 equiv) in DMF (1 mL) was added NaBH(AcO).sub.3 (32.6 mg, 0.154 mmol, 2 equiv). The resulting solution was stirred at room temperature for 2 hours. Without any additional work-up, the mixture was purified by Prep-HPLC (conditions: SunFire 018 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B:ACN; Flow rate:25 mL/minute; Gradient:15 B to 25 B in 12 minutes; 254 nm) to afford 7-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[1-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentyl)-3,3-difluoropiperidin-4-yl]-5-methyl-4-oxothieno[3,2-c]pyridine-2-carboxamide formic acid (14 mg, 19.81%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.88 (d, J=8.8 Hz, 1H), 8.60 (s, 1H), 8.15 (s, 0.3H, FA), 7.98 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.36 (dd, J=8.3, 2.3 Hz, 1H), 6.97 (s, 2H), 6.53 (s, 0.3H, FA salt), 5.13 (dd, J=12.9, 5.3 Hz, 1H), 4.35 (s, 1H), 4.20 (t, J=6.5 Hz, 2H), 3.88 (s, 6H), 3.82 (s, 2H), 3.63 (s, 3H), 3.15 (s, 1H), 2.95-2.84 (m, 2H), 2.65-2.55 (m, 3H), 2.44 (s, 8H), 2.18 (t, J=11.3 Hz, 1H), 2.10-2.01 (m, 1H), 1.91-1.74 (m, 4H), 1.57-1.41 (m, 4H). LCMS (ESI) m/z: [M+H]+=863.35.

Example 29—Preparation of Compounds D16-D90

[1045] In analogy to the procedures described in the examples above, compounds D16-D90 were prepared using the appropriate starting materials

TABLE-US-00010 Compound No. LCMS .sup.1H NMR D16 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.87 (d, J = 8.8 Hz, [M + H]+ = 863.35 1H), 8.59 (s, 1H), 8.15 (s, 0.3H, FA), 7.97 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 6.96 (s, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.38-4.20 (m, 3H), 3.88 (s, 6H), 3.79 (s, 2H), 3.63 (s, 3H), 3.15 (s, 1H), 2.96-2.83 (m, 2H), 2.70-2.56 (m, 3H), 2.41 (s, 8H), 2.19 (t, J = 11.4 Hz, 1H), 2.08- 2.00 (m, 1H), 1.92-1.73 (m, 4H), 1.58-1.43 (m, 4H). D17 879.15 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.89 (d, J = 8.8 Hz, 1H), 8.60 (s, 1H), 8.17 (s, 2H, FA), 8.01 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 7.6 Hz, 2H), 5.15-4.95 (m, 1H), 4.47-4.14 (m, 3H), 3.89 (s, 3H), 3.62 (s, 3H), 3.59-3.52 (m, 2H), 3.33-3.14 (m, 4H), 3.03- 2.79 (m, 3H), 2.69-2.54 (m, 8H), 2.46-2.26 (m, 3H), 2.25-2.16 (m, 7H), 2.05-1.90 (m, 1H), 1.90-1.69 (m, 2H). D18 929.25 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.95 (d, J = 9.0 Hz, 1H), 8.62 (d, J = 13.0 Hz, 1H), 8.14 (s, 0.47H, FA), 8.00 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.00 (s, 2H), 6.56-6.45 (m, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.62 (s, 2H), 4.31 (d, J = 16.9 Hz, 1H), 4.18 (d, J = 17.0 Hz, 2H), 4.00 (s, 2H), 3.90 (s, 6H), 3.65 (d, J = 9.8 Hz, 7H), 3.22 (dd, J = 15.8, 3.3 Hz, 2H), 3.01-2.84 (m, 3H), 2.64-2.53 (m, 6H), 2.44-2.31 (m, 5H), 2.02-1.88 (m, 3H), 1.88- 1.66 (m, 4H). D19 915.25 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.98 (s, 1H, TFA salt), 8.92 (d, J = 8.8 Hz, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.03 (s, 2H), 6.56-6.48 (m, 2H), 5.05 (dd, J = 13.1, 5.0 Hz, 1H), 4.50-4.10 (m, 7H), 3.93 (s, 6H), 3.74 (s, 4H), 3.64 (s, 3H), 3.04-2.84 (m, 4H), 2.81-2.76 (m, 8H), 2.69-2.55 (m, 5H), 2.40-2.30 (m, 2H), 2.12-1.94 (m, 5H), 1.91-1.75 (m, 2H). D20 752.2  .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.63 (s, 1H), 8.23 (s, 2H, FA), 8.14 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.14 (s, 2H), 6.72-6.64 (m, 2H), 5.13-5.04 (m, 1H), 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 3.86 (s, 6H), 3.81 (s, 2H), 3.68 (s, 3H), 3.56 (s, 6H), 3.17 (s, 2H), 2.91 (m, J = 17.7, 13.4, 5.4 Hz, 1H), 2.59 (d, J = 17.0 Hz, 2H), 2.45 (d, J = 6.9 Hz, 2H), 2.40-2.22 (m, 5H), 2.04-1.93 (m, 1H), 1.72 (t, J = 5.4 Hz, 4H). D21 734.34 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.87 (d, J = 53.7 Hz, 2H, TFA), 8.26 (d, J = 2.0 Hz, 1H), 7.90 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 2.2 Hz, 2H), 6.70 (dd, J = 4.8, 2.4 Hz, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.50- 4.28 (m, 3H), 4.20 (d, J = 17.0 Hz, 2H), 3.95 (s, 6H), 3.73 (s, 2H), 3.65 (s, 5H), 2.96 (s, 3H), 2.78 (d, J = 4.7 Hz, 2H), 2.63 (s, 2H), 2.43-2.31 (m, 1H), 2.12 (d, J = 13.6 Hz, 2H), 2.03-1.79 (m, 3H). D22 818.15 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.51 (s, 1H, TFA), 9.05 (s, 1H, TFA), 8.61 (s, 1H), 8.03 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.19-7.10 (m, 2H), 7.06 (s, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (s, 1H), 4.44-4.30 (m, 3H), 4.24 (d, J = 17.0 Hz, 1H), 3.99 (d, J = 12.7 Hz, 2H), 3.96 (s, 6H), 3.76 (s, 1H), 3.65 (s, 3H), 3.50 (m, 1H), 3.40 (m, 1H), 3.25 (m, 1H), 3.21 (m, 2H), 3.00- 2.70 (m, 5H), 2.69-2.55 (m, 2H), 2.45-2.29 (m, 2H), 2.09 (s, 2H), 2.03-1.93 (m, 1H). D23 854.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.30 (s, 0.3H, FA), 7.85 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 8.6, 2.3 Hz, 1H), 7.05 (s, 2H), 5.11 (dd, J = 12.5, 5.5 Hz, 1H), 4.50-4.37 (m, 1H), 4.31 (s, 2H), 4.02 (s, 6H), 3.75 (s, 3H), 3.69 (s, 4H), 3.40-3.35 (m, 2H), 3.31-3.21 (m, 2H), 3.19 (t, J = 9.9 Hz, 1H), 2.97 (d, J = 12.0 Hz, 1H), 2.89 (ddd, J = 18.3, 14.2, 5.1 Hz, 1H), 2.78 (d, J = 3.2 Hz, 1H), 2.73 (d, J = 9.9 Hz, 1H), 2.47 (dd, J = 28.7, 12.4 Hz, 1H), 2.40 (s, 3H), 2.31 (t, J = 11.7 Hz, 1H), 2.19-2.04 (m, 1H), 2.01 (dd, J = 11.9, 4.4 Hz, 1H), 1.96 (d, J = 7.4 Hz, 1H). D24 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.37 (d, J = 1.8 Hz, 1H), 7.89 [M + H]+ = 846.25 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 11.8 Hz, 2H), 7.08 (s, 2H), 5.16 (dd, J = 13.3, 5.0 Hz, 1H), 4.74 (m, 1H) 4.43 (d, J = 6.3 Hz, 4H), 4.10 (d, J = 12.5 Hz, 1H), 4.02 (s, 6H), 3.95 (d, J = 12.6 Hz, 2H), 3.87 (s, 1H), 3.76 (s, 3H), 3.53 (d, 2H), 3.22 (s, 1H), 2.92 (s, 8H), 2.89-2.74 (m, 2H), 2.60-2.42 (m, 1H), 2.21 (s, 5H), 1.90 (t, J = 11.8 Hz, 2H). D25 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.88 (s, 1H), 7.67 [M + H].sup.+ = 846.25. (d, J = 9.2 Hz, 1H), 7.13-7.03 (t, 4H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.75 (s, 1H), 4.52-4.33 (m, 4H), 4.12 (d, J = 12.9 Hz, 2H), 4.02 (s, 6H), 3.93 (s, 1H), 3.75 (s, 3H), 3.65-3.46 (m, 3H), 3.25 (s, 1H), 2.99 (d, J = 12.6 Hz, 2H), 2.92-2.73 (m, 7H), 2.57-2.40 (m, 1H), 2.27 (s, 1H), 2.21 (s, 5H), 1.90 (q, J = 12.2, 11.6 Hz, 2H). D26 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6, D.sub.2O) δ 8.45 (s, 1H), 7.90 (s, 1H), [M + H].sup.+ = 943.45. 7.75 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 6.99-6.95 (m, 2H), 5.02 (dd, J = 12.8, 5.6 Hz, 1H), 4.76-4.58 (m, 1H), 4.35-4.12 (m, 4H), 3.96-3.83 (m, 7H), 3.72- 3.48 (m, 7H), 3.39 (d, J = 11.5 Hz, 2H), 3.31-3.07 (m, 7H), 2.97 (t, J = 12.3 Hz, 2H), 2.86 (s, 3H), 2.83-2.72 (m, 1H), 2.69-2.55 (m, 2H), 2.19-2.00 (m, 3H), 1.87-1.56 (m, 5H), 1.49-1.32 (m, 2H). D27 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6, D.sub.2O) δ 8.45 (s, 1H), 7.90 (s, 1H), [M + H].sup.+ = 935.55. 7.75 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 6.99-6.95 (m, 2H), 5.02 (dd, J = 12.8, 5.6 Hz, 1H), 4.76-4.58 (m, 1H), 4.35-4.12 (m, 4H), 3.96-3.83 (m, 7H), 3.72- 3.48 (m, 7H), 3.39 (d, J = 11.5 Hz, 2H), 3.31-3.07 (m, 7H), 2.97 (t, J = 12.3 Hz, 2H), 2.86 (s, 3H), 2.83-2.72 (m, 1H), 2.69-2.55 (m, 2H), 2.19-2.00 (m, 3H), 1.87-1.56 (m, 5H), 1.49-1.32 (m, 2H). D28 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.58 (s, 1H, FA), 8.35 (s, 1H), [M + H].sup.+ = 875.50. 7.85-7.78 (m, 2H), 7.42 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.3, 2.3 Hz, 1H), 7.02 (s, 2H), 5.12 (dd, J = 12.2, 5.4 Hz, 1H), 4.52-4.39 (m, 1H), 4.36 (s, 2H), 4.20 (t, J = 6.3 Hz, 2H), 4.06 (t, J = 8.0 Hz, 4H), 4.00 (s, 6H), 3.74 (s, 3H), 3.26-3.18 (m, 1H), 3.07-2.97 (m, 1H), 2.89-2.69 (m, 3H), 2.59-2.36 (m, 5H), 2.34-2.23 (m, 1H), 2.20-2.07 (m, 1H), 2.02-1.85 (m, 4H), 1.69-1.54 (m, 4H). D29 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.52 (s, 2H, FA), 8.22 (s, 1H), [M + H].sup.+ = 853.45. 7.86-7.76 (m, 2H), 7.46 (dd, J = 8.3, 2.4 Hz, 2H), 7.05 (s, 2H), 5.09 (dd, J = 12.5, 5.2 Hz, 1H), 4.55 (d, J = 13.7 Hz, 1H), 4.48 (s, 2H), 4.34-4.26 (m, 2H), 4.20 (t, J = 8.2 Hz, 4H), 4.14-4.05 (m, 2H), 4.02 (s, 6H), 3.74 (s, 3H), 3.29-3.18 (m, 1H), 2.86-2.60 (m, 6H), 2.58-2.46 (m, 2H), 2.14-1.87 (m, 7H), 1.69-1.44 (m, 2H). D30 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6 with a drop of D2O) δ 9.07 (d, J = [M + H].sup.+ = 922.35 8.5 Hz, 1H, FA salt), 8.49 (s, 1H), 7.91 (s, 1H), 7.76 (dd, J = 8.5, 7.3 Hz, 1H), 7.42 (dd, J = 11.9, 7.9 Hz, 2H), 6.92 (s, 2H), 5.01 (dd, J = 12.8, 5.5 Hz, 1H), 4.53 (br s, 1H), 4.28 (s, 4H), 3.85-3.31 (m, 6H), 3.78 (s, 4H), 3.60 (s, 3H), 3.55 (d, J = 5.6 Hz, 2H), 3.35- 3.21 (m, 3H), 2.87-2.55 (m, 10H), 2.48-2.40 (m, 2H), 2.09- 1.93 (m, 3H). D31 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.27 (s, 1H), 8.14 [M + H].sup.+ = 925.15. (s, 0.4H, FA), 7.98 (dd, J = 5.3, 3.5 Hz, 2H), 7.96-7.86 (m, 2H), 7.79 (d, J = 7.0 Hz, 2H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.03 (dd, J = 13.0, 7.8 Hz, 2H), 6.86 (s, 1H), 6.48 (t, J = 5.9 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 3.85 (s, 2H), 3.71 (d, J = 16.7 Hz, 1H), 3.60 (s, 3H), 3.52-3.37 (m, 2H), 3.23 (q, J = 6.5 Hz, 3H), 2.99 (d, J = 6.6 Hz, 2H), 2.88 (ddd, J = 16.7, 13.7, 5.2 Hz, 1H), 2.59 (d, J = 18.0 Hz, 2H), 2.49-2.41 (m, 1H), 2.22 (s, 1H), 2.06-1.94 (m, 1H), 1.66-1.45 (m, 2H), 1.42-1.00 (m, 11H). D32 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1.0H, FA), 8.21 (s, [M + H].sup.+ = 886.20 1H), 7.78 (s, 1H), 7.64 (dd, J = 8.6, 7.2 Hz, 1H), 7.33 (dd, J = 7.8, 2.1 Hz, 2H), 6.88 (s, 2H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.32- 4.26 (m, 2H), 4.17-4.08 (m, 1H), 4.02 (s, 2H), 3.92 (s, 6H), 3.90- 3.86 (m, 2H), 3.73 (s, 3H), 3.69 (t, J = 5.2 Hz, 2H), 3.54-3.43 (m, 6H), 3.09 (t, J = 12.2 Hz, 2H), 2.91-2.80 (m, 4H), 2.78-2.61 (m, 2H), 2.56 (s, 3H), 2.27-2.18 (m, 2H), 2.14-2.06 (m, 1H), 2.02-1.89 (m, 2H). D33 LCMS (ESI) m/z: [M + H]+ = 921.65 D34 LCMS (ESI) m/z: [M + H]+ = 921.45 D35 LCMS (ESI) m/z: [M + H]+ = 935.6 D36 LCMS (ESI) m/z: [M + H]+ = 907.4 D37 LCMS (ESI) m/z: [M + H]+ = 893.45 D38 LCMS (ESI) m/z: [M + H]+ = 879.25 D39 LCMS (ESI) m/z: [M + H]+ = 893.5 D40 LCMS (ESI) m/z: [M + H]+ = 921.75 D41 LCMS (ESI) m/z: [M + H]+ = 893.15 D42 LCMS (ESI) m/z: [M + H]+ = 907.65 D43 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.82-8.73 (m, [M + H]+ = 893.3 1H), 8.36 (d, J = 4.1 Hz, 1H), 8.22 (s, 2H, FA), 7.92 (d, J = 4.3 Hz, 1H), 7.65 (dd, J = 8.5, 6.6 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.26- 7.18 (m, 1H), 6.91 (s, 2H), 5.11-5.00 (m, 1H), 3.85 (d, J = 2.3 Hz, 6H), 3.61 (d, J = 3.9 Hz, 6H), 3.45-3.38 (m, 4H), 3.25 (t, J = 5.8 Hz, 1H), 3.19 (t, J = 6.5 Hz, 1H), 2.93-2.83 (m, 1H), 2.72-2.66 (m, 1H), 2.65-2.60 (m, 2H), 2.59-2.53 (m, 7H), 2.48-2.44 (m, 3H), 2.26 (d, J = 2.3 Hz, 8H), 2.05-1.94 (m, 3H), 1.55 (dd, J = 12.5, 6.1 Hz, 1H), 1.46-1.36 (m, 1H), 1.08-0.97 (m, 1H). D44 LCMS (ESI) m/z: [M + H]+ = 893.3 D45 929.45 D46 943.45 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.22 (s, 1H, FA), 7.96 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 6.92 (s, 2H), 6.81 (s, 1H), 6.73-6.63 (m, 1H), 5.06 (dd, J = 12.6, 5.4 Hz, 1H), 4.75-4.07 (m, 4H), 4.04-3.93 (m, 4H), 3.85 (s, 6H), 3.63 (s, 4H), 3.54-3.51 (m, 4H), 2.93- 2.55 (m, 8H), 2.20 (s, 7H), 2.12-2.00 (m, 3H), 1.93-1.82 (m, 2H). D47 LCMS (ESI) m/z: [M + H]+ = 461.45 D48 LCMS (ESI) m/z: [M + H]+ = 951.4 D49 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.97 (t, J = 5.8 Hz, [M + H]+ = 937.4 1H), 8.40 (s, 1H), 8.16 (s, 1H FA), 7.99 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.6, 2.2 Hz, 1H), 6.99 (s, 2H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 4.09 (t, J = 6.5 Hz, 1H), 4.00 (s, 2H), 3.90 (s, 6H), 3.62 (s, 3H), 3.60-3.49 (m, 4H), 3.46- 3.42 (m, 6H), 3.02-2.60 (m, 9H), 2.59-2.55 (m, 7H), 2.37 (t, J = 7.0 Hz, 2H), 2.07-1.87 (m, 3H), 1.78-1.68 (m, 2H), 1.67-1.57 (m, 4H), 1.49-1.39 (m, 1H). D50 LCMS (ESI) m/z: [M + H]+ = 923.4 D51 LCMS (ESI) m/z: [M + H]+ = 907.4 D52 LCMS (ESI) m/z: [M + H]+ = 893.4 D53 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.80 (t, J = 5.7 Hz, [M + H].sup.+ = 879. 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (s, 2H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.58 (d, J = 12.5 Hz, 5H), 3.37 (d, J = 13.7 Hz, 8H), 3.24 (t, J = 6.2 Hz, 2H), 2.89 (td, J = 17.8, 15.7, 5.3 Hz, 1H), 2.69 (s, 3H), 2.55 (s, 3H), 2.34 (d, J = 6.2 Hz, 3H), 2.22 (s, 6H), 2.17 (d, J = 8.5 Hz, 1H), 2.01 (s, 1H), 1.89 (dd, J = 12.1, 6.6 Hz, 2H). D54 LCMS (ESI) m/z: [M + H]+ = 921.25 D55 LCMS (ESI) m/z: [M + H]+ = 907.35 D56 LCMS (ESI) m/z: [M + H]+ = 454.5 D57 LCMS (ESI) m/z: [M + H]+ = 893.35 D58 LCMS (ESI) m/z: [M + H]+ = 907.35 D59 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H, FA), 7.83-7.74 [M + H].sup.+ = 863.50. (m, 1H), 7.67 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 1.9 Hz, 1H), 7.06 (s, 2H), 5.10 (dd, J = 12.2, 5.4 Hz, 1H), 4.36 (s, 2H), 4.27 (t, J = 6.1 Hz, 2H), 4.02 (s, 6H), 3.74 (s, 3H), 3.24-3.17 (m, 1H), 3.03-2.93 (m, 2H), 2.88 (s, 6H), 2.83-2.67 (m, 3H), 2.57- 2.42 (m, 3H), 2.27 (t, J = 11.1 Hz, 1H), 2.19-2.09 (m, 2H), 1.99- 1.88 (m, 3H), 1.71-1.57 (m, 4H). D60 D61 LCMS (ESI) m/z: [M + H]+ = 469.3 D62 LCMS (ESI) m/z: [M + H]+ = 909.2 D63 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.10 (d, J = 3.2 Hz, 1H), 8.86 [M + H]+ = 893.25 (dd, J = 26.1, 5.8 Hz, 1H), 8.55 (d, J = 38.1 Hz, 1H), 8.15 (s, 1H, FA), 8.04-7.87 (m, 1H), 7.66 (dd, J = 25.8, 8.5 Hz, 1H), 7.38- 7.24 (m, 1H), 7.20-7.07 (m, 1H), 7.03-6.90 (m, 2H), 5.08 (dd, J = 12.7, 6.4 Hz, 1H), 4.37-4.25 (m, 1H), 4.04 (s, 2H), 3.89 (d, J = 15.0 Hz, 6H), 3.77-3.53 (m, 7H), 3.45-3.41 (m, 3H), 3.24 (s, 3H), 3.16-3.04 (m, 2H), 3.03-2.73 (m, 4H), 2.64-2.55 (m, 10H), 2.41-2.36 (m, 2H), 2.05-1.85 (m, 2H). D64 LCMS (ESI) m/z: [M + H]+ = 865.25 D65 LCMS (ESI) m/z: [M + H]+ = 879.35 D66 LCMS (ESI) m/z: [M + H]+ = 879.3 D67 921.5  D68 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.80 (dd, J = 11.0, [M + H]+ = 893.5 5.8 Hz, 1H), 8.54 (s, 1H), 8.14 (s, 1H FA), 8.01-7.92 (m, 1H), 7.65 (dd, J = 18.7, 8.5 Hz, 1H), 7.37-7.15 (m, 2H), 6.99 (d, J = 11.3 Hz, 2H), 5.11-5.01 (m, 1H), 4.48-4.20 (m, 2H), 4.13 (s, 2H), 3.92 (s, 6H), 3.62 (d, J = 9.3 Hz, 3H), 3.48-3.36 (m, 10H), 2.98-2.72 (m, 4H), 2.70-2.59 (m, 9H), 2.42-2.34 (m, 1H), 2.14- 1.92 (m, 2H), 1.78-1.56 (m, 3H). D69 LCMS (ESI) m/z: [M + H]+ = 879.4 D70 LCMS (ESI) m/z: [M + H]+ = 865.25 D71 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 7.81 (d, J = 8.3 Hz, 1H), 7.46 [M + H].sup.+ = 813.25. (s, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.4, 2.3 Hz, 1H), 6.95 (s, 2H), 6.41 (s, 1H), 5.11 (dd, J = 12.4, 5.4 Hz, 1H), 4.37 (d, J = 13.5 Hz, 1H), 4.22 (t, J = 5.8 Hz, 2H), 4.06 (s, 2H), 3.99-3.92 (m, 7H), 3.71 (s, 3H), 3.59-3.51 (m, 1H), 3.06-2.93 (m, 1H), 2.91-2.68 (m, 4H), 2.66-2.51 (m, 8H), 2.23-2.05 (m, 3H), 1.96- 1.82 (m, 4H), 1.54-1.35 (m, 2H). D72 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.04-8.96 (m, [M + H]+ = 907.45 1H), 8.39 (s, 1H), 8.29 (s, 2H, FA), 7.94 (s, 1H), 7.68 (dd, J = 8.5, 3.4 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 6.91- 6.86 (m, 2H), 5.07 (dd, J = 12.7, 5.3 Hz, 1H), 4.44-4.34 (m, 1H), 3.84 (s, 6H), 3.62 (s, 4H), 3.53-3.48 (m, 10H), 2.93-2.82 (m, 2H), 2.63-2.55 (m, 6H), 2.33-2.23 (m, 3H), 2.21-2.07 (m, 9H), 2.00-1.80 (m, 3H). D73 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.01-8.92 (m, [M + H]+ = 893.3 1H), 8.39 (s, 1H), 8.23 (s, 3H, FA), 7.95 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.91 (s, 2H), 5.08 (dd, J = 12.7, 5.3 Hz, 1H), 4.33-4.24 (m, 1H), 3.85 (s, 6H), 3.62 (s, 5H), 3.44 (s, 5H), 2.97-2.81 (m, 2H), 2.77-2.69 (m, 3H), 2.64-2.53 (m, 5H), 2.39-2.33 (m, 3H), 2.27 (s, 6H), 2.17-2.09 (m, 2H), 2.04-1.84 (m, 4H), 1.68 (s, 2H). D74 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.00-8.93 (m, [M + H]+ = 893.3 1H), 8.37 (s, 1H), 8.20 (s, 1H, FA), 7.95 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.30-7.23 (m, 1H), 6.91 (s, 2H), 5.08 (dd, J = 12.8, 5.3 Hz, 1H), 4.31-4.19 (m, 2H), 4.12 (s, 1H), 3.92 (s, 1H), 3.87-3.80 (m, 7H), 3.63-3.56 (m, 6H), 3.45-3.40 (m, 8H), 2.91-2.83 (m, 1H), 2.64-2.55 (m, 5H), 2.32-2.20 (m, 10H), 2.08-1.96 (m, 1H). D75 LCMS (ESI) m/z: [M + H]+ = 879.45 D76 LCMS (ESI) m/z: [M + H]+ = 907.35 D77 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.24 (s, 1H), 7.87 (s, 1H), 7.80 [M + H].sup.+ = 867.50. (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.39 (dd, J = 8.6, 2.3 Hz, 1H), 7.07 (s, 2H), 5.12 (dd, J = 12.3, 5.4 Hz, 1H), 4.60 (d, J = 14.2 Hz, 1H), 4.42 (s, 2H), 4.40-4.29 (m, 2H), 4.20-4.12 (m, 1H), 4.02 (s, 7H), 3.87-3.78 (m, 2H), 3.75 (s, 4H), 3.66-3.45 (m, 4H), 3.21-3.12 (m, 1H), 2.99-2.89 (m, 8H), 2.86-2.70 (m, 3H), 2.19-2.07 (m, 3H), 1.72-1.57 (m, 2H). D78 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.09 (s, 1H), 8.66 (d, J = 7.6 Hz, [M + H].sup.+ = 881.50. 1H), 8.41 (s, 1H), 8.23 (s, 1H, FA), 7.95 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 8.7, 2.3 Hz, 1H), 6.91 (s, 2H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.35 (d, J = 13.1 Hz, 1H), 4.05-3.92 (m, 3H), 3.85 (s, 6H), 3.62 (s, 3H), 3.57 (s, 2H), 3.47-3.41 (m, 6H), 3.17-3.11 (m, 1H), 2.94-2.83 (m, 1H), 2.76- 2.66 (m, 1H), 2.61-2.55 (m, 7H), 2.22 (s, 6H), 2.06-1.98 (m, 1H), 1.92-1.79 (m, 2H), 1.55-1.32 (m, 2H). D79 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.35 (d, J = 1.6 Hz, 1H), 7.88 [M + H].sup.+ = 889.25 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.08 (s, 2H), 5.13 (dd, J = 12.1, 5.3 Hz, 1H), 4.58- 4.45 (m, 1H), 4.42 (s, 2H), 4.02 (s, 6H), 3.87-3.77 (m, 4H), 3.76 (s, 3H), 3.69-3.57 (m, 4H), 3.49-3.38 (m, 3H), 3.16 (d, J = 11.8 Hz, 1H), 3.03-2.97 (m, 2H), 2.92 (s, 6H), 2.90-2.70 (m, 3H), 2.70-2.41 (m, 2H), 2.19-1.94 (m, 3H). D80 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 2H, FA), 8.32 (s, 1H), [M + H].sup.+ = 841.35 7.87 (s, 1H), 7.80 (dd, J = 8.6, 7.3 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 2H), 7.06 (s, 2H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.41-4.31 (m, 4H), 4.23-4.17 (m, 1H), 4.02 (s, 6H), 3.99-3.82 (m, 1H), 3.75 (s, 3H), 3.49-3.38 (m, 2H), 2.89 (s, 6H), 2.88-2.82 (m, 4H), 2.78-2.65 (m, 2H), 2.23-2.12 (m, 3H), 2.06-1.93 (m, 8H), 1.86-1.75 (m, 2H). D81 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.79 (s, 1H), 8.37 [M + H].sup.+ = 828.30. (s, 1H), 8.23 (s, 2H FA), 7.94 (s, 1H), 7.81 (dd, J = 8.5, 7.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 6.91 (s, 2H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.23 (t, J = 6.1 Hz, 2H), 3.84 (s, 6H), 3.62 (s, 3H), 3.53 (s, 2H), 3.17-3.11 (m, 3H), 2.93-2.88 (m, 2H), 2.64-2.59 (m, 2H), 2.42-2.31 (m, 3H), 2.19 (s, 6H), 2.07-1.98 (m, 1H), 1.95-1.84 (m, 2H), 1.81-1.74 (m, 2H), 1.71- 1.54 (m, 5H), 1.30-1.08 (m, 3H). D82 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.56 (s, 2H, FA), 8.27 (s, 1H), [M + H]+ = 838.98. 7.87-7.77 (m, 2H), 7.47 (dd, J = 7.7, 2.6 Hz, 2H), 7.03 (s, 2H), 5.21-5.10 (m, 1H), 4.30 (t, J = 5.7 Hz, 2H), 4.24 (s, 2H), 4.17- 4.08 (m, 1H), 4.00 (s, 7H), 3.75 (s, 3H), 3.29-3.14 (m, 2H), 3.10- 2.98 (m, 2H), 2.95-2.86 (m, 1H), 2.81-2.69 (m, 9H), 2.50 (dd, J = 15.0, 8.0 Hz, 1H), 2.21-2.11 (m, 1H), 2.04-1.80 (m, 7H), 1.74-1.63 (m, 2H). D83 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.11 (s, 1H), 9.40 (s, 1H, TFA), [M + H].sup.+ = 863. 8.63 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.3, 2.3 Hz, 1H), 7.02 (s, 2H), 5.13 (dd, J = 12.8, 5.4 Hz, 1H), 4.26 (dd, J = 9.4, 5.4 Hz, 4H), 3.93 (s, 7H), 3.63 (s, 4H), 3.40 (d, J = 1.3 Hz, 1H), 3.02-2.82 (m, 3H), 2.76 (d, J = 4.7 Hz, 7H), 2.66-2.53 (m, 2H), 2.53-2.52 (m, 1H), 2.26-1.90 (m, 7H), 1.77 (s, 1H), 1.60 (s, 1H). D84 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.82 (t, J = 8.0 Hz, [M + H]+ = 845.40. 1H), 8.48 (d, J = 67.2 Hz, 1H), 8.19 (s, 1H, FA), 7.96 (d, J = 2.3 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 6.93 (s, 2H), 6.57 (s, 1H), 5.09 (dd, J = 12.9, 5.5 Hz, 1H), 4.81-4.45 (m, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.86 (s, 6H), 3.65-3.61 (m, 4H), 3.15-3.08 (m, 1H), 2.95-2.78 (m, 3H), 2.62- 2.57 (m, 2H), 2.34-2.25 (m, 7H), 2.20-1.92 (m, 4H), 1.90- 1.73 (m, 3H), 1.66-1.36 (m, 6H). D85 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.85 (d, J = 8.0 Hz, [M + H].sup.+ = 845.35 1H), 8.50 (d, J = 66.8 Hz, 1H), 8.14 (s, 1H, FA), 8.00 (d, J = 1.1 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.3, 2.2 Hz, 1H), 7.03 (s, 2H), 6.53 (s, 1H), 5.13 (dd, J = 13.0, 5.3 Hz, 1H), 4.27-4.17 (m, 4H), 3.93 (s, 7H), 3.64 (d, J = 1.5 Hz, 3H), 2.96-2.84 (m, 2H), 2.76 (s, 6H), 2.63-2.58 (m, 2H), 2.47-2.34 (m, 2H), 2.12-1.95 (m, 3H), 1.89-1.68 (m, 3H), 1.66- 1.40 (m, 5H), 1.30-1.21 (m, 1H). D86 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, Methanol-d4) δ 8.31 (br s, 1H, FA), 8.27 (s, [M + H]+ = 881.45. 1H), 7.88 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.06 (s, 2H), 5.10 (dd, J = 12.4, 5.3 Hz, 1H), 4.42 (s, 2H), 4.22-4.12 (m, 1H), 4.02 (s, 6H), 3.75 (s, 3H), 3.69-3.53 (m, 7H), 3.22-3.08 (m, 4H), 2.92 (s, 9H), 2.82-2.69 (m, 5H), 2.26 (d, J = 14.0 Hz, 2H), 2.16-1.95 (m, 3H), 1.93-1.81 (m, 2H), 1.81-1.67 (m, 2H). D87 LCMS (ESI) m/z: .sup.1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.61 (d, J = 7.9 Hz, [M + H]+ = 841.35. 1H), 8.39 (s, 1H), 8.18 (s, 1H, FA), 7.93 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.91 (s, 2H), 5.11 (dd, J = 13.0, 5.3 Hz, 1H), 4.19 (t, J = 6.4 Hz, 2H), 4.03 (s, 1H), 3.85 (s, 6H), 3.64-3.56 (m, 5H), 2.75-2.72 (m, 1H), 2.69-2.60 (m, 3H), 2.60-2.53 (m, 4H), 2.30-2.22 (m, 7H), 1.97- 1.66 (m, 8H), 1.60-1.43 (m, 5H). D88 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.60 (d, J = 7.9 Hz, [M + H].sup.+ = 841.35. 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.19 (s, 2H, FA), 7.92 (s, 1H), 7.87- 7.74 (m, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 7.2, 2.6 Hz, 1H), 6.90 (s, 2H), 5.11-5.04 (m, 1H), 4.23 (t, J = 6.3 Hz, 2H), 4.03 (s, 1H), 3.85 (s, 6H), 3.61 (s, 3H), 3.55 (s, 2H), 2.93-2.84 (m, 1H), 2.78-2.70 (m, 1H), 2.69-2.54 (m, 7H), 2.21 (s, 6H), 2.08-1.99 (m, 1H), 1.93-1.70 (m, 7H), 1.59-1.47 (m, 5H). D89 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.61 (d, J = 7.7 Hz, [M + H]+ = 827.35. 1H), 8.42 (s, 1H), 8.21 (s, 1H, FA), 7.94 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.3, 2.3 Hz, 1H), 6.91 (s, 2H), 5.12 (dd, J = 13.0, 5.4 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.84 (s, 6H), 3.74-3.67 (m, 1H), 3.62 (s, 3H), 3.55 (s, 2H), 2.95-2.84 (m, 3H), 2.64-2.54 (m, 2H), 2.35-2.29 (m, 2H), 2.21 (s, 6H), 2.07-1.94 (m, 3H), 1.83-1.73 (m, 4H), 1.62-1.42 (m, 6H). D90 LCMS (ESI) m/z: .sup.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.88 (d, J = 8.8 Hz, [M + H]+ = 863.35.. 1H), 8.60 (s, 1H), 8.15 (s, 0.3H, FA), 7.98 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.3, 2.3 Hz, 1H), 6.97 (s, 2H), 6.53 (s, 0.3H, FA salt), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 4.35 (s, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.88 (s, 6H), 3.82 (s, 2H), 3.63 (s, 3H), 3.15 (s, 1H), 2.95-2.84 (m, 2H), 2.65-2.55 (m, 3H), 2.44 (s, 8H), 2.18 (t, J = 11.3 Hz, 1H), 2.10-2.01 (m, 1H), 1.91-1.74 (m, 4H), 1.57-1.41 (m, 4H).

Example 30—Preparation of Compounds D91-D220, DD1, and DD2

[1046] In analogy to the procedures described in the examples above, compounds D91-D220, DD1, and DD2 were prepared using the appropriate starting materials

TABLE-US-00011 Compound No. LCMS .sup.1H NMR D91 662.30 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.27-8.21 (m, 1H), 7.92 (s, 1H), 7.74-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.56-7.50 (m, 1H), 6.99 (s, 2H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.53-4.38 (m, 2H), 4.18-4.10 (m, 2H), 4.10-4.01 (m, 2H), 3.97 (s, 6H), 3.83-3.74 (m, 2H), 3.71 (s, 3H), 3.67-3.57 (m, 1H), 2.99-2.85 (m, 1H), 2.84-2.75 (m, 1H), 2.56-2.40 (m, 1H), 2.26-2.15 (m, 1H). D92 637.35 .sup.1H NMR (300 MHz, Methanol-d4) δ 7.82-7.78 (m, 1H), 7.73 (s, 1H), 7.70-7.64 (m, 2H), 7.60-7.52 (m, 2H), 7.05 (s, 2H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.58-4.42 (m, 2H), 4.27 (s, 2H), 4.24- 4.15 (m, 2H), 4.00 (s, 6H), 3.97-3.89 (m, 2H), 3.80-3.70 (m, 4H), 3.03-2.75 (m, 2H), 2.60-2.41 (m, 1H), 2.29-2.16 (m, 1H). D93 674.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.68 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38- 7.22 (m, 3H), 7.19 (t, J = 1.9 Hz, 1H), 7.15-7.06 (m, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.41-4.18 (m, 2H), 4.06-3.92 (m, 3H), 3.80-3.76 (m, 3H), 3.60 (s, 3H), 3.02-2.83 (m, 3H), 2.60 (d, J = 16.5 Hz, 1H), 2.48-2.31 (m, 1H), 1.96 (dd, J = 27.3, 11.8 Hz, 3H), 1.70 (d, J = 12.2 Hz, 2H). D94 808.55 .sup.1H NMR (300 MHz, Methanol-d4) δ 7.53-7.48 (m, 2H), 7.40- 7.33 (m, 2H), 7.01-6.98 (m, 2H), 6.28 (s, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.51-4.42 (m, 2H), 4.41-4.35 (m, 2H), 4.06-3.96 (m, 10H), 3.71 (s, 3H), 3.49-3.40 (m, 4H), 3.25-3.07 (m, 6H), 3.02-2.85 (m, 3H), 2.84-2.76 (m, 1H), 2.60-2.51 (m, 1H), 2.50- 2.40 (m, 2H), 2.25-2.14 (m, 1H), 2.11-1.97 (m, 2H), 1.83- 1.48 (m, 5H). D95 605.36 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.49 (s, 1H), 8.67 (s, 1H), 8.23-8.16 (m, 1H), 8.00 (s, 1H), 7.52 (t, J = 2.2 Hz, 1H), 7.38 (dd, J = 7.8, 1.9 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 6.94 (s, 2H), 6.80 (dd, J = 8.0, 2.5 Hz, 1H), 5.17 (dd, J = 10.7, 5.2 Hz, 1H), 3.86 (s, 6H), 3.64 (s, 3H), 3.63-3.55 (m, 2H), 2.81-2.70 (m, 1H), 2.68- 2.56 (m, 1H), 2.32-2.10 (m, 8H). D96 631.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.46 (s, 1H), 7.96 (s, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H), 6.70-6.61 (m, 3H), 6.51 (d, J = 8.0 Hz, 1H), 5.26 (dd, J = 10.4, 5.2 Hz, 1H), 4.01 (s, 1H), 3.89 (s, 6H), 3.82 (d, J = 12.1 Hz, 2H), 3.67 (s, 3H), 2.88 (q, J = 10.2, 8.1 Hz, 2H), 2.81- 2.62 (m, 2H), 2.31-2.12 (m, 2H), 1.94 (d, J = 12.2 Hz, 2H), 1.81- 1.64 (m, 2H). D97 711.20 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H, FA), 7.43 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.01-6.91 (m, 3H), 6.85 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.29 (s, 1H), 5.16-5.08 (m, 1H), 4.44-4.30 (m, 2H), 4.18-3.99 (m, 2H), 3.98-3.92 (m, 6H), 3.75-3.67 (m, 7H), 3.62 (s, 1H), 3.08-2.95 (m, 2H), 2.88 (s, 3H), 2.82-2.70 (m, 1H), 2.50-2.39 (m, 1H), 2.22-2.11 (m, 1H), 2.05-2.00 (m, 4H). D98 789.2 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.86 (s, 1H), 8.57 (s, 1H, FA), 7.92 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.23-7.05 (m, 2H), 6.79 (d, J = 2.3 Hz, 2H), 6.60-6.50 (m, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.42-4.12 (m, 3H), 3.90- 3.73 (m, 8H), 3.60 (s, 3H), 3.24-3.09 (m, 1H), 3.00-2.84 (m, 2H), 2.82-2.69 (m, 2H), 2.64-2.54 (m, 2H), 2.46-2.32 (m, 2H), 2.27-2.07 (m, 1H), 2.03-1.95 (m, 1H), 1.93-1.72 (m, 4H), 1.66- 1.49 (m, 2H). D99 779.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.16 (s, FA, 1H), 7.88 (s, 1H), 7.70 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 5.3 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.97 (s, 2H), 6.73-6.61 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.14 (m, 2H), 3.88 (s, 6H), 3.81 (s, 2H), 3.62 (s, 3H), 3.58 (s, 4H), 3.13-3.02 (m, 2H), 2.99-2.78 (m, 2H), 2.64-2.55 (m, 1H), 2.47-2.38 (m, 2H), 2.38-2.20 (m, 4H), 2.19-2.06 (m, 2H), 2.03-1.92 (m, 1H), 1.87-1.53 (m, 7H), 1.32- 1.06 (m, 2H). D100 809.55 .sup.1H NMR (300 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.01 (s, 2H), 6.88 (s, 1H), 6.83-6.78 (m, 1H), 6.76 (s, 1H), 5.14 (dd, J = 13.2, 5.2 Hz, 1H), 4.56-4.30 (m, 4H), 4.04- 3.97 (m, 9H), 3.86-3.76 (m, 3H), 3.75-3.71 (m, 4H), 3.69-3.53 (m, 4H), 3.36-3.34 (m, 1H), 3.23-3.07 (m, 5H), 2.99-2.78 (m, 2H), 2.62-2.43 (m, 1H), 2.37-1.99 (m, 9H), 1.72-1.61 (m, 1H). D101 804.55 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.61 (s, 1H) FA, 8.36 (s, 1H), 8.04 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.10 (s, 2H), 6.94-6.88 (m, 1H), 6.87-6.81 (m, 1H), 5.20 (dd, J = 13.2, 5.1 Hz, 1H), 4.54- 4.39 (m, 4H), 4.08 (s, 6H), 3.81 (s, 3H), 3.76-3.72 (m, 4H), 3.65- 3.55 (m, 2H), 3.26-3.11 (m, 2H), 3.02-2.81 (m, 2H), 2.77- 2.40 (m, 7H), 2.31-2.18 (m, 1H), 2.16-2.07 (m, 2H), 2.00 (s, 5H), 1.72-1.49 (m, 2H). D102 874.5 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.88 (d, J = 8.9 Hz, 1H), 8.59 (s, 1H), 8.17 (s, 2H, FA), 7.96 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 7.9 Hz, 2H), 6.93 (s, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.38-4.16 (m, 3H), 3.85 (s, 8H), 3.63 (s, 5H), 3.19-3.14 (m, 2H), 2.95-2.76 (m, 5H), 2.64-2.58 (m, 1H), 2.41-2.36 (m, 2H), 2.26 (d, J = 4.0 Hz, 6H), 2.21-2.15 (m, 1H), 2.00-1.86 (m, 2H), 1.82-1.73 (m, 3H), 1.54-1.50 (m, 1H), 1.46-1.38 (m, 2H), 1.30-1.19 (m, 2H). D103 650.2 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.42 (d, 1H), 8.46 (s, 1H), 8.06-7.94 (m, 3H), 7.86-7.73 (m, 2H), 7.42 (d, 1H), 6.82- 6.72 (m, 2H), 5.11 (dd, 1H), 4.91-4.78 (m, 1H), 4.42-4.15 (m, 4H), 3.89-3.79 (m, 2H), 3.61 (s, 3H), 3.01-2.83 (m, 1H), 2.66- 2.53 (m, 1H), 2.45-2.28 (m, 1H), 2.05-1.95 (m, 1H). D104 927.45 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.14-9.84 (m, 2H, TFA), 9.07 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 2.9 Hz, 2H), 6.54-6.45 (m, 2H), 5.05 (dd, J = 13.2, 5.2 z, 1H), 4.71-4.57 (m, 1H), 4.43-4.33 (m, 2H), 4.31- 4.16 (m, 4H), 4.08-4.00 (m, 2H), 3.93 (s, 6H), 3.78 (s, 2H), 3.69 (s, 3H), 3.51 (s, 5H), 3.45 (s, 2H), 3.39 (s, 2H), 3.19 (s, 2H), 3.01- 2.89 (m, 3H), 2.80 (s, 3H), 2.70-2.54 (m, 1H), 2.38-2.32 (m, 1H), 2.10 (s, 4H), 1.94 (d, J = 14.0 Hz, 3H). D105 688.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.07 (s, 1H, TFA), 8.84-8.76 (m, 1H), 8.48 (s, 1H), 8.01 (s, 1H), 7.40-7.18 (m, 2H), 7.09-7.02 (m, 4H), 5.21-5.13 (m, 1H), 4.26 (d, J = 5.0 Hz, 2H), 4.15-4.01 (m, 2H), 3.93 (s, 6H), 3.64 (s, 3H), 3.30-3.14 (m, 2H), 2.78 (d, J = 4.5 Hz, 6H), 2.75-2.71 (m, 1H), 2.70-2.61 (m, 2H), 2.23-2.13 (m, 2H), 2.06-1.97 (m, 2H), 1.93-1.82 (m, 2H). D106 696.3 .sup.1H NMR (300 MHz, Methanol-d4) δ 7.78-7.67 (m, 2H), 7.60 (d, J = 5.4 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.37-7.28 (m, 2H), 7.04 (s, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.49-4.32 (m, 2H), 4.20 (s, 2H), 3.98 (s, 6H), 3.76 (s, 3H), 3.60 (s, 1H), 3.47 (d, J = 10.6 Hz, 2H), 3.25-3.12 (m, 3H), 3.00-2.80 (m, 4H), 2.51 (dd, J = 12.9, 4.8 Hz, 1H), 2.24-2.03 (m, 5H), 1.84 (s, 2H). D107 825.4 .sup.1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H, FA), 7.86 (s, 1H), 7.68 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 6.93 (s, 2H), 6.78 (s, 1H), 6.65 (dd, J = 8.4, 2.2 Hz, 1H), 5.78-5.68 (m, 1H), 5.63 (dd, J = 9.5, 4.0 Hz, 1H), 5.28-5.19 (m, 1H), 3.85 (s, 6H), 3.74 (s, 4H), 3.61 (s, 3H), 3.56 (s, 2H), 3.51 (s, 1H), 3.22-3.16 (m, 2H), 3.12-2.98 (m, 2H), 2.87-2.78 (m, 1H), 2.65-2.54 (m, 2H), 2.47-2.38 (m, 2H), 2.11-2.03 (m, 1H), 1.87- 1.80 (m, 1H), 1.76-1.72 (m, 4H), 0.89-0.83 (m, 3H), 0.83- 0.77 (m, 3H). D108 688.35 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.56 (s, 1H, FA salt), 8.24 (s, 1H), 7.84 (s, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.05 (s, 2H), 6.74-6.64 (m, 2H), 6.57 (d, J = 8.2 Hz, 1H), 5.09 (dd, J = 9.6, 4.8 Hz, 1H), 4.34 (s, 2H), 4.01 (s, 7H), 3.74 (s, 5H), 2.94-2.88 (m, 1H), 2.85 (s, 6H), 2.81-2.71 (m, 3H), 2.43-2.13 (m, 2H), 2.10-2.00 (m, 2H), 1.85-1.75 (m, 2H). D109 670.2 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.86 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.38-7.32 (m, 1H), 7.29 (s, 1H), 6.77 (d, J = 2.2 Hz, 2H), 6.56 (t, J = 2.2 Hz, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.42-4.17 (m, 2H), 3.98 (s, 1H), 3.82-3.71 (m, 8H), 3.58 (s, 3H), 3.04-2.80 (m, 3H), 2.61 (d, J = 17.7 Hz, 1H), 2.41-2.30 (m, 1H), 2.05-1.87 (m, 3H), 1.71 (dd, J = 22.0, 10.0 Hz, 2H). D110 724.3 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.57 (s, 1H, FA salt), 7.68 (s, 1H), 7.44-7.35 (m, 2H), 7.00 (s, 2H), 6.87 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.2, 2.3 Hz, 1H), 5.14 (dd, J = 13.1, 5.1 Hz, 1H), 4.48- 4.30 (m, 2H), 4.14 (s, 2H), 3.98 (s, 6H), 3.73 (s, 7H), 3.33-3.20 (m, 1H), 3.08 (s, 4H), 2.99-2.73 (m, 2H), 2.58-2.41 (m, 1H), 2.17 (d, J = 12.6 Hz, 1H), 2.07 (s, 4H), 1.41 (d, J = 6.8 Hz, 6H). D111 718.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.89 (s, 1H), 7.74- 7.55 (m, 2H), 7.39 (d, J = 8.8 Hz, 1H), 6.95 (s, 2H), 6.77-6.67 (m, 2H), 5.17-5.00 (m, 1H), 4.42-4.11 (m, 2H), 3.87 (s, 8H), 3.72- 3.55 (m, 7H), 3.02-2.81 (m, 1H), 2.75-2.54 (m, 4H), 2.46-2.28 (m, 2H), 2.00 (s, 3H). D112 875.45 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.42 (d, J = 15.6 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.08 (s, 2H), 5.27-5.10 (m, 1H), 4.44 (d, J = 14.5 Hz, 5H), 4.02 (s, 6H), 3.75 (s, 3H), 3.63 (s, 8H), 3.46 (s, 3H), 3.14 (d, J = 12.3 Hz, 1H), 3.01-2.89 (m, 9H), 2.90-2.77 (m, 1H), 2.78-2.38 (m, 3H), 2.26- 2.16 (m, 1H), 2.10-1.91 (m, 2H). D113 696.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H, FA), 7.80 (s, 1H), 7.69-7.56 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.28-7.13 (m, 2H), 7.01-6.88 (m, 2H), 5.04-4.89 (m, 1H), 4.31 (d, 2H), 4.19 (d, J = 16.2 Hz, 2H), 3.91-3.72 (m, 6H), 3.60 (s, 5H), 3.48 (s, 1H), 3.33- 2.91 (m, 4H), 2.90-2.71 (m, 2H), 2.71-2.56 (m, 1H), 2.43- 2.31 (m, 1H), 2.29-2.12 (m, 1H), 2.11-1.80 (m, 4H), 1.70 (d, J = 13.8 Hz, 1H), 1.48 (s, 1H). D114 713.35 .sup.1H NMR (300 MHz, DMSO-d6 + a drop of D2O) δ 8.45 (s, 1H), 7.97 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.01 (s, 2H), 6.91-6.83 (m, 1H), 6.80 (d, J = 2.3 Hz, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (t, J = 5.7 Hz, 1H), 4.38-4.10 (m, 4H), 3.92 (s, 6H), 3.53-3.45 (m, 1H), 3.42-3.36 (m, 3H), 3.39-3.25 (m, 3H), 2.92-2.75 (m, 1H), 2.77 (s, 6H), 2.66-2.54 (m, 1H), 2.43-2.24 (m, 2H), 2.17-2.07 (m, 1H), 2.05-1.95 (m, 1H). D115 642.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.39 (d, J = 7.1 Hz, 1H), 8.43 (s, 1H), 7.92 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.78 (dd, J = 6.6, 2.3 Hz, 4H), 6.58 (t, J = 2.2 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.84 (d, J = 6.8 Hz, 1H), 4.40-4.15 (m, 4H), 3.82 (s, 8H), 3.60 (s, 3H), 2.95-2.83 (m, 1H), 2.62 (s, 1H), 2.45-2.34 (m, 1H), 2.05-1.94 (m, 1H). D116 669.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.41 (d, J = 7.1 Hz, 1H), 8.45 (s, 1H), 8.16 (s, 0.2H, FA), 7.98 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.95 (s, 2H), 6.82-6.72 (m, 2H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.89-4.79 (m, 1H), 4.40-4.15 (m, 4H), 3.87 (s, 6H), 3.84- 3.74 (m, 4H), 3.62 (s, 3H), 2.95-2.83 (m, 1H), 2.63 (s, 1H), 2.39 (s, 7H), 2.05-1.95 (m, 1H). D117 718.3 .sup.1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 8.99 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 8.05-7.94 (m, 3H), 7.86-7.73 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.38-7.17 (m, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.48-4.40 (m, 1H), 4.39-4.18 (m, 2H), 3.62 (s, 3H), 3.31- 3.12 (m, 5H), 3.01-2.83 (m, 1H), 2.65-2.55 (m, 2H), 2.45-2.34 (m, 1H), 2.33-2.19 (m, 2H), 2.05-1.85 (m, 3H), 1.76-1.70 (m, 4H). D118 751.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.98-8.89 (m, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.15 (s, 0.2H, FA salt), 8.02 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.36 (dt, J = 8.6, 2.2 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.20-7.10 (m, 2H), 5.12 (dd, J = 13.2, 5.2, 1H), 4.70- 4.49 (m, 1H), 4.36 (d, J = 16.9 Hz, 1H), 4.29-4.08 (m, 2H), 3.91 (s, 3H), 3.87 (s, 1H), 3.62 (s, 5H), 3.51-3.42 (m, 1H), 3.21-3.08 (m, 1H), 3.01-2.83, (m, 1H), 2.66-2.55 (m, 1H), 2.45-2.37 (m, 1H), 2.27 (s, 6H), 2.08-1.92 (m, 3H). D119 726.35 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.56 (s, 1H, FA salt), 7.75 (s, 1H), 7.59 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.04 (s, 2H), 6.88 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 5.19-5.08 (m, 1H), 4.72 (s, 2H), 4.40 (d, J = 5.2 Hz, 2H), 4.27 (s, 2H), 4.00 (s, 6H), 3.82-3.62 (m, 8H), 3.42 (s, 3H), 3.24-3.18 (m, 3H), 3.00-2.71 (m, 2H), 2.56- 2.45 (m, 1H), 2.15-2.09 (m, 5H). D120 712.3 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.57 (s, 1H), 7.63 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 6.93 (s, 2H), 6.85 (d, J = 2.2 Hz, 1H), 6.80- 6.73 (m, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.47-4.27 (m, 2H), 4.02 (s, 5H), 3.95 (s, 6H), 3.72 (s, 3H), 3.70 (s, 4H), 3.06-2.72 (m, 6H), 2.60-2.37 (m, 1H), 2.23-2.11 (m, 1H), 2.01 (t, J = 5.6 Hz, 4H). D121 696.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H, FA), 7.83 (s, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 9.3 Hz, 2H), 6.91 (d, J = 1.9 Hz, 2H), 5.01 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 4.21 (d, 1H), 3.80 (d, J = 1.6 Hz, 7H), 3.71-3.60 (m, 6H), 3.50 (s, 1H), 3.28- 3.01 (m, 2H), 2.98-2.77 (m, 1H), 2.59 (d, J = 17.1 Hz, 4H), 2.39- 2.24 (m, 1H), 2.05-1.90 (m, 2H), 1.89-1.78 (m, 1H), 1.77-1.58 (m, 3H), 1.57-1.42 (m, 1H). D122 613.25 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.86 (s, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 5.3 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 6.96 (s, 2H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.33 (d, J = 16.4 Hz, 1H), 4.25-4.07 (m, 2H), 3.85 (s, 6H), 3.62 (s, 4H), 3.55-3.40 (m, 3H), 2.99-2.83 (m, 1H), 2.71-2.55 (m, 2H), 2.46-2.34 (m, 1H), 2.18-2.08 (m, 1H), 2.08-1.97 (m, 1H). D123 627.2 .sup.1H NMR (400 MHz, DMSO-d6 with a drop of D2O) δ 8.30 (s, 0.1H, FA), 7.82 (s, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.35-7.28 (m, 1H), 7.23-7.18 (m, 1H), 6.90 (s, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.40-4.18 (m, 2H), 3.88-3.78 (m, 8H), 3.60 (s, 3H), 3.42-3.32 (m, 1H), 2.97-2.83 (m, 1H), 2.82-2.70 (m, 2H), 2.68-2.55 (m, 1H), 2.49-2.31 (m, 3H), 2.05-1.97 (m, 1H), 1.55 (d, J = 12.4 Hz, 2H). D124 687.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.67 (d, J = 7.7 Hz, 1H), 8.41 (s, 1H), 8.22 (s, 1H, FA), 7.94 (s, 1H), 7.23-7.14 (m, 1H), 6.89 (d, J = 14.8 Hz, 4H), 6.67 (d, J = 7.4 Hz, 1H), 4.46 (s, 2H), 4.00-3.87 (m, 1H), 3.84 (s, 6H), 3.75 (s, 1H), 3.72 (s, 1H), 3.61 (s, 3H), 3.56 (s, 2H), 3.28 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 11.9 Hz, 2H), 2.54 (d, J = 6.8 Hz, 2H), 2.22 (s, 6H), 1.93-1.85 (m, 2H), 1.72-1.59 (m, 2H). D125 552.1 .sup.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.14-7.99 (m, 3H), 7.76-7.70 (m, 2H), 7.70-7.59 (m, 4H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (d, J = 17.5 Hz, 1H), 4.43 (d, J = 17.5 Hz, 1H), 3.63 (s, 3H), 3.00-2.87 (m, 1H), 2.70-2.58 (m, 1H), 2.45-2.32 (m, 1H), 2.11-2.01 (m, 1H). D126 846.4 .sup.1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 7.7 Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H, FA), 7.94 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.90 (s, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.16 (m, 2H), 4.01-3.97 (m, 1H), 3.90 (d, J = 12.3 Hz, 1H), 3.84 (s, 6H), 3.72 (d, J = 10.4 Hz, 1H), 3.78-3.56 (m, 3H), 3.52 (s, 2H), 3.07-3.02 (m, 1H), 2.98-2.82 (m, 5H), 2.64-2.55 (m, 3H), 2.52-2.28 (m, 1H), 2.19 (s, 6H), 2.03-1.87 (m, 3H), 1.82-1.77 (m, 2H), 1.58-1.51 (m, 2H). D127 846.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 7.6 Hz, 1H), 8.41 (s, 1H), 8.20 (s, 1H, FA), 7.94 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.17- 7.08 (m, 2H), 6.93 (s, 2H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.45- 4.16 (m, 2H), 4.12 (s, 1H), 4.01 (d, J = 12.4 Hz, 1H), 3.86 (s, 6H), 3.78-3.65 (m, 3H), 3.62 (s, 3H), 3.15 (d, J = 12.9 Hz, 1H), 3.05- 2.82 (m, 5H), 2.64-2.55 (m, 3H), 2.42-2.34 (m, 1H), 2.32 (s, 6H), 2.01-1.87 (m, 3H), 1.81-1.77 (m, 2H), 1.58-1.50 (m, 2H). D128 678.1 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.70 (d, J = 7.7 Hz, 1H), 8.43 (s, 1H), 8.08-7.91 (m, 3H), 7.80 (d, J = 6.7 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 25.7 Hz, 2H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.44-4.15 (m, 2H), 4.11-3.90 (m, 1H), 3.82 (d, J = 12.5 Hz, 2H), 3.61 (s, 3H), 3.01-2.91 (m, 2H), 2.90 (s, 1H), 2.74 (s, 1H), 2.73-2.70 (m, 1H), 2.68-2.55 (m, 1H), 2.43- 231 (m, 1H), 2.07-1.85 (m, 3H), 1.80-1.61 (m, 2H). D129 704.3 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.92 (dd, J = 9.0, 2.9 Hz, 1H), 8.57 (d, J = 2.9 Hz, 1H), 7.89 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.5, 2.6 Hz, 1H), 7.26 (s, 1H), 7.09 (s, 1H), 7.01 (s, 1H), 6.87 (s, 1H), 5.17-5.07 (m, 1H), 4.62-4.57 (m, 1H), 4.36 (d, J = 16.8 Hz, 1H), 4.28-4.10 (m, 2H), 3.92-3.80 (m, 4H), 3.61 (s, 3H), 3.48-3.40 (m, 1H), 3.20-3.09 (m, 1H), 2.99- 2.86 (m, 1H), 2.72-2.56 (m, 3H), 2.44-2.36 (m, 1H), 2.13-1.92 (m, 3H), 1.24 (t, J = 7.6 Hz, 3H). D130 839.4 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.26-8.96 TFA (m, 1H), 8.83 (s, 1H), 8.47 (s, 1H), 8.02 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.38-7.22 (m, 2H), 7.02 (s, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45-4.11 (m, 5H), 4.09-3.76 (m, 9H), 3.67-3.61 (m, 5H), 3.28-3.06 (m, 6H), 3.04-2.85 (m, 3H), 2.84-2.71 (m, 6H), 2.69-2.56 (m, 2H), 2.46-2.26 (m, 2H), 2.23-1.92 (m, 4H), 1.92- 1.72 (m, 2H). D131 706.25 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.94-8.87 (m, 1H), 8.56 (d, J = 2.8 Hz, 1H), 7.92 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.40-7.32 (m, 1H), 7.26 (d, J = 1.5 Hz, 1H), 6.79 (d, J = 2.2 Hz, 2H), 6.57 (t, J = 2.2 Hz, 1H), 5.15-5.07 (m, 1H), 4.70-4.51 (m, 1H), 4.35 (d, J = 16.8 Hz, 1H), 4.27-4.18 (m, 1H), 4.14 (s, 1H), 3.88 (d, J = 13.0 Hz, 1H), 3.82 (s, 6H), 3.60 (s, 3H), 3.47-3.40 (m, 1H), 3.15-3.11 (m, 1H), 2.94-2.86 (m, 1H), 2.64-2.56 m, 1H), 2.42-2.38 (m, 1H), 2.04-1.89 (m, 3H). D132 696.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 1.3 Hz, 1H), 6.89 (s, 2H), 6.73-6.66 (m, 2H), 5.02 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.12 (m, 2H), 3.84 (s, 6H), 3.72-3.62 (m, 4H), 3.60-3.55 (m, 7H), 2.93-2.80 (m, 1H), 2.70- 2.52 (m, 6H), 2.52-2.25 (m, 1H), 2.43-2.27 (m, 1H), 2.03- 1.95 (m, 1H), 1.80-1.76 (m, 4H). D133 753.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.20 (s, 1H, FA), 7.96 (s, 1H), 7.87 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.91 (s, 2H), 6.54-6.43 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.11 (m, 2H), 3.85 (s, 6H), 3.62 (s, 8H), 3.57-3.51 (m, 3H), 3.30- 3.25 (m, 2H), 3.08-3.02 (m, 2H), 2.99-2.78 (m, 1H), 2.64-2.58 (m, 2H), 2.45-2.24 (m, 4H), 2.00-1.92 (m, 1H), 1.76-1.70 (m, 4H). D134 846.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.89 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41-7.34 (m, 2H), 7.07 (s, 2H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 10.6 Hz, 4H), 4.02 (s, 6H), 4.00- 3.93 (m, 3H), 3.76 (s, 3H), 3.69-3.57 (m, 2H), 3.39 (s, 2H), 3.24 (d, J = 13.0 Hz, 1H), 2.92 (s, 9H), 2.85-2.81 (m, 1H), 2.55-2.46 (m, 1H), 2.30-2.15 (m, 5H), 1.99-1.87 (m, 2H). D135 846.5 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1H, FA), 8.37 (s, 1H), 7.86 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.40-7.33 (m, 2H), 7.05 (s, 2H), 5.15 (d, J = 8.1 Hz, 1H), 4.49-4.41 (m, 3H), 4.35 (d, J = 13.8 Hz, 2H), 4.01 (s, 6H), 3.86 (d, J = 12.1 Hz, 2H), 3.76 (s, 3H), 3.37 (s, 1H), 3.16-3.10 (m, 1H), 2.98-2.91 (m, 1H), 2.89-2.79 (m, 9H), 2.71-2.61 (m, 2H), 2.57-2.49 (m, 2H), 2.25-2.17 (m, 1H), 2.07-1.97 (m, 4H), 1.81-1.68 (m, 2H). D136 670.3 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.68 (s, TFA, 1H), 7.93 (s, 1H), 7.72 (d, J = 5.3 Hz, 1H), 7.66-7.57 (m, 2H), 7.20- 7.12 (m, 2H), 7.08 (s, 2H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (d, J = 13.9, 4.3 Hz, 1H), 4.43-4.19 (m, 3H), 3.97 (s, 6H), 3.95- 3.74 (m, 4H), 3.73-3.62 (m, 4H), 3.61-3.53 (m, 1H), 2.99-2.85 (m, 1H), 2.64-2.57 (m, 1H), 2.45-2.36 (m, 1H), 2.04-1.93 (m, 1H), 1.50 (dd, J = 6.5, 3.3 Hz, 6H). D137 858.6 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 1.3 Hz, 2H), 6.79 (d, J = 7.2 Hz, 2H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.45-4.31 (m, 6H), 4.12-3.90 (m, 9H), 3.88-3.81 (m, 1H), 3.79-3.66 (m, 4H), 3.62-3.54 (m, 2H), 3.03-2.85 (m, 8H), 2.84-2.74 (m, 1H), 2.55- 2.10 (m, 9H). D138 739.45 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.97 (s, 1H, TFA), 8.81 (d, J = 4.9 Hz, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.04 (s, 2H), 6.71 (dd, J = 5.7, 2.4 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.13 (m, 4H), 3.95 (s, 6H), 3.76 (s, 2H), 3.64 (s, 4H), 3.38 (d, J = 12.2 Hz, 2H), 3.19-3.09 (m, 2H), 2.94- 2.82 (m, 1H), 2.79 (d, J = 4.2 Hz, 3H), 2.60 (d, J = 16.2 Hz, 1H), 2.43-2.25 (m, 1H), 2.14 (d, J = 13.7 Hz, 2H), 2.06-1.96 (m, 3H). D139 707.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.8 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 6.97 (s, 2H), 6.70 (d, J = 7.5 Hz, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.36-4.15 (m, 2H), 3.90 (s, 8H), 3.63 (d, J = 4.3 Hz, 8H), 2.96-2.85 (m, 2H), 2.77 (s, 2H), 2.63-2.60 (m, 1H), 2.38 (dd, J = 13.2, 4.6 Hz, 1H), 2.06-1.95 (m, 2H), 1.87 (s, 3H) D140 846.25 .sup.1H NMR (300 MHz, Acetonitrile-d3) δ 8.29 (s, 1H), 7.74 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.39-7.27 (m, 2H), 6.98 (s, 2H), 5.07 (dd, J = 13.3, 5.2 Hz, 1H), 4.87-4.65 (m, 1H), 4.42-4.23 (m, 3H), 3.94 (s, 7H), 3.83 (s, 1H), 3.64 (d, J = 20.7 Hz, 4H), 3.55- 3.37 (m, 2H), 3.30-2.99 (m, 3H), 2.81-2.80 (m, 6H), 2.52-2.30 (m, 3H), 2.27-2.10 (m, 4H), 1.87 (s, 2H), 1.73 (s, 1H), 1.32 (d, J = 21.7 Hz, 2H). D141 846.2 .sup.1H NMR (300 MHz, Acetonitrile-d3) δ 8.29 (s, 1H), 7.75 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.41-7.30 (m, 2H), 6.97 (s, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.79 (d, J = 22.1 Hz, 1H), 4.32 (q, J = 10.1, 9.0 Hz, 3H), 3.93 (s, 7H), 3.67 (s, 4H), 3.62-3.48 (m, 3H), 2.95-2.90 (m, 4H), 2.80 (s, 6H), 2.43 (dd, J = 13.1, 5.0 Hz, 1H), 2.22 (q, J = 22.0, 16.5 Hz, 5H), 1.94-1.82 (m, 2H), 1.74 (s, 1H), 1.31 (d, J = 21.7 Hz, 2H). D142 860.5 .sup.1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.2 Hz, 1H), 8.28 (s, 1H, FA), 7.95 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.92 (s, 2H), 5.16 (dd, J = 13.4, 5.1 Hz, 1H), 4.42-4.13 (m, 3H), 3.84 (s, 6H), 3.80 (s, 2H), 3.62 (s, 3H), 3.57 (s, 2H), 3.17 (s, 1H), 3.00 (s, 3H), 2.96 (dd, J = 12.8, 5.2 Hz, 2H), 2.80-2.69 (m, 3H), 2.62-2.58 (m, 2H), 2.43- 2.35 (m, 2H), 2.22 (s, 6H), 2.04-1.97 (m, 1H), 1.84-1.80 (m, 4H), 1.71-1.46 (m, 2H). D143 777.55 .sup.1H NMR (400 MHz, DMSO-d6 with a drop of D2O) δ 8.5-8.50 (m, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 1H), 7.26 (s, 1H), 6.97 (s, 2H), 5.12 (dd, J = 13.3, 4.9 Hz, 1H), 4.58-4.53 (m, 1H), 4.36 (d, J = 16.9 Hz, 1H), 4.22 (dd, J = 17.0, 3.6 Hz, 1H), 4.13 (s, 1H), 4.04 (s, 2H), 3.88 (s, 7H), 3.61 (s, 3H), 3.41-3.28 (m, 1H), 3.11 (t, J = 12.3 Hz, 1H), 2.99 (s, 3H), 2.97- 2.88 (m, 1H), 2.81-2.72 (m, 1H), 2.59 (s, 6H), 2.42-2.34 (m, 1H), 2.06-2.01 (m, 2H), 1.96-1.91 (m, 1H). D144 670.2 .sup.1H NMR (400 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.71 (d, J = 5.4 Hz, 1H), 7.62 (d, J = 5.4 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 10.2 Hz, 2H), 7.09 (s, 2H), 5.24-5.12 (m, 1H), 4.69-4.53 (m, 2H), 4.52-4.37 (m, 3H), 4.04 (s, 6H), 3.88 (s, 2H), 3.76 (s, 3H), 3.74-3.51 (m, 3H), 3.00-2.86 (m, 1H), 2.85-2.76 (m, 1H), 2.61- 2.42 (m, 1H), 2.25-2.15 (m, 1H), 1.62 (d, J = 6.4 Hz, 6H). D145 858.6 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.57 (br s, 2H, FA), 8.36 (d, J = 1.5 Hz, 1H), 7.88 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 11.0 Hz, 4H), 5.15 (dd, J = 13.7, 6.0 Hz, 1H), 4.67-4.62 (m, 3H), 4.45-4.36 (m, 3H), 4.18 (s, 2H), 3.99 (s, 6H), 3.91-3.81 (m, 2H), 3.76 (s, 3H), 3.67 (s, 1H), 3.53 (s, 2H), 2.94-2.81 (m, 2H), 2.72 (s, 6H), 2.58-2.13 (m, 9H). D146 727.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.68 (m, J = 7.7 Hz, 1H), 8.41 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.44 (m, J = 8.5 Hz, 1H), 7.21 (m, J = 2.3 Hz, 1H), 6.95 (s, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45-4.26 (m, 1H), 4.25-4.12 (m, 1H), 4.05-3.95 (m, 2H), 3.92 (s, 6H), 3.83-3.81 (m, 1H), 3.80-3.76 (m, 2H), 3.62 (s, 3H), 3.00-2.81 (m, 3H), 2.55 (s, 2H), 2.39 (s, 6H), 2.06-1.96 (m, 1H), 1.95-1.81 (m, 2H), 1.78-1.55 (m, 2H). D147 645.3 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.52 (s, 0.2H, FA), 7.75 (s, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.38-7.32 (m, 2H), 7.04 (s, 2H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.49-4.35 (m, 2H), 4.16 (s, 2H), 3.99 (s, 6H), 3.42 (s, 4H), 3.17 (m, 4H), 2.94-2.85 (m, 1H), 2.85-2.75 (m, 1H), 2.56-2.45 (m, 1H), 2.24-2.13 (m, 1H). D148 860.5 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 4.5 Hz, 2H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.43-4.03 (m, 5H), 3.91 (d, J = 3.2 Hz, 6H), 3.82 (d, J = 11.9 Hz, 2H), 3.59 (s, 3H), 3.16 (s, 1H), 2.92 (s, 2H), 2.77 (s, 3H), 2.75-2.56 (m, 11H), 2.46-2.30 (m, 2H), 1.99 (d, J = 12.0 Hz, 1H), 1.80 (s, 4H), 1.56 (d, J = 12.7 Hz, 2H). D149 767.4 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H, FA), 8.27 (s, 1H), 7.85 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 7.05 (s, 2H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.53 (t, J = 8.3 Hz, 1H), 4.52- 4.34 (m, 2H), 4.31 (s, 2H), 4.01 (s, 6H), 3.75 (s, 3H), 3.31-3.17 (m, 4H), 2.99-2.72 (m, 8H), 2.59-2.43 (m, 1H), 2.46-2.36 (m, 2H), 2.23-2.13 (m, 1H), 2.01-1.97 (m, 2H), 1.88 (t, J = 5.6 Hz, 2H), 1.82 (t, J = 5.6 Hz, 2H). D150 810.55 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.54 (s, FA 2H), 8.27 (s, 1H), 7.87 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 10.4 Hz, 2H), 7.07 (s, 2H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.53-4.33 (m, 4H), 4.11-3.97 (m, 7H), 3.96-3.86 (m, 2H), 3.75 (s, 3H), 3.02-2.87 (m, 8H), 2.87-2.65 (m, 6H), 2.58-2.43 (m, 1H), 2.30-2.01 (m, 6H), 1.94-1.69 (m, 4H). D151 763.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.17 (s, 1H), 9.01- 8.91 (m, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.02 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.23-7.12 (m, 2H), 7.04 (s, 2H), 5.13-5.01 (m, 1H), 4.62 (s, 1H), 4.41-4.16 (m, 6H), 4.01 (s, 1H), 3.93 (s, 6H), 3.63 (s, 3H), 3.49 (dd, J = 30.5, 13.7 Hz, 1H), 3.22 (t, J = 12.3 Hz, 1H), 2.92 (s, 1H), 2.78 (d, J = 4.6 Hz, 6H), 2.60 (d, J = 17.0 Hz, 1H), 2.40 (d, J = 13.6 Hz, 1H), 2.00 (dd, J = 20.3, 10.8 Hz, 3H). D152 763.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.08 (s, 1H), 9.00- 8.90 (m, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.42-7.32 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.04 (s, 2H), 5.18-5.05 (m, 1H), 4.60 (s, 1H), 4.36 (d, J = 16.9 Hz, 1H), 4.25 (d, J = 4.4 Hz, 3H), 4.23-4.08 (m, 1H), 3.93 (s, 6H), 3.63 (s, 3H), 3.54-3.07 (m, 3H), 3.02-2.84 (m, 1H), 2.82-2.80 (m, 1H), 2.78 (d, J = 4.6 Hz, 6H), 2.61 (d, J = 16.5 Hz, 1H), 2.46-2.35 (m, 1H), 1.98 (d, J = 25.6 Hz, 3H). D153 794.2 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 3H, FA), 7.62 (d, J = 5.4 Hz, 1H), 7.47-7.37 (m, 2H), 6.90-6.82 (m, 3H), 6.79 (d, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.47-4.32 (m, 4H), 3.95 (s, 6H), 3.75 (s, 3H), 3.72 (s, 4H), 3.59 (d, J = 12.0 Hz, 2H), 3.23-3.19 (m, 1H), 3.01-3.75 (m, 6H), 2.68 (s, 3H), 2.57-2.44 (m, 1H), 2.41 (s, 3H), 2.23-2.15 (m, 1H), 2.13-2.01 (m, 7H), 1.63 (s, 2H). D154 683.3 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.50-9.43 (m, 1H, TFA), 7.94 (s, 1H), 7.72 (d, J = 5.4 Hz, 1H), 7.67-7.60 (m, 2H), 7.34-7.24 (m, 2H), 7.09 (s, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.97-4.62 (m, 1H), 4.59-4.49 (m, 1H), 4.40 (d, J = 17.0 Hz, 1H), 4.28 (d, J = 16.9 Hz, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.98 (s, 6H), 3.83 (d, J = 13.9 Hz, 1H), 3.64 (s, 3H), 3.58 (d, J = 13.5 Hz, 2H), 3.29 (t, J = 11.8 Hz, 1H), 3.07 (d, J = 12.9 Hz, 1H), 2.93 (ddd, J = 17.9, 13.5, 5.4 Hz, 1H), 2.77-2.54 (m, 3H), 2.40 (td, J = 13.1, 4.5 Hz, 1H), 2.14 (s, 3H), 2.03-1.88 (m, 2H). D155 763.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1H, FA), 8.36 (d, J = 0.7 Hz, 1H), 7.87 (s, 1H), 7.68 (d, J = 9.3 Hz, 1H), 7.20-7.14 (m, 2H), 7.07 (s, 2H), 5.17-5.08 (m, 1H), 4.73-4.63 (m, 1H), 4.50- 4.42 (m, 2H), 4.38 (s, 2H), 4.34-4.22 (m, 1H), 4.09 (d, J = 13.7 Hz, 1H), 4.02 (s, 6H), 3.75 (s, 3H), 3.44-3.38 (m, 1H), 3.23- 3.14 (m, 1H), 2.98-2.92 (m, 1H), 2.89 (s, 6H), 2.83-2.76 (m, 1H), 2.55-2.44 (m, 1H), 2.23-2.13 (m, 2H), 2.13-2.02 (m, 1H). D156 763.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H, FA), 8.38 (s, 1H), 7.87 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.07 (s, 2H), 5.20-5.13 (m, 1H), 4.71-4.59 (m, 2H), 4.51-4.41 (m, 2H), 4.37 (s, 2H), 4.10 (s, 1H), 4.02 (s, 6H), 3.93 (d, J = 12.9 Hz, 1H), 3.75 (s, 3H), 3.16-3.08 (m, 1H), 2.98-2.91 (m, 1H), 2.87 (s, 6H), 2.84-2.78 (m, 1H), 2.58-2.47 (m, 1H), 2.26-2.15 (m, 2H), 2.13-2.04 (m, 1H). D157 844.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.17 (s, 2H), 7.11 (s, 1H), 5.05 (dd, J = 13.4, 4.8 Hz, 1H), 4.40-4.15 (m, 3H), 3.86 (s, 4H), 3.82-3.80 (m, 3H), 3.61 (s, 3H), 3.16 (s, 1H), 2.95-2.80 (m, 2H), 2.80-2.65 (m, 4H), 2.64-2.54 (m, 3H), 2.51 (s, 6H), 2.45- 2.35 (m, 2H), 2.04-1.96 (m, 1H), 1.87-1.75 (m, 4H), 1.64-1.47 (m, 2H), 1.17 (t, J = 7.6 Hz, 3H). D158 696.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.92 (s, 1H, TFA salt), 7.53 (s, 2H), 7.42 (d, J = 8.9 Hz, 1H), 6.84 (s, 2H), 6.72 (s, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.17 (m, 4H), 3.88 (s, 6H), 3.77 (s, 2H), 3.65 (s, 2H), 3.62 (s, 3H), 3.21-3.12 (m, 2H), 2.98-2.85 (m, 1H), 2.64-2.60 (m, 2H), 2.57 (s, 1H), 2.42-2.37 (m, 1H), 2.35 (s, 3H), 2.14 (d, J = 14.0 Hz, 2H), 2.00 (t, J = 11.7 Hz, 3H). D159 849.4 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H, FA), 8.39 (d, J = 5.2 Hz, 1H), 7.86 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.23 (d, J = 8.3, 2.4 Hz, 1H), 7.05 (s, 2H), 5.17 (dd, J = 13.3, 6.9, 5.1 Hz, 1H), 4.49-4.39 (m, 3H), 4.35 (s, 2H), 4.11 (t, 2H), 4.01 (s, 6H), 3.75 (s, 3H), 3.29-3.14 (m, 1H), 3.07-2.98 (m, 1H), 2.97- 2.88 (m, 1H), 2.86 (s, 6H), 2.83-2.76 (m, 1H), 2.59-2.47 (m, 3H), 2.45-2.33 (m, 1H), 2.32-2.25 (m, 1H), 2.24-2.15 (m, 1H), 2.08-1.98 (m, 1H), 1.98-1.92 (m, 1H), 1.92-1.83 (m, 2H), 1.69- 1.52 (m, 4H). D160 822.4 .sup.1H NMR (400 MHz, Methanol-d4) δ 7.82 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.3, 2.3 Hz, 1H), 7.14 (d, J = 1.3 Hz, 1H), 7.04 (d, J = 3.1 Hz, 2H), 5.12 (dd, J = 12.5, 5.4 Hz, 1H), 4.98 (d, J = 6.5 Hz, 1H), 4.40 (s, 2H), 4.00-3.99 (s, 6H), 3.69-3.63 (s, 3H), 3.60-3.49 (m, 4H), 3.37 (s, 1H), 3.23- 3.12 (m, 2H), 3.12-3.07 (m, 2H), 3.07-2.93 (m, 1H), 2.92- 2.74 (m, 4H), 2.66 (d, J = 1.2 Hz, 3H), 2.65 (s, 1H), 2.05 (m, 1H), 2.16-2.05 (m, 6H), 2.03-1.97 (m, 3H), 1.64 (q, J = 12.1 Hz, 2H). D161 807.43 D162 846.35 .sup.1H NMR (400 MHz, Methanol-d4 with a drop of D2O) δ 8.37 (s, 1H), 8.36 (br s, 1H, FA), 7.87 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39- 7.31 (m, 2H), 7.08 (s, 2H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.49- 4.34 (m, 5H), 4.02 (s, 6H), 3.86 (d, J = 12.3 Hz, 2H), 3.75 (s, 3H), 3.30-3.26 (m, 1H), 3.16-3.09 (m, 1H), 2.92 (s, 7H), 2.86-2.74 (m, 3H), 2.71-2.60 (m, 2H), 2.56-2.48 (m, 2H), 2.24-2.15 (m, 1H), 2.05-1.92 (m, 4H), 1.71 (q, J = 12.6 Hz, 2H). D163 849.4 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.88 (d, J = 8.8 Hz, 1H), 8.59 (s, 1H), 8.24 (s, 1H, FA), 7.97 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 8.4, 2.2 Hz, 1H), 6.93 (s, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.33 (q, J = 22.5 Hz, 3H), 4.07 (t, J = 6.3 Hz, 2H), 3.85 (s, 6H), 3.62 (s, 5H), 3.20-3.08 (m, 1H), 2.97-2.83 (m, 2H), 2.66-2.56 (m, 1H), 2.46-2.31 (m, 4H), 2.26 (s, 6H), 2.20-2.08 (m, 1H), 2.05-1.92 (m, 1H), 1.91- 1.82 (m, 1H), 1.83-1.71 (m, 3H), 1.57-1.38 (m, 4H). D164 763.2 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.97-8.90 (m, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.27 (s, 1H, FA), 7.96 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.23-7.14 (m, 2H), 6.91 (s, 2H), 5.10-5.02 (m, 1H), 4.75-4.56 (m, 1H), 4.41-4.16 (m, 3H), 4.04-3.92 (m, 1H), 3.84 (s, 6H), 3.51 (s, 3H), 3.57-3.46 (m, 2H), 3.22 (t, J = 12.3 Hz, 1H), 2.97-2.85 (m, 1H), 2.69-2.56 (m, 1H), 2.45-2.32 (m, 1H), 2.17 (s, 6H), 2.06-1.89 (m, 3H). D165 763.35 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.55 (s, FA, 1H), 8.37 (s, 1H), 7.86 (s, 1H), 7.54-7.45 (m, 1H), 7.43-7.32 (m, 2H), 7.07 (s, 2H), 5.23-5.11 (m, 1H), 4.74-4.56 (m, 1H), 4.48-4.35 (m, 4H), 4.12- 4.02 (m, 7H), 3.97-3.87 (m, 1H), 3.78-3.72 (s, 3H), 3.27-3.05 (m, 2H), 2.88-2.78 (m, 8H), 2.56-2.47 (m, 1H), 2.28-2.14 (m, 2H), 2.13-2.05 (m, 1H). D166 875.5 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.06 (s, 1H, TFA salt), 8.91 (dd, J = 9.0, 2.8 Hz, 1H), 8.61 (s, 1H), 8.01 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.38-7.27 (m, 2H), 7.03 (s, 2H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.38 (d, J = 17.0 Hz, 2H), 4.28-4.19 (m, 3H), 3.92 (s, 6H), 3.63 (s, 3H), 3.57-3.45 (m, 7H), 3.37-3.35 (m, 4H), 3.05-2.99 (m, 1H), 2.93-2.89 (m, 1H), 2.88-2.83 (m, 2H), 2.80- 2.74 (m, 6H), 2.65-2.58 (m, 2H), 2.43-2.36 (m, 2H), 2.05- 1.96 (m, 1H), 1.94-1.76 (m, 2H). D167 846.4 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.88 (d, J = 8.7 Hz, 1H), 8.60 (s, 1H), 8.23 (s, 2H, FA salt), 7.97 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.93 (s, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.53-4.09 (m, 4H), 3.86 (s, 6H), 3.80 (s, 2H), 3.64 (d, J = 8.8 Hz, 5H), 3.20- 3.14 (m, 1H), 2.99-2.83 (m, 2H), 2.74 (t, J = 11.9 Hz, 2H), 2.65- 2.54 (m, 3H), 2.44-2.34 (m, 1H), 2.29 (s, 6H), 2.04-1.94 (m, 1H), 1.85-1.79 (m, 4H), 1.62-1.52 (m, 2H). D168 629.15 .sup.1H NMR (400 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.71 (d, J = 5.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.26 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 7.08 (s, 2H), 5.38-5.06 (m, 2H), 4.76 (s, 2H), 4.65 (d, J = 16.6 Hz, 2H), 4.55-4.40 (m, 2H), 4.37-4.32 (m, 2H), 4.08-3.95 (m, 6H), 3.75 (s, 3H), 2.98-2.86 (m, 1H), 2.85-2.76 (m, 1H), 2.58- 2.45 (m, 1H), 2.22-2.18 (m, 1H). D169 643.1 .sup.1H NMR (400 MHz, Methanol-d4) δ 7.90 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.3, 2.3 Hz, 1H), 7.08 (s, 2H), 5.34 (s, 1H), 5.15 (dd, J = 12.5, 5.4 Hz, 1H), 4.78 (dd, J = 12.0, 6.3 Hz, 2H), 4.64 (s, 2H), 4.38 (d, J = 10.8 Hz, 2H), 4.00 (s, 6H), 3.75 (s, 3H), 2.96-2.83 (m, 1H), 2.83-2.66 (m, 2H), 2.20-2.10 (m, 1H). D170 629.1 .sup.1H NMR (400 MHz, Methanol-d4) δ 7.83-7.74 (m, 2H), 7.71 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 5.4 Hz, 1H), 7.13-7.05 (m, 4H), 5.38- 5.08 (m, 2H), 4.77 (s, 2H), 4.66 (s, 2H), 4.55-4.40 (m, 2H), 4.35 (s, 2H), 4.07-3.92 (m, 6H), 3.75 (s, 3H), 3.00-2.86 (m, 1H), 2.85-2.75 (m, 1H), 2.57-2.42 (m, 1H), 2.27-2.10 (m, 1H). D171 889.45 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.08 (s, 1H, TFA salt), 8.83 (d, J = 8.7 Hz, 1H), 8.53 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.40-7.28 (m, 2H), 6.82 (d, J = 2.2 Hz, 2H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.42-4.22 (m, 5H), 3.86 (s, 6H), 3.62 (s, 3H), 3.50-3.45 (m, 8H), 3.07-2.95 (m, 2H), 2.95-2.90 (m, 1H), 2.89- 2.74 (m, 9H), 2.68-2.54 (m, 2H), 2.45-2.30 (m, 6H), 2.01- 1.79 (m, 3H). D172 941.40 .sup.1H NMR (300 MHz, MeOD) δ 8.27 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 6.92-6.76 (m, 4H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.85-4.68 (m, 1H), 4.67-4.51 (m, 2H), 4.48-4.31 (m, 4H), 4.23-4.18 (m, 2H), 3.96 (s, 7H), 3.81-3.70 (m, 7H), 3.69-3.39 (m, 8H), 3.26-3.05 (m, 2H), 3.02-2.72 (m, 5H), 2.60-2.40 (m, 4H), 2.36-2.08 (m, 7H). D173 822.35 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.39 (s, 1H, FA), 7.82 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.33-7.22 (m, 2H), 7.04 (s, 2H), 5.13 (dd, J = 12.4, 5.4 Hz, 1H), 5.03-4.96 (m, 1H), 4.69-4.59 (m, 1H), 4.40 (s, 2H), 4.01 (s, 6H), 3.74 (s, 3H), 3.63-3.52 (m, 2H), 3.22-3.13 (m, 2H), 3.11-2.96 (m, 3H), 2.93- 2.70 (m, 5H), 2.64-2.56 (m, 5H), 2.23-2.04 (m, 6H), 2.02- 1.87 (m, 4H), 1.91-1.53 (m, 2H). D174 794.25 .sup.1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.69-7.59 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.16-7.07 (m, 2H), 6.99 (s, 2H), 4.99 (dd, J = 13.3, 5.1 Hz, 1H), 4.86-4.78 (m, 1H), 4.42-4.24 (m, 2H), 4.21 (d, J = 6.4 Hz, 2H), 3.88 (s, 6H), 3.60 (s, 3H), 3.37 (dd, J = 28.0, 12.1 Hz, 4H), 3.16 (s, 1H), 3.01 (t, J = 12.7 Hz, 2H), 2.92 (d, J = 6.9 Hz, 2H), 2.90-2.78 (m, 2H), 2.70-2.64 (m, 1H), 2.39 (s, 2H), 2.08-1.73 (m, 11H), 1.44 (q, J = 12.1 Hz, 2H). D175 915.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.07 (s, 1H, TFA salt), 8.93 (d, J = 8.8 Hz, 1H), 8.62 (s, 1H), 8.02 (s, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.03 (s, 2H), 6.77-6.65 (m, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.49-4.38 (m, 1H), 4.39-4.14 (m, 5H), 3.93 (s, 6H), 3.70 (s, 2H), 3.64 (s, 3H), 3.29 (s, 6H), 3.07-2.95 (m, 2H), 2.95- 2.89 (m, 1H), 2.91-2.69 (m, 9H), 2.68-2.56 (m, 2H), 2.45-2.28 (m, 2H), 2.17-1.78 (m, 7H). D176 682.45 .sup.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.32 (d, J = 7.7 Hz, 1H, TFA), 7.94 (s, 1H), 7.72 (d, J = 5.4 Hz, 1H), 7.63 (d, J = 5.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.49-7.39 (m, 2H), 7.09 (s, 2H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 (dd, J = 13.2, 7.9 Hz, 1H), 4.40 (d, J = 16.9 Hz, 1H), 4.27 (dd, J = 17.3, 1.8 Hz, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.98 (s, 6H), 3.88 (d, J = 13.7 Hz, 1H), 3.73 (s, 2H), 3.64 (s, 2H), 3.51 (s, 1H), 3.47 (d, J = 7.4 Hz, 1H), 3.31 (s, 1H), 3.08 (d, J = 12.8 Hz, 1H), 3.00-2.87 (m, 1H), 2.61 (d, J = 19.7 Hz, 3H), 2.40 (dt, J = 13.3, 6.7 Hz, 1H), 2.22 (d, J = 10.8 Hz, 2H), 2.12 (q, J = 8.9, 8.5 Hz, 1H), 2.06-1.98 (m, 1H), 1.92 (d, J = 11.0 Hz, 1H). D177 749.25 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H, FA), 8.39 (s, 1H), 7.86 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.05 (s, 3H), 7.03-6.97 (m, 1H), 5.24-5.12 (m, 2H), 4.48-4.35 (m, 2H), 4.21 (s, 2H), 4.06- 3.97 (m, 7H), 3.96-3.83 (m, 2H), 3.75 (s, 3H), 3.57 (t, J = 8.4 Hz, 1H), 2.99-2.87 (m, 1H), 2.85-2.80 (m, 1H), 2.74 (s, 6H), 2.56- 2.46 (m, 1H), 2.24-2.15 (m, 1H). D178 682.2 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.28 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 5.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.92 (s, 2H), 6.54-6.44 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.17 (d, J = 16.8 Hz, 1H), 3.85 (s, 6H), 3.61 (s, 6H), 3.52 (s, 2H), 2.98-2.83 (m, 1H), 2.58 (d, J = 17.1 Hz, 1H), 2.46-2.28 (m, 6H), 2.02-1.88 (m, 1H), 1.72 (t, J = 5.3 Hz, 4H). D179 848.25 .sup.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.01 (s, 1H), 8.95 (s, 1H, TFA), 8.61 (s, 1H), 8.02 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.03 (s, 2H), 6.71 (d, J = 7.9 Hz, 1H), 6.17 (s, 1H), 5.24 (dd, J = 12.4, 5.2 Hz, 1H), 4.25 (d, J = 5.0 Hz, 2H), 3.93 (s, 9H), 3.64 (s, 3H), 2.92-2.83 (m, 4H), 2.81-2.75 (m, 7H), 2.68-2.59 (m, 2H), 2.51-2.41 (m, 2H), 2.17-2.04 (m, 2H), 1.98-1.82 (m, 4H), 1.64- 1.47 (m, 2H). D180 749.3 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.88 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.08 (s, 2H), 6.88-6.68 (m, 2H), 5.32-5.07 (m, 2H), 4.54-4.3 (m, 4H), 4.03 (s, 6H), 3.99-3.88 (m, 2H), 3.75 (s, 3H), 3.67-3.54 (m, 1H), 2.92 (s, 7H), 2.83-2.72 (m, 2H), 2.58- 2.38 (m, 1H), 2.23-2.09 (m, 1H). D181 832.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H, FA), 8.32 (s, 1H), 7.86 (s, 1H), 7.65 (d, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.05 (s, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.83-4.77 (m, 1H), 4.48-4.35 (d, J = 16.8 Hz, 2H), 4.32 (s, 2H), 4.01 (s, 6H), 3.93 (d, J = 13.0 Hz, 2H), 3.75 (s, 3H), 3.45-3.38 (m, 2H), 3.08-2.95 (m, 3H), 2.95- 2.89 (m, 1H), 2.84 (s, 6H), 2.81-2.70 (m, 2H), 2.57-2.42 (m, 2H), 2.21-2.13 (m, 1H), 2.04 (t, J = 12.7 Hz, 2H), 1.74-1.56 (m, 2H). D182 832.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.65 (br s, FA, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.39-7.30 (m, 2H), 7.06 (s, 2H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.83-4.78(m, 1H), 4.51-4.39 (m, 2H), 4.33 (s, 2H), 4.01 (s, 6H), 3.87-3.68 (m, 5H), 3.48-3.39 (m, 2H), 3.08-2.96 (m, 1H), 2.97-2.88 (m, 3H), 2.85 (s, 6H), 2.83-2.71 (m, 2H), 2.58-2.39 (m, 2H), 2.23-2.15 (m, 1H), 2.13-1.98 (m, 2H), 1.79-1.59(m, 2H). D183 696.15 .sup.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.21 (s, 1H, FA), 7.87 (s, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.66-7.55 (m, 2H), 6.93 (s, 2H), 6.78 (d, J = 2.1 Hz, 1H), 6.69-6.60 (m, 1H), 5.12-4.97 (m, 1H), 3.85 (s, 6H), 3.73 (s, 4H), 3.62 (s, 3H), 3.53 (s, 2H), 2.97- 2.81 (m, 1H), 2.70-2.53 (m, 2H), 2.46-2.31 (m, 4H), 2.07-1.95 (m, 1H), 1.80-1.67 (m, 4H). D184 807.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.45 (s, 1H, TFA salt), 9.23 (s, 1H, TFA salt), 7.85 (s, 1H), 7.69 (dd, J = 8.3, 2.6 Hz, 1H), 7.33 (d, J = 1.4 Hz, 1H), 7.03 (s, 2H), 6.78 (d, J = 2.2 Hz, 1H), 6.66 (dd, J = 8.3, 2.1 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.35- 4.19 (m, 2H), 3.99-3.79 (m, 10H), 3.61 (s, 3H), 3.54-3.50 (m, 2H), 3.48-3.46 (m, 2H), 3.25-3.16 (m, 2H), 3.10-2.83 (m, 7H), 2.66-2.60 (m, 1H), 2.56-2.53 (m, 3H), 2.20-2.10 (m, 2H), 2.06- 1.88 (m, 5H), 1.58-1.39 (m, 2H). D185 793.25 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.49 (s, 1H, FA), 7.80-7.57 (m, 4H), 7.07 (s, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.67 (dd, J = 8.4, 2.1 Hz, 1H), 5.07 (dd, J = 12.4, 5.4 Hz, 1H), 4.39 (s, 2H), 4.01 (s, 6H), 3.79 (d, J = 16.3 Hz, 7H), 3.55 (d, J = 11.6 Hz, 2H), 3.23- 3.07 (m, 2H), 2.96-2.81 (m, 1H), 2.81-2.67 (m, 2H), 2.58 (s, 4H), 2.39 (s, 2H), 2.16-2.00 (m, 3H), 1.99-1.89 (m, 5H), 1.55 (s, 2H). D186 682.2 .sup.1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.73-7.55 (m, 2H), 7.40 (d, J = 8.9 Hz, 1H), 6.98 (s, 2H), 6.83-6.67 (m, 2H), 5.09- 4.91 (m, 1H), 4.44-4.12 (m, 4H), 3.89 (s, 6H), 3.73 (s, 2H), 3.61 (s, 5H), 3.34 (d, J = 12.2 Hz, 2H), 3.09 (t, J = 11.9 Hz, 2H), 2.90- 2.75 (m, 1H), 2.70-2.57 (m, 1H), 2.44-2.28 (m, 1H), 2.17-1.88 (m, 5H). D187 846.1 .sup.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.97 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.18 (s, 1H, FA), 7.98 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.28 (dd, J = 8.7, 2.3 Hz, 1H), 6.92 (s, 2H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.71-4.58 (m, 1H), 4.01 (d, J = 12.9 Hz, 2H), 3.85 (s, 6H), 3.62 (s, 3H), 3.56 (s, 2H), 3.08 (t, J = 11.7 Hz, 3H), 2.96-2.76(m, 3H), 2.73-2.53 (m, 4H), 2.22 (s, 6H), 2.08-1.86 (m, 3H), 1.53-1.46 (m, 2H). D188 927.58 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 2H, FA), 8.36 (s, 1H), 7.85 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.06 (s, 2H), 6.85 (d, J = 2.1 Hz, 1H), 6.77 (dd, J = 8.2, 2.2 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.62 (s, 1H), 4.47 (s, 2H), 4.46-4.32 (m, 2H), 4.22 (t, J = 9.6 Hz, 2H), 4.02 (s, 6H), 3.95 (t, J = 9.3 Hz, 2H), 3.75 (s, 3H), 3.67 (s, 4H), 3.23-3.04 (m, 2H), 2.99-2.89 (m, 2H), 2.85-2.74(m, 1H), 2.69 (d, J = 6.9 Hz, 2H), 2.55-2.45 (m, 5H), 2.39 (s, 3H), 2.29 (t, J = 11.7 Hz, 1H), 2.21-2.13 (m, 1H), 2.08-1.99 (m, 1H), 1.98- 1.86 (m, 4H), 1.31 (s, 2H). D189 808.35 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.22 (s, 2H, TFA), 7.94-7.83 (m, 2H), 7.75-7.60 (m, 2H), 7.37-7.26 (m, 2H), 7.06 (d, J = 1.7 Hz, 2H), 5.17-4.97 (m, 2H), 4.27 (d, J = 27.8 Hz, 2H), 3.94 (s, 6H), 3.63 (s, 3H), 3.55-3.49 (m, 1H), 3.46 (s, 3H), 3.26- 3.17 (m, 2H), 3.06-2.83 (m, 6H), 2.68-2.53 (m, 3H), 2.10-1.79 (m, 10H), 1.58-1.39 (m, 2H). D190 763.15 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.25 (d, J = 8.5 Hz, 1H), 8.55 (s, 1H), 8.17 (s, 1H, FA), 7.99 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.5, 2.2 Hz, 1H), 6.93 (s, 2H), 5.16-5.04 (m, 2H), 4.14-4.01 (m, 3H), 3.86 (s, 6H), 3.66-3.57 (m, 6H), 3.00-2.81 (m, 1H), 2.65-2.54 (m, 2H), 2.25 (s, 6H), 2.07-2.01 (m, 1H). D191 832.4 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.56 (s, FA, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.02 (s, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.3, 2.1 Hz, 1H), 5.07 (dd, J = 12.4, 5.4 Hz, 1H), 4.60-4.39 (m, 1H), 4.27 (s, 2H), 4.15 (t, J = 7.8 Hz, 2H), 4.00 (s, 6H), 3.96-3.83 (m, 2H), 3.72 (s, 3H), 3.63-3.51 (m, 1H), 3.28- 3.21 (m, 1H), 3.09-3.00 (m, 1H), 2.95-2.60 (m, 9H), 2.58- 2.39 (m, 1H), 2.36-2.23 (m, 1H), 2.18-1.93 (m, 3H). D192 777.25 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.05 (s, 1H, TFA), 8.94 (d, J = 8.8 Hz, 1H), 8.57 (s, 1H), 8.02 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.04 (s, 2H), 5.10 (dd, J = 12.8, 5.3 Hz, 1H), 4.76-4.63 (m, 1H), 4.58-4.52 (m, 1H), 4.25 (d, J = 4.8 Hz, 2H), 4.18 (d, J = 13.6 Hz, 1H), 3.93 (s, 6H), 3.76-3.51 (m, 5H), 2.93-2.83 (m, 1H), 2.82-2.75 (m, 6H), 2.66-2.54 (m, 2H), 2.09-1.92 (m, 3H). D193 794.2 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 3H), 8.08 (d, J = 5.4 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 5.1 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.82 (s, 2H), 5.02 (dd, J = 13.2, 5.1 Hz, 1H), 4.85-4.74 (m, 1H), 4.38 (d, J = 17.1 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 3.96 (s, 2H), 3.86 (s, 6H), 3.62 (s, 3H), 3.16 (d, J = 9 Hz, 2H), 2.96-2.80 (m, 1H), 2.74-2.52 (m, 3H), 2.48-2.12 (m, 9H), 2.05-1.90 (m, 1H), 1.85-1.50 (m, 9H), 1.40- 1.20 (m, 2H). D194 642.15 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 5.3 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.94 (s, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-4.14 (m, 2H), 3.87 (s, 6H), 3.62 (d, J = 3.5 Hz, 5H), 3.17 (t, J = 4.9 Hz, 4H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.61 (d, J = 5.0 Hz, 5H), 2.45-2.33 (m, 1H), 2.03-1.95 (m, 1H). D195 874.2 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.89 (d, J = 9.0 Hz, 1H), 8.59 (s, 1H), 8.26 (s, 3H, FA), 7.96 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.92 (s, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.43-4.29 (m, 2H), 3.84 (s, 6H), 3.65- 3.59 (m, 5H), 3.24-3.00 (m, 3H), 2.98-2.79 (m, 3H), 2.66-2.55 (m, 7H), 2.21 (s, 6H), 2.22-2.04 (m, 3H), 2.04-1.88 (m, 2H), 1.79-1.76 (m, 6H). D196 875.35 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.91 (dd, J = 8.8 Hz, 0.16H, TFA salt), 8.34 (s, 1H), 7.88 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.07 (s, 2H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (s, 3H), 4.43 (d, J = 15.7 Hz, 2H), 4.02 (s, 6H), 3.75 (s, 3H), 3.68 (d, J = 11.2 Hz, 4H), 3.62 (s, 4H), 3.49-3.43 (m, 2H), 3.38 (s, 2H), 3.17 (d, J = 11.5 Hz, 1H), 2.99 (t, J = 5.3 Hz, 2H), 2.92 (s, 6H), 2.80 (d, J = 17.3 Hz, 1H), 2.65 (dd, J = 28.9, 12.3 Hz, 1H), 2.57-2.41 (m, 2H), 2.22-2.14 (m, 1H), 2.12-2.04 (m, 1H), 2.02- 1.97 (m, 1H). D197 735.34 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.00 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.16 (s, 2H), 7.09 (d, J = 2.1 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.2, 2.1 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 31.5 Hz, 2H), 4.37 (dd, J = 16.3, 9.0 Hz, 4H), 4.17 (d, J = 23.2 Hz, 2H), 4.02 (s, 6H), 3.76 (s, 7H), 3.54 (d, J = 12.4 Hz, 4H), 3.18-2.98 (m, 2H), 2.91 (s, 4H), 2.79 (ddd, J = 17.6, 4.7, 2.4 Hz, 1H), 2.50 (qd, J = 13.2, 4.7 Hz, 1H), 2.34-2.02 (m, 4H). D198 736.2 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.35 (s, 1H), 7.40 (s, 1H), 7.14 (s, 2H), 6.70 (s, 2H), 5.06 (dd, J = 13.1, 5.1 Hz, 1H), 4.45-4.27 (m, 3H), 4.19 (d, J = 16.7 Hz, 3H), 4.02 (d, J = 10.1 Hz, 2H), 3.95 (s, 6H), 3.88 (s, 1H), 3.72 (s, 2H), 3.67 (s, 3H), 3.65 (s, 2H), 3.43 (s, 2H), 3.16 (s, 1H), 3.05-2.81 (m, 3H), 2.76-2.54 (m, 1H), 2.28 (s, 2H), 2.12 (d, J = 13.6 Hz, 2H), 2.02-1.80 (m, 3H). D199 794.2 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 3H), 8.08 (d, J = 5.4 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 5.1 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.82 (s, 2H), 5.02 (dd, J = 13.2, 5.1 Hz, 1H), 4.85-4.74 (m, 1H), 4.38 (d, J = 17.1 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 3.96 (s, 2H), 3.86 (s, 6H), 3.62 (s, 3H), 3.16 (d, J = 9 Hz, 2H), 2.96-2.80 (m, 1H), 2.74-2.52 (m, 3H), 2.48-2.12 (m, 9H), 2.05-1.90 (m, 1H), 1.85-1.50 (m, 9H), 1.40- 1.20 (m, 2H). D200 875.45 .sup.1H NMR (400 MHz, Methanol-d4) δ 8.48-8.35 (m, 1H), 7.87 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.46-7.34 (m, 2H), 7.07 (s, 2H), 5.18 (ddd, J = 20.4, 13.3, 5.1 Hz, 1H), 4.55-4.44 (m, 5H), 4.47- 4.36 (m, 6H), 4.02 (s, 3H), 3.70-3.54 (m, 6H), 3.65-3.60 (m, 2H), 3.49-3.42 (m, 1H), 3.15-3.08 (m, 2H), 3.01-2.94 (m, 2H), 2.92 (s, 6H), 2.88-2.86 (m, 3H), 2.85-2.82 (m, 1H), 2.83-2.73 (m, 1H), 2.59-2.52 (m, 1H), 2.51-2.37 (m, 1H), 2.24-2.15 (m, 1H), 2.00-1.95 (m, 1H). D201 752.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.18 (s, 1H), 7.93 (s, 1H), 7.42-7.36 (m, 1H), 6.95 (s, 2H), 6.68 (d, J = 7.2 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.29 (s, 1H), 4.17 (d, J = 24.7 Hz, 3H), 3.93 (s, 8H), 3.68 (s, 3H), 3.58 (s, 6H), 2.98-2.76 (m, 2H), 2.61 (s, 1H), 2.56 (d, J = 7.4 Hz, 2H), 2.45-2.29 (m, 5H), 2.05- 1.93 (m, 1H), 1.79-1.71 (m, 4H). D202 697.3 . .sup.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.24 (s, 1H), 8.21 (s, 1H, FA), 8.06 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 6.91 (s, 2H), 6.78 (s, 1H), 6.65 (d, J = 8.4, 2.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.85 (s, 7H), 3.73 (s, 4H), 3.66 (s, 4H), 3.52 (s, 2H), 2.95- 2.81 (m, 1H), 2.60 (s, 1H), 2.40 (s, 3H), 2.05-1.95 (m, 1H), 1.73 (s, 4H). D203 683.5 .sup.1H NMR (300 MHz, Methanol-d4) δ 9.04 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.10-6.94 (m, 2H), 6.89 (d, J = 2.2 Hz, 1H), 6.85-6.75 (m, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.57-4.26 (m, 4H), 4.11-3.92 (m, 7H), 3.78 (s, 7H), 3.56 (s, 2H), 3.09 (s, 1H), 3.05-2.72 (m, 2H), 2.68-2.38 (m, 1H), 2.37-1.94 (m, 5H). D204 683.2 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.28 (s, 1H), 8.47 (s, 1H, FA), 8.10 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.02 (s, 2H), 6.96-6.87 (m, 2H), 6.20 (s, 1H, FA salt), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (s, 2H), 4.38-4.09 (m, 2H), 3.86 (s, 6H), 3.68 (s, 3H), 3.63 (s, 3H), 3.51 (s, 2H), 3.21-3.13 (m, 2H), 2.98-2.87 (m, 1H), 2.65-2.56 (m, 2H), 2.47-2.35 (m, 1H), 2.14 (s, 2H), 2.01-1.91 (m, 1H), 1.79 (s, 2H). D205 666.45 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.59-6.52 (m, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.16 (m, 2H), 3.81 (s, 6H), 3.62 (s, 2H), 3.54 (s, 3H), 3.22-3.11 (m, 4H), 2.98-2.84 (m, 1H), 2.72-2.56 (m, 5H), 2.46- 2.36 (m, 1H), 2.33 (s, 3H), 2.04 (s, 3H), 2.02-1.94 (m, 1H). D206 630.2 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.25 (s, 1H), 8.14 (s, 0.1H, FA), 8.09 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.09 (s, 1H), 7.05-6.97 (m, 3H), 6.54 (s, 0.2H, FA salt), 5.09 (dd, J = 13.2, 5.1 Hz, 2H), 4.47-4.15 (m, 6H), 3.90 (s, 8H), 3.67 (s, 3H), 3.03- 2.77 (m, 1H), 2.71-2.60 (m, 1H), 2.43-2.30 (m, 1H), 2.10-1.93 (m, 1H). D207 682.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.22 (s, 1H, FA), 8.09 (d, J = 5.3 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J = 5.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.78 (s, 2H), 6.69 (d, J = 7.9 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-4.11 (m, 2H), 3.84 (s, 6H), 3.63 (s, 3H), 3.55 (d, J = 10.1 Hz, 6H), 2.98-2.82 (m, 1H), 2.62 (s, 1H), 2.45-2.21 (s, 5H), 2.06-1.90 (m, 1H), 1.72 (t, J = 5.5 Hz, 4H). D208 696.25 .sup.1H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.55 (d, J = 3.1 Hz, 1H), 8.16 (FA, s, 1H), 7.89 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 6.81 (d, J = 16.7 Hz, 3H), 6.72-6.57 (m, 1H), 5.17-4.96 (m, 1H), 3.85 (s, 6H), 3.81-3.68 (m, 5H), 3.57 (s, 3H), 3.49 (s, 4H), 2.98-2.79 (m, 2H), 2.76-2.63 (m, 1H), 2.63- 2.55 (m, 1H), 2.07-1.90 (m, 1H), 1.82-1.65 (m, 4H). D209 697.3 .sup.1H NMR (300 MHz, Methanol-d4) δ 9.10 (s, 1H), 8.01 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.03 (s, 2H), 6.86 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.3, 2.1 Hz, 1H), 5.08 (dd, J = 12.4, 5.4 Hz, 1H), 4.21 (s, 2H), 4.01 (s, 6H), 3.88 (s, 4H), 3.77 (s, 3H), 3.28-3.00 (m, 4H), 2.97- 2.58 (m, 3H), 2.22-1.99 (m, 5H). D210 667.35 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.74 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H, FA), 7.37 (d, J = 8.0 Hz, 1H), 7.06 (s, 2H), 6.70-6.69 (m, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.33-4.16 (m, 2H), 3.88 (s, 6H), 3.72-3.65 (m, 5H), 3.58 (s, 4H), 2.98-2.82 (m, 1H), 2.66-2.56 (m, 4H), 2.45-2.24 (m, 2H), 2.05-1.96 (m, 1H), 1.78 (s, 4H). D211 662.3 .sup.1H NMR (300 MHz, MeOD) δ 8.17-8.06 (m, 3H), 7.77-7.68 (m, 3H), 7.57 (d, J = 7.1 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.56-4.37 (m, 2H), 4.25-4.12 (m, 1H), 3.85 (d, J = 12.7 Hz, 2H), 3.75 (s, 3H), 3.26-3.19 (m, 2H), 3.03-2.74 (m, 2H), 2.62-2.41 (m, 1H), 2.25-2.13 (m, 3H), 2.03-1.85 (m, 2H). D212 630.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.23 (s, 1H), 8.24 (s, 1H, FA), 8.06 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 8.2, 2.5 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.91 (s, 2H), 5.09 (dd, J = 13.1, 5.0 Hz, 1H), 4.85-4.75 (m, 1H), 4.45-4.16 (m, 2H), 3.85 (s, 6H), 3.72-3.63 (m, 7H), 3.13-3.07 (m, 2H), 2.94-2.83 (m, 1H), 2.65-2.59 (m, 1H), 2.42-2.35 (m, 1H), 2.04-1.98 (m, 1H). D213 630.15 .sup.1H NMR (300 MHz, Methanol-d4) δ 9.10 (s, 1H), 8.01 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.27-7.16 (m, 2H), 7.02 (s, 2H), 5.23-5.04 (m, 2H), 4.54-4.43 (m, 4H), 4.43-4.39 (m, 2H), 4.12-3.93 (m, 8H), 3.77 (s, 3H), 3.00-2.86 (m, 1H), 2.85-2.75 (m, 1H), 2.60- 2.42 (m, 1H), 2.25-2.13 (m, 1H). D214 697.15 .sup.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.99 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.88 (s, 2H), 6.68 (d, J = 8.1 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.38-4.13 (m, 2H), 3.85 (s, 6H), 3.63 (s, 3H), 3.57 (d, J = 4.5 Hz, 6H), 2.97-2.83 (m, 1H), 2.77 (s, 3H), 2.63-2.54 (m, 2H), 2.37 (dd, J = 13.2, 4.6 Hz, 2H), 2.02-1.94 (m, 1H), 1.73 (t, J = 5.5 Hz, 4H). D215 683.2 .sup.1H NMR (400 MHz, Methanol-d4) δ 9.47 (s, 1H), 7.99 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.19 (s, 2H), 6.86 (d, J = 2.2 Hz, 1H), 6.77 (m, J = 8.2, 2.3 Hz, 1H), 5.16-5.07 (m, 1H), 4.37 (d, J = 7.8 Hz, 2H), 4.30 (s, 2H), 3.98 (s, 6H), 3.78 (s, 3H), 3.74 (s, 4H), 3.24 (s, 4H), 2.96-2.83 (m, 1H), 2.83-2.73 (m, 1H), 2.56-2.40 (m, 1H), 2.21- 2.09 (m, 5H). D216 682.3 .sup.1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.55 (d, J = 3.2 Hz, 1H), 7.89 (d, J = 3.2 Hz, 1H), 7.44-7.27 (m, 2H), 6.84 (s, 2H), 6.76-6.62 (m, 2H), 5.08 (dd, J = 13.1, 5.1 Hz, 1H), 4.38-4.12 (m, 2H), 3.86 (s, 6H), 3.67-3.53 (m, 6H), 3.50 (s, 3H), 3.02- 2.80 (m, 1H), 2.66-2.52 (m, 4H), 2.43-2.26 (m, 2H), 2.06-1.91 (m, 1H), 1.75 (s, 4H). D217 667.45 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.74 (s, 1H), 8.16 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.38 (s, 2H), 6.89 (d, J = 2.1 Hz, 1H), 6.81 (dd, J = 8.2, 2.3 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.45-4.36 (m, 4H), 4.05 (s, 6H), 3.91-3.68 (m, 7H), 3.62-3.40 (m, 2H), 3.29-3.12 (m, 2H), 3.01-2.74 (m, 2H), 2.50 (qd, J = 13.0, 4.7 Hz, 1H), 2.39-1.98 (m, 5H). D218 747.45 .sup.1H NMR (300 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.24 (s, 1H, FA), 7.86 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.48-7.37 (m, 2H), 7.30 (s, 2H), 5.23 (ddd, J = 13.2, 5.2, 2.2 Hz, 1H), 4.71 (dd, J = 15.5, 7.7 Hz, 1H), 4.53-4.41 (m, 4H), 4.10 (d, J = 1.1 Hz, 7H), 3.98 (d, J = 13.1 Hz, 1H), 3.84 (s, 3H), 3.32 (d, J = 13.3 Hz, 1H), 3.20 (d, J = 6.3 Hz, 1H), 3.05-2.96 (m, 7H), 2.92-2.82 (m, 1H), 2.58 (qd, J = 13.1, 4.7 Hz, 1H), 2.33-2.09 (m, 3H). D219 654.4 .sup.1H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 14.9 Hz, 2H), 6.93 (d, J = 2.2 Hz, 2H), 6.51 (s, 1H), 5.03 (dd, J = 13.4, 5.1 Hz, 1H), 4.43-4.20 (m, 2H), 4.06-3.93 (m, 3H), 3.78 (s, 6H), 3.59 (s, 3H), 3.01 (t, J = 12.1 Hz, 2H), 2.88-2.72 (m, 1H), 2.70-2.62 (m, 1H), 2.43-2.24 (m, 1H), 1.97 (dd, J = 22.7, 10.4 Hz, 3H), 1.73 (t, J = 10.8 Hz, 2H). D220 794.7 .sup.1H NMR (400 MHz, Methanol-d4) δ 7.78-7.69 (m, 3H), 7.61 (d, J = 5.4 Hz, 1H), 7.08 (s, 2H), 7.06-6.97 (m, 2H), 5.14 (dd, J = 13.4, 5.2 Hz, 1H), 4.55-4.37 (m, 4H), 4.02 (s, 6H), 3.76 (s, 3H), 3.65 (d, J = 12.5 Hz, 2H), 3.59-3.53 (m, 1H), 3.40-3.33 (m, 1H), 3.28- 3.16 (m, 2H), 3.10 (d, J = 6.7 Hz, 2H), 3.04-2.87 (m, 3H), 2.84- 2.75 (m, 1H), 2.74-2.64 (m, 1H), 2.57-2.41 (m, 2H), 2.36- 2.21 (m, 2H), 2.21-1.93 (m, 9H), 1.71-1.57 (m, 2H). DD1 775.10 .sup.1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.05-8.89 (m, 2H), 8.61 (d, J = 8.4 Hz, 2H), 8.32 (dd, J = 6.4, 2.9 Hz, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 7.36-7.24 (m, 2H), 6.90 (s, 2H), 4.87 (d, J = 47.4 Hz, 2H), 4.55 (s, 1H), 3.83 (s, 7H), 3.62 (s, 4H), 3.46 (s, 2H), 2.13 (s, 8H). DD2 654.20 .sup.1H NMR (300 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.44-8.36 (m, 2H), 7.74-7.67 (m, 2H), 7.61-7.50 (m, 2H), 7.36-7.27 (m, 2H), 7.00 (s, 2H), 4.12-3.86 (m, 12H), 3.75 (s, 3H), 3.11-2.98 (m, 4H).

Example 31—BRD9 Bromodomain TR-FRET Competition Binding Assay

[1047] This example demonstrates the ability of the compounds of the disclosure to biochemically inhibit BRD9 bromodomain in a competition binding assay.

[1048] Procedure: His-Flag-BRD9 (P133-K239; Swiss Prot Q9H8M2; SEQ ID NO:1 mgsshhhhhhenlyfq/gdykddddkgslevlfqg/PAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMII KHPMDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSK) was cloned, expressed, purified, and then treated with TEV protease. Cleaved His tag was removed by purification. The binding of a biotinylated small molecule ligand of BRD9 was assessed via the LANCE® TR-FRET platform (PerkinElmer), and the compounds were assayed for inhibitory activity against this interaction.

[1049] Results: A mixture of biotinylated-ligand and SureLight™ Allophycocyanin-Streptavidin (APC-SA, PerkinElmer AD0201) in 50 mM HEPES (pH 7.4), 50 mM NaCl, 1 mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01% (w/v) bovine serum albumin was added to a white 384-well PerkinElmer Proxiplate Plus plate. DMSO or 3-fold serially diluted compounds were then added to the Proxiplate followed by addition of Flag-BRD9. After a 10-minute incubation at room temperature, Eu-W1024 anti-FLAG (PerkinElmer, AD0273) was added. The final reaction mixture that contained 3.75 nM biotinylated ligand, 3 nM Flag-BRD9, 7.5 nM SureLight™ Allophycocyanin-Streptavidin, and 0.2 nM Eu-W1024 anti-FLAG was incubated at room temperature for 90 minutes.

[1050] The plates were then read on a PerkinElmer Envision plate reader to determine the ratio of emission at 665 nm over 615 nm. Data was normalized to a DMSO control (100%) and a no protein control (0%) and then fit to a four parameter, non-linear curve fit to calculate an IC.sub.50 (μM) as shown in Table 5. As shown by the results in Table 5, a number of compounds of the present disclosure exhibit an IC.sub.50 value of <1 μM for BRD9 binding, indicating their affinity for targeting BRD9.

TABLE-US-00012 TABLE 5 Bromodomain TR-FRET Binding Compound No. Bromodomain TR-FRET BRD9 IC.sub.50 (nM) B1 +++ B2 ++++ B3 +++ B4 +++ B5 ++++ B6 ++++ B7 ++ B8 +++ B9 +++ B10 +++ B11 ++ D1 ++ D2 ++++ D3 +++ D4 +++ D5 ++ D6 ++++ D7 ++ D8 ++ D9 +++ D10 ++++ D11 ++++ D12 ++++ D13 ++++ D14 +++ D15 ++++ “+” indicates inhibitory effect of ≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicates inhibitory effect of ≥10 nM; “++++” indicates inhibitory effect of <10 nM; “NT” indicates not tested

Example 32—SYO1 BRD9 NanoLuc Degradation Assay

[1051] This example demonstrates the ability of the compounds of the disclosure to degrade a Nanoluciferase-BRD9 fusion protein in a cell-based degradation assay.

[1052] Procedure: A stable SYO-1 cell line expressing 3×FLAG-NLuc-BRD9 was generated. On day 0 cells were seeded in 30 μL media into each well of 384-well cell culture plates. The seeding density was 8000 cells/well. On day 1, cells were treated with 30 nL DMSO or 30 nL of 3-fold serially DMSO-diluted compounds (10 points in duplicates with 1 μM as final top dose). Subsequently plates were incubated for 6 hours in a standard tissue culture incubator and equilibrated at room temperature for 15 minutes. Nanoluciferase activity was measured by adding 15 μL of freshly prepared Nano-Glo Luciferase Assay Reagent (Promega N1130), shaking the plates for 10 minutes and reading the bioluminescence using an EnVision reader.

[1053] Results: The Inhibition % was calculated using the following formula: % Inhibition=100×(Lum.sub.HC−Lum.sub.Sample)/(Lum.sub.HC−Lum.sub.LC). DMSO treated cells are employed as High Control (HC) and 1 μM of a known BRD9 degrader standard treated cells are employed as Low Control (LC). The data was fit to a four parameter, non-linear curve fit to calculate IC.sub.50 (μM) values as shown in Table 6A and Table 6B. As shown by the results in Table 6A and Table 6B, a number of compounds of the present disclosure exhibit an IC.sub.50 value of <1 μM for the degradation of BRD9, indicating their use as compounds for reducing the levels and/or activity of BRD9 and their potential for treating BRD9-related disorders.

TABLE-US-00013 TABLE 6A SYO1 BRD9-NanoLuc Degradation Compound No. SYO1 BRD9-NanoLuc degradation IC.sub.50 (nM) D1 + D2 +++ D3 ++++ D4 +++ D5 + D6 + D7 ++ D8 ++ D9 + D10 ++++ D11 + D12 ++++ D13 ++++ D14 ++ D15 ++++ “+” indicates inhibitory effect of ≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicates inhibitory effect of ≥10 nM; “++++” indicates inhibitory effect of <10 nM; “NT” indicates not tested

TABLE-US-00014 TABLE 6B SYO1 BRD9-NanoLuc Degradation Compound No. SYO1 BRD9-NanoLuc degradation IC.sub.50 (nM) D16 ++++ D17 ++++ D18 ++++ D19 ++++ D20 ++++ D21 ++++ D22 ++++ D23 ++++ D24 ++++ D25 ++++ D26 ++++ D27 ++++ D28 ++++ D29 ++++ D30 +++ D31 +++ D32 ++ D33 ++++ D34 ++ D35 ++++ D36 ++++ D37 ++++ D38 ++++ D39 ++++ D40 ++++ D41 ++++ D42 ++++ D43 ++++ D44 +++ D45 + D46 ++++ D47 +++ D48 +++ D49 ++++ D50 ++++ D51 +++ D52 +++ D53 +++ D54 ++ D55 ++ D56 +++ D57 ++++ D58 +++ D59 +++ D60 ++++ D61 ++ D62 +++ D63 ++ D64 ++ D65 ++++ D66 ++++ D67 +++ D68 +++ D69 +++ D70 ++++ D71 +++ D72 ++++ D73 ++++ D74 ++++ D75 ++++ D76 +++ D77 ++++ D78 ++++ D79 ++++ D80 ++ D81 ++ D82 ++ D83 ++++ D84 ++++ D85 ++++ D86 ++++ D87 ++++ D88 +++ D89 ++++ D90 ++++ “+” indicates inhibitory effect of ≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicates inhibitory effect of ≥10 nM; “++++” indicates inhibitory effect of <10 nM; “NT” indicates not tested

TABLE-US-00015 TABLE 6C SYO1 BRD9-NanoLuc Degradation Compound No. SYO1 BRD9-NanoLuc degradation IC.sub.50 (nM) D91 ++++ D92 ++++ D93 ++++ D94 ++++ D95 ++ D96 ++++ D97 ++++ D98 ++++ D99 ++++ D100 ++++ D101 ++++ D102 ++++ D103 ++++ D104 ++++ D105 ++++ D106 ++++ D107 ++++ D108 ++++ D109 ++++ D110 ++++ D111 ++++ D112 ++++ D113 ++++ D114 ++++ D115 ++++ D116 ++++ D117 ++++ D118 ++++ D119 ++++ D120 ++++ D121 ++++ D122 ++++ D123 ++++ D124 ++++ D125 ++++ D126 ++++ D127 ++++ D128 ++++ D129 ++++ D130 ++++ D131 ++++ D132 ++++ D133 ++++ D134 ++++ D135 ++++ D136 ++++ D137 ++ D138 ++++ D139 ++++ D140 ++++ D141 ++++ D142 + D143 + D144 ++++ D145 ++ D146 ++++ D147 ++++ D148 + D149 ++++ D150 ++++ D151 ++++ D152 ++++ D153 ++++ D154 ++++ D155 ++++ D156 ++++ D157 ++++ D158 ++++ D159 ++++ D160 ++++ D161 ++++ D162 ++++ D163 ++++ D164 ++++ D165 ++++ D166 ++++ D167 ++++ D168 ++++ D169 ++++ D170 ++++ D171 +++ D172 + D173 ++++ D174 ++++ D175 ++++ D176 ++++ D177 ++++ D178 ++++ D179 ++++ D180 ++++ D181 ++++ D182 ++++ D183 ++++ D184 ++++ D185 ++++ D186 ++++ D187 ++++ D188 ++++ D189 ++++ D190 ++++ D191 ++++ D192 ++++ D193 ++++ D194 ++++ D195 ++++ D196 ++++ D197 ++++ D198 +++ D199 ++++ D200 ++++ D201 ++++ D202 ++++ D203 ++++ D204 ++ D205 ++++ D206 ++++ D207 ++++ D208 ++++ D209 ++++ D210 ++++ D211 +++ D212 ++++ D213 ++++ D214 ++++ D215 ++++ D216 ++++ D217 ++++ D218 +++ D219 ++++ D220 ++++ DD1 + DD2 + “+” indicates inhibitory effect of ≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicates inhibitory effect of ≥10 nM; “++++” indicates inhibitory effect of <10 nM; “NT” indicates not tested

Other Embodiments

[1054] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

[1055] While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[1056] Other embodiments are in the claims.