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Compound and use thereof

文档序号：473795 发布日期：2021-12-31 浏览：15次 中文

阅读说明：本技术 化合物及其用途 (Compound and use thereof ) 是由 S·K·拉佩尔 杨朝霞 J·T·罗威 J·H·沃伊特 M·内瑟顿 F·布吕塞尔 于 2020-01-29 设计创作，主要内容包括：本发明涉及用于治疗BAF相关病症,如癌症和病毒感染的方法和组合物。(The present invention relates to methods and compositions for treating BAF-related disorders, such as cancer and viral infections.)

1. A compound having the structural formula I:

Wherein

R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl, optionally substituted C1-C6Heteroalkyl or optionallySubstituted C3-C10A carbocyclic group;

Z1is CR2Or N;

R2is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

X1is N or CH, and X2Is C-R7(ii) a Or X1Is C-R7And X2Is N or CH;

R7is optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;

X3is N or CH;

X4is N or CH;

g is optionally substituted C3-C10Carbocyclyl, C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

or a pharmaceutically acceptable salt thereof.

2. A compound having the structure of formula II:

A-L-B

in the formula II, the compound is shown in the specification,

wherein

L is a linker;

b is a degradation moiety; and is

A has the structure of formula III:

wherein

R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl, optionally substituted C 1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

Z1is CR2Or N;

R2is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

X1is N or CH, and X2Is C-R7"; or X1Is C-R7", and X2Is N or CH;

R7"isOptionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;

R7' is H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

X3is N or CH;

X4is N or CH;

g' isOptionally substituted C3-C10Carbocyclyl, C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

g' is optionally substituted C3-C10Carbocyclylene, C2-C9Heterocyclylene radical, optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group; and is

A1Is the bond between a and the linker,

wherein G' isOr R7"is

Or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl or optionally substituted C3-C10A carbocyclic group.

4. The compound of claim 3, wherein R1Is H.

5. The compound of claim 3, wherein R1Is optionally substituted C1-C6An alkyl group.

6. The compound of claim 5, wherein R1Is that

7. The compound of claim 6, wherein R1Is optionally substituted C2-C6An alkenyl group.

8. The compound of claim 7, wherein R1Is that

9. The compound of claim 8, wherein R1Is optionally substituted C3-C10A carbocyclic group.

10. The compound of claim 9, wherein R1Is that

11. The compound of claim 3, wherein R1Is H or

12. The compound of claim 11, wherein R1Is H.

13. The compound of claim 11, wherein R1Is that

14. The compound of any one of claims 1 to 13A compound of formula (I) wherein Z1Is N.

15. The compound of any one of claims 1 to 13, wherein Z is1Is CR2。

16. The compound of claim 15, wherein R2Is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl or optionally substituted C 6-C10And (4) an aryl group.

17. The compound of claim 16, wherein R2Is H, halogen or optionally substituted C1-C6An alkyl group.

18. The compound of claim 17, wherein R2Is H, F or

19. The compound of any one of claims 2 to 18, wherein X1Is N, and X2Is C-R7″。

20. The compound of any one of claims 2 to 18, wherein X1Is CH, and X2Is C-R7″。

21. The compound of any one of claims 2 to 18, wherein X1Is C-R7", and X2Is N.

22. The compound of any one of claims 2 to 18, wherein X1Is C-R7", and X2Is CH.

23. The compound of any one of claims 2 to 22, whereinR7Is optionally substituted C1-C6Alkyl, optionally substituted C1-C6A heteroalkyl group, an optionally substituted carbocyclyl group having 3 to 6 atoms, or an optionally substituted heterocyclyl group having 3 to 6 atoms.

24. The compound of claim 23, wherein R7Is optionally substituted C1-C6An alkyl group.

25. The compound of claim 24, wherein R7"is

26. The compound of claim 23, wherein R7Is optionally substituted C1-C6A heteroalkyl group.

27. The compound of claim 23, wherein R 7Is optionally substituted C1-C6Alkoxy or optionally substituted amino.

28. The compound of claim 26 or 27, wherein R7"is-NR3R4OR-OR4Wherein R is3Is H or optionally substituted C1-C6Alkyl, and R4Is optionally substituted C1-C6An alkyl group.

29. The compound of claim 28, wherein R7"is-NR3R4。

30. The compound of claim 29, wherein X1Is N, and X2Is C-NR3R4。

31. The compound of claim 29, wherein X1Is C-NR3R4And X2Is N.

32. The compound of claim 28, wherein R7is-OR4。

33. The compound of claim 32, wherein X1Is N, and X2Is C-OR4。

34. The compound of claim 32, wherein X1Is C-OR4And X2Is N.

35. The compound of any one of claims 28-34, wherein R3Is H.

36. The compound of any one of claims 28 to 35, wherein R3Is that

37. The compound of any one of claims 28 to 36, wherein Y is4Is that

38. The compound of claim 23, wherein R7"is an optionally substituted carbocyclyl having 3 to 6 atoms.

39. The compound of claim 38, wherein R7"is

40. The compound of claim 23, wherein R 7"is an optionally substituted heterocyclic group having 3 to 6 atoms.

41. The compound of claim 40, wherein R7"is

42. The compound of claim 23, wherein R7"is an optionally substituted sulfone or an optionally substituted sulfonamide.

43. The compound of claim 42, wherein R7"is

44. The compound of any one of claims 2 to 43, wherein R7"is

45. The compound of claim 44, wherein R7"is

46. The compound of claim 45, wherein R7"is

47. The compound of any one of claims 2 to 46, wherein G "is

48. The compound of claim 47, wherein G' is optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

49. The compound of claim 48, wherein G' is optionally substituted C6-C10An arylene group.

50. The compound of claim 49, wherein G' is

Wherein

RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substitutedSubstituted C 2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd is

Is optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1The substitution is carried out by the following steps,

wherein R isG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

51. The compound of claim 50, wherein RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd is

Is optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1The substitution is carried out by the following steps,

wherein R isG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

52. The compound of claim 51, wherein RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

53. The compound of claim 52, wherein RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1、F、Cl、

54. The compound of claim 53, wherein RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1、F、

55. The compound of claim 54, wherein RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1、F、Cl、

56. The compound of claim 55, wherein RG3' is a1。

57. The compound of claim 55, wherein RG1' is H; rG2' isRG3' is a1；RG4' isAnd R isG5' is H.

58. The compound of claim 55, wherein RG1' is H; rG2' isRG3' is a1；RG4' is H; and R isG5' is

59. The compound of claim 55, wherein RG1' is H; rG2' isRG3' is a1；RG4' is Cl or F; and R isG5' is H.

60. The compound of claim 55, wherein RG1' is H; rG2' isRG3' is a1；RG4' is H; and R isG5' is H.

61. The compound of claim 55, wherein R G1' is H; rG2' isRG3' is a1；RG4' isAnd R isG5' is H.

62. The compound of claim 51, wherein RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd is

Is optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A1The substitution is carried out by the following steps,

wherein R isG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

63. The compound of claim 51, wherein RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd is

Is optionally substituted C2-C9Heteroaryl optionally substituted with A1The substitution is carried out by the following steps,

wherein R isG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

64. The compound of claim 62, wherein G' is Wherein R isG6' is H, A1Or optionally substituted C1-C6An alkyl group.

65. The compound of claim 63, wherein G' is Wherein R isG6' is H, A1Or optionally substituted C1-C6An alkyl group.

66. The compound of claim 64 or 65, wherein RG6' is H, A1Or

67. The compound of claim 66, wherein RG6' is H.

68. The compound according to claim 48, wherein said compound is selected from the group consisting of,wherein G' is optionally substituted C2-C9A heteroarylene group.

69. The compound of claim 68, wherein G' is

Wherein

RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG7' and RG8′、RG8' and RG9′、RG9' and RG10' and/or RG10' and RG11Are combined with the carbon atom to which each is attached to formAnd is

Is optionally substituted C6-C10Aryl radicals, renOptionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A1The substitution is carried out by the following steps,

wherein R isG7′、RG8′、RG9′、RG10' and RG11One of' is A1(ii) a OrQuilt A1And (4) substitution.

70. The compound of claim 69, wherein RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C 2-C5A heterocyclic group.

71. The compound of claim 69 or 70, wherein G' is

72. The compound of any one of claims 69 to 71, wherein RG7' is H; rG8' isRG9' is a1(ii) a And R isG11' is H.

73. The compound of claim 68, wherein G' is

Wherein

RG12′、RG13' and RG14' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG12' and RG14Are combined with the carbon atom to which each is attached to formAnd is

Is optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1The substitution is carried out by the following steps,

wherein R isG12′、RG13' and RG14One of' is A1Or is orQuilt A1And (4) substitution.

74. The compound of any one of claims 2 to 22, wherein R 7"is

75. The compound of claim 74, wherein G "is optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group.

76. The compound of claim 75, wherein G "is optionally substituted C6-C10And (4) an aryl group.

77. The compound of claim 76, wherein G "is

Wherein

RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

78. The compound of claim 77, wherein RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C 3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

79. The compound of claim 78, wherein RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

80. The compound of claim 79, wherein RG1、RG2、RG3、RG4And RG5Each of which is independently H, F, Cl,

81. The compound of claim 80, wherein RG1、RG2、RG3、RG4And RG5Each of which is independently H, F,

82. The compound of claim 81, wherein RG1、RG2、RG3、RG4And RG5Each of which is independently H, F, Cl,

83. The compound of claim 82, wherein RG1、RG2、RG3、RG4And RG5Two or more of which are H.

84. The compound of claim 83, wherein RG1Is H; rG2Is thatRG3Is thatRG4Is thatAnd R isG5Is H.

85. The compound of claim 83, wherein RG1Is H; rG2Is thatRG3Is thatRG4Is H; and R isG5Is that

86. The compound of claim 83, wherein RG1Is H; rG2Is thatRG3Is thatRG4Is Cl or F; and R is G5Is H.

87. The compound of claim 83, wherein RG1Is H; rG2Is thatRG3Is thatRG4Is H; and R isG5Is H.

88. The compound of claim 83, wherein RG1Is H; rG2Is thatRG3Is thatRG4Is thatAnd R isG5Is H.

89. The compound of claim 78, wherein RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heterocyclic group.

90. The compound of claim 78, wherein RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heteroaryl group.

91. The compound of claim 89, wherein G "is

Wherein R isG6Is H or optionally substituted C1-C6An alkyl group.

92. The compound of claim 90, wherein G "is

Wherein R isG6Is H or optionally substituted C1-C6An alkyl group.

93. The compound of claim 91 or 92, wherein RG6Is H or

94. The compound of claim 93, wherein RG6Is H.

95. The compound of claim 75, wherein G "is optionally substituted C2-C9A heteroaryl group.

96. The compound of claim 95, wherein G "is

Wherein

RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C 1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

97. The compound of claim 96, wherein RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

98. The compound of claim 96 or 97, wherein G "is

99. The compound of claim 98, wherein RG7Is H; rG8Is thatRG9Is H; and R isG11Is H.

100. The compound of claim 89, wherein G "is

Wherein

RG12、RG13And RG14Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C 1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG12And RG14Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

101. The compound of any one of claims 74-100, wherein R7' is H, optionally substituted C1-C6Alkyl or optionally substituted C3-C10A carbocyclic group.

102. The compound of claim 101, wherein R7' is H or optionally substituted C1-C6An alkyl group.

103. The compound of claim 102, wherein R7' is H,

104. The compound of claim 103, wherein R7' is H or

105. The compound of claim 104, wherein R7' is H.

106. The compound of claim 104, wherein R7' is

107. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIa:

Or a pharmaceutically acceptable salt thereof.

108. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIc:

or a pharmaceutically acceptable salt thereof.

109. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIe:

or a pharmaceutically acceptable salt thereof.

110. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIf:

or a pharmaceutically acceptable salt thereof.

111. The compound of any one of claims 2-106, wherein a has the structure of formula IIIg:

or a pharmaceutically acceptable salt thereof.

112. The compound of any one of claims 2 to 106, wherein a has the structure of formula ihh:

or a pharmaceutically acceptable salt thereof.

113. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIj:

or a pharmaceutically acceptable salt thereof.

114. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIn:

or a pharmaceutically acceptable salt thereof.

115. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIo:

or a pharmaceutically acceptable salt thereof.

116. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIs:

or a pharmaceutically acceptable salt thereof.

117. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIu:

or a pharmaceutically acceptable salt thereof.

118. The compound of any one of claims 2 to 106, wherein a has the structure of formula IIIv:

or a pharmaceutically acceptable salt thereof.

119. The compound of any one of claims 2 to 118, wherein said degradation moiety is a ubiquitin ligase binding moiety.

120. The compound of claim 119, wherein the ubiquitin ligase binding moiety comprises a Cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2) or a von hippel-lindau (VHL) ligand, or a derivative or analog thereof.

121. The compound of claim 119 or 120, wherein the degradation moiety comprises the structure of formula Y:

wherein

A2Is a bond between the degradation moiety and the linker;

v1 is 0, 1, 2, 3, 4 or 5;

u1 is 1, 2 or 3;

T1is a key or

T2Is that

R5AIs H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

each RJ1Independently is halogen, optionally substituted C 1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

JAabsent, is O, optionally substituted amino, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group; and is

J is absent, is optionally substituted C3-C10Carbocyclylene, optionally substituted C6-C10Arylene, optionally substituted C2-C9Heterocyclylene or optionally substituted C2-C9A heteroarylene group, a heteroaryl group,

or a pharmaceutically acceptable salt thereof.

122. The compound of claim 121, wherein T is2Is that

123. The compound of claim 122, wherein T2Is that

124. The compound of claim 122, wherein T2Is that

125. The compound of any one of claims 121-124, wherein the structure of formula Y has the structure of formula Y1:

or a pharmaceutically acceptable salt thereof.

126. The compound of claim 125, wherein T is1Is a bond.

127. The compound of claim 125, wherein T is1Is that

128. The compound of any one of claims 121-127, wherein the structure of formula Y has the structure of formula Y2:

or a pharmaceutically acceptable salt thereof.

129. The compound of any one of claims 121-127, wherein the structure of formula Y has the structure of formula Z:

or a pharmaceutically acceptable salt thereof.

130. The compound of any one of claims 121 to 129, wherein u1 is 2.

131. The compound of claim 130, wherein the structure of formula Z has the structure of formula AA 0:

or a pharmaceutically acceptable salt thereof.

132. The compound of any one of claims 121 to 129, wherein u1 is 1.

133. The compound of claim 132, wherein the structure of formula Z has the structure of formula AB:

or a pharmaceutically acceptable salt thereof.

134. The compound of any one of claims 121 to 129, wherein u1 is 3.

135. The compound of claim 134, wherein the structure of formula Z has the structure of formula AC:

or a pharmaceutically acceptable salt thereof.

136. The compound of any one of claims 121-135, wherein JAIs absent.

137. The compound of any one of claims 121-135, wherein JAIs optionally substituted C1-C6An alkyl group.

138. The compound of claim 137, wherein JAIs that

139. The compound of claim 138, wherein the structure of formula AA0 has the structure of formula AA 0:

or a pharmaceutically acceptable salt thereof.

140. The compound of any one of claims 121 to 139, wherein v1 is 0, 1, 2, or 3.

141. The compound of claim 140, wherein v1 is 0.

142. The compound of claim 141, wherein the structure of formula AA has the structure of formula AA 1:

or a pharmaceutically acceptable salt thereof.

143. The compound of any one of claims 121-142, wherein RA5Is H or optionally substituted C1-C6An alkyl group.

144. The compound of claim 143, wherein RA5Is H.

145. The compound of claim 143, wherein RA5Is methyl.

146. The compound of any one of claims 121-142, wherein RA5Is optionally substituted C1-C6A heteroalkyl group.

147. The compound of claim 146, wherein RA5Is that

148. The compound of claim 139, wherein the structure of formula AA has the structure of formula AA 1:

or a pharmaceutically acceptable salt thereof.

149. The compound of claim 133, wherein the structure of formula AB has the structure of formula AB 1:

or a pharmaceutically acceptable salt thereof.

150. The compound of claim 135, wherein the structure of formula AC has the structure of formula AC 1:

or a pharmaceutically acceptable salt thereof.

151. The compound of any one of claims 121 to 150, wherein J is absent.

152. The compound of claim 151, wherein the structure of formula AA1 has the structure of formula AA 2:

or a pharmaceutically acceptable salt thereof.

153. The compound of any one of claims 121 to 150, wherein J is optionally substituted C3-C10Carbocyclylene or optionally substituted C6-C10An arylene group.

154. The compound of claim 153, wherein the structure of formula AA has the structure of formula AA 4:

or a pharmaceutically acceptable salt thereof.

155. The compound of any one of claims 121 to 150, wherein J is optionally substituted C2-C9Heterocyclylene or optionally substituted C2-C9A heteroarylene group.

156. The compound of claim 155, wherein the structure of formula AA has the structure of formula AA 3:

or a pharmaceutically acceptable salt thereof.

157. The compound of claim 155, wherein the structure of formula AA has the structure of formula a:

wherein

Y1Is that

RA5Is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RA6is H or optionally substituted C1-C6An alkyl group; and R isA7Is H or optionally substituted C1-C6An alkyl group; or RA6And RA7Together with the carbon atom to which each is bound, form an optionally substituted C3-C6Carbocyclyl or optionally substituted C2-C5A heterocyclic group; or RA6And R A7Together with the carbon atom to which each is bound, form an optionally substituted C3-C6Carbocyclyl or optionally substituted C2-C5A heterocyclic group;

RA8is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RA1、RA2、RA3and RA4Is independently H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, thiol, or optionally substituted amino; or RA1And RA2、RA2And RA3And/or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd is

Is optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A2The substitution is carried out by the following steps,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2Substitution; or a pharmaceutically acceptable salt thereof.

158. The compound of claim 157, RA1、RA2、RA3And RA4Is independently H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C 2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino;or RA1And RA2、RA2And RA3And/or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd is

Is optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A2The substitution is carried out by the following steps,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2Substituted, or a pharmaceutically acceptable salt thereof.

159. The compound of claim 158, wherein RA1、RA2、RA3And RA4Is H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, optionally substituted amino; or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd is

Is optionalSubstituted C2-C9Heterocyclyl, optionally substituted with A2,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

160. The compound of claim 159, wherein RA1、RA2、RA3And RA4Is independently H, A2、F、Or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to form And is

Is optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2The substitution is carried out by the following steps,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

161. The compound of any one of claims 157 to 160, wherein Y is1Is that

162. The compound of claim 161, wherein Y is1Is that

163. The compound of claim 161, wherein Y is1Is that

164. The compound of claim 163, wherein Y1Is that

165. The compound of claim 164, wherein Y1Is that

166. The compound of any one of claims 157 to 165, wherein the structure of formula a has the structure of formula a 1:

or a pharmaceutically acceptable salt thereof.

167. The compound of any one of claims 157 to 165, wherein the structure of formula a has the structure of formula a 2:

or a pharmaceutically acceptable salt thereof.

168. The compound of any one of claims 157 to 165, wherein the structure of formula a has the structure of formula a 3:

or a pharmaceutically acceptable salt thereof.

169. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula a 4:

or a pharmaceutically acceptable salt thereof.

170. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula a 5:

Or a pharmaceutically acceptable salt thereof.

171. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula a 6:

or a pharmaceutically acceptable salt thereof.

172. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula a 7:

or a pharmaceutically acceptable salt thereof.

173. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula A8:

or a pharmaceutically acceptable salt thereof.

174. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula a 9:

or a pharmaceutically acceptable salt thereof.

175. The compound of any one of claims 157 to 167, wherein the structure of formula a has the structure of formula a 10:

or a pharmaceutically acceptable salt thereof.

176. The compound of any one of claims 157 to 175, wherein of the formula aThe structure is that Or a derivative or analogue thereof.

177. The compound of claim 176, wherein the structure of formula a is

178. The compound of claim 177, wherein the structure of formula a isOr a derivative or analogue thereof.

179. The compound of any one of claims 157 to 175, whereinIs that

Wherein R isA9Is H, A2Optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group.

180. The compound of claim 179, wherein the structure of formula a is

181. The compound of claim 180, wherein RA9Is H.

182. The compound of claim 180, wherein RA9Is A2。

183. The compound of claim 182, wherein the structure of formula a is

184. The compound of claim 155, wherein the structure of formula AA has the structure of formula B:

wherein

RA5Is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RA1、RA2、RA3and RA4Is independently H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, thiol, or optionally substituted amino; or RA1And RA2、RA2And RA3And/or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd is

Is optionally substituted C6-C10Aryl, optionally substituted C 3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A2The substitution is carried out by the following steps,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2The substitution is carried out by the following steps,

or a pharmaceutically acceptable salt thereof.

185. The compound of claim 184, wherein RA1、RA2、RA3And RA4Is H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, optionally substituted amino; or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd is

Is optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2The substitution is carried out by the following steps,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

186. The compound of claim 185, wherein RA1、RA2、RA3And RA4Is independently H, A2、F、Or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd is

Is optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2The substitution is carried out by the following steps,

wherein R isA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

187. The compound of any one of claims 184-186, wherein the structure of formula B has the structure of formula B1:

or a pharmaceutically acceptable salt thereof.

188. The compound of any one of claims 184-186, wherein the structure of formula B has the structure of formula B2:

or a pharmaceutically acceptable salt thereof.

189. The compound of any one of claims 184-186, wherein the structure of formula B has the structure of formula B3:

or a pharmaceutically acceptable salt thereof.

190. The compound of any one of claims 184-186, wherein the structure of formula B has the structure of formula B4:

or a pharmaceutically acceptable salt thereof.

191. The compound of any one of claims 184-186, wherein the structure of formula B is

192. The compound of any one of claims 2 to 118, wherein said degradation moiety comprises the structure of formula C:

wherein

RB1Is H, A2Optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RB2is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RB3is A2Optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

RB4is H, optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C 6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

RB5is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

v2 is 0, 1, 2, 3 or 4;

each RB6Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclic group, optionallySubstituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and is

RB7And RB8Each of which is independently H, halogen, optionally substituted C1-C6Alkyl or optionally substituted C6-C10An aryl group, a heteroaryl group,

wherein R isB1And RB3Is A2，

Or a pharmaceutically acceptable salt thereof.

193. The compound of claim 192, wherein the structure of formula C isOr a derivative or analogue thereof.

194. The compound of any one of claims 2 to 118, wherein said degradation moiety comprises the structure of formula D:

wherein

A2Is a bond between B and the linker;

RC1、RC2and RC7Each of which is independently H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RC3is optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C 6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclic groupOr optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

RC5is optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

v3 is 0, 1, 2, 3 or 4;

each RC8Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v4 is 0, 1, 2, 3 or 4; and is

Each RC9Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol or optionally substituted amino,

or a pharmaceutically acceptable salt thereof.

195. The compound of claim 194, wherein the structure of formula D is

Or a derivative or analogue thereof.

196. The compound of any one of claims 2 to 118, wherein said degradation moiety comprises the structure of formula E:

Wherein

A2Is a bond between B and the linker;

RC10and RC11Each of which is independently H, optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

v5 is 0, 1, 2, 3 or 4;

each RC12Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v6 is 0, 1, 2, 3 or 4; and is

Each R21Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl radical, optionally substitutedSubstituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol or optionally substituted amino,

or a pharmaceutically acceptable salt thereof.

197. The compound of claim 196, wherein the structure of formula E is

Or a derivative or analogue thereof.

198. The compound of any one of claims 2 to 118, wherein the degrading moiety comprises the structure of formula FA:

Wherein

Is thatOr by A2Substituted and substituted with one or more substituents independently selected from H, RFF1And oxo;

is a single or double bond;

u2 is 0, 1, 2 or 3;

A2is a bond between a degrading agent and the linker;

YFais CRFbRFc、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl,P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

YFbIs NH, NRFF1、CH2、CHRFF1、C(RFF1)2O or S;

YFcis CRFdRFe、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

RFb、RFc、RFdAnd RFeEach of which is independently H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxy, alkoxy, amino, -NH alkyl, or-N alkyl2；

Or RFbAnd RFcTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or RFdAnd RFeTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; and is

Or RFdAnd RFbTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

YFdand YFfIs independently CH 2、CHRFF2、C(RFF2)2、C(O)、N、NH、NRFF3O, S or S (O);

YFeis linked to Y and contains 1 to 5 continuous carbon atoms forming a 3-to 8-membered ringFdAnd YFfA bond or a divalent moiety of (a),

wherein 1, 2 or 3 carbon atoms may be replaced by nitrogen, oxygen or sulfur atoms;

wherein one of the ring atoms is replaced by A2Substituted and the other ring atoms are independently selected from H and R by one or moreFF1Substituted with a group of (1); and is

Wherein Y isFeThe consecutive atoms of (a) may be connected by a single or double bond;

each RFF1Independently is H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxy, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxy, or haloalkyl;

each RFF2Independently is alkyl, alkene, alkyne, halogen, hydroxy, 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), -NHSO2Alkyl, -N (alkyl) SO2Alkyl, -NHSO2Aryl, -N (alkyl) SO2Aryl, -NHSO2Alkenyl, -N (alkyl) SO2Alkenyl, -NHSO2Alkynyl, -N (alkyl) SO2Alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, -SH, -S alkyl, or haloalkyl; and is

RFF3Is alkyl, alkenyl, alkynyl, -C (O) H, -C (O) OH, -C (O) alkyl or-C (O) Oalkyl,

wherein if Y isFdOr YFfQuilt A2Substituted, then YFeIs a bond, or a pharmaceutically acceptable salt thereof.

199. The compound of any one of claims 2 to 118, wherein said degrading moiety comprises the structure of formula FB:

in the formula FB,

wherein

Is thatOr by A2Substituted and substituted with one or more substituents independently selected from H, RFF1And oxo;

A2is a bond between a degrading agent and the linker;

YFais CRFbRFc、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

YFbAnd YFgEach of which is independently NH, NRFF1、CH2、CHRFF1、C(RFF1)2O or S;

YFcis CRFdRFe、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

RFb、RFc、RFd、RFe、RFfAnd RFgEach of which is independently H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxy, alkoxy, amino, -NH alkyl, or-N alkyl2；

Or RFbAnd RFcTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or RFdAnd RFeTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

Or RFfAnd RFgTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or RFdAnd RFbTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

or RFdAnd RFfTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

or RFbAnd RFgTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

YFdand YFfIs independently CH2、CHRFF2、C(RFF2)2、C(O)、N、NH、NRFF3O, S or S (O);

YFeis linked to Y and contains 1 to 5 continuous carbon atoms forming a 3-to 8-membered ringFdAnd YFfA bond or a divalent moiety of (a),

wherein 1, 2 or 3 carbon atoms may be replaced by nitrogen, oxygen or sulfur atoms;

wherein one of the ring atoms is substituted by A2Substituted and the other ring atoms are independently selected from H and R by one or moreFF1Substituted with a group of (1); and is

Wherein Y isFeThe consecutive atoms of (a) may be connected by a single or double bond;

each RFF1Independently is H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxy, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxy, or haloalkyl;

Each RFF2Independently is alkyl, alkene, alkyne, halogen, hydroxy, 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), -NHSO2Alkyl, -N (alkyl) SO2Alkyl, -NHSO2Aryl, -N (alkyl) SO2Aryl, -NHSO2Alkenyl, -N (alkyl) SO2Alkenyl, -NHSO2Alkynyl, -N (alkyl) SO2Alkynyl, aliphaticHeteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, -SH, -Salkyl, or haloalkyl; and is

RFF3Is alkyl, alkenyl, alkynyl, -C (O) H, -C (O) OH, -C (O) alkyl or-C (O) Oalkyl,

wherein if Y isFdOr YFfQuilt A2Substituted, then YFeIs a bond, or a pharmaceutically acceptable salt thereof.

200. The compound of any one of claims 2 to 118, wherein said degradation moiety comprises the structure of formula F1:

wherein

A2Is a bond between a degrading agent and the linker; and is

RF1Either is absent or is in the presence of O,

or a pharmaceutically acceptable salt thereof.

201. The compound of any one of claims 2 to 118, wherein said degradation moiety comprises the structure of formula F2:

Wherein

A2Is a bond between a degrading agent and the linker; and is

RF1Either is absent or is in the presence of O,

or a pharmaceutically acceptable salt thereof.

202. The compound of any one of claims 2 to 118, wherein said degradation moiety comprises the structure of formula G:

wherein

A2Is a bond between a degrading agent and the linker; and is

RF1Either is absent or is in the presence of O,

or a pharmaceutically acceptable salt thereof.

203. The compound of any one of claims 2 to 202, wherein the linker has the structure of formula IV:

A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2

formula IV

Wherein

A1Is a bond between the linker and a;

A2is a bond between B and the linker;

B1、B2、B3and B4Each of which is independently optionally substituted C1-C2Alkyl, optionally substituted C1-C3Heteroalkyl, O, S, S (O)2Or NRN；

Each RNIndependently is H, optionally substituted C1-4Alkyl, optionally substituted C2-4Alkenyl, optionally substituted C2-4Alkynyl, optionally substituted C2-6Heterocyclyl, optionally substituted C6-12Aryl or optionally substituted C1-7A heteroalkyl group;

C1and C2Each of which is independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl;

f. each of g, h, i, j, and k is independently 0 or 1; and is

D is optionally substituted C1-10Alkyl, optionally substituted C2-10Alkenyl, optionally substituted C2-10Alkynyl, optionally substituted C 2-6Heterocyclyl, optionally substituted C6-12Aryl, optionally substituted C2-C10Polyethylene glycol or optionally substituted C1-10Heteroalkyl, or A1-(B1)f-(C1)g-(B2)h-is connected to- (B)3)i-(C2)j-(B4)k-A2The chemical bond of (1).

204. The compound of claim 203, wherein B1、B2、B3And B4Each of which is independently optionally substituted C1-C4Alkyl, optionally substituted C1-C4Heteroalkyl radicals or NRN。

205. The compound of claim 202 or 203, wherein each R isNIndependently is H or optionally substituted C1-4An alkyl group.

206. The compound of any one of claims 202-205, wherein each R isNIndependently is H or methyl.

207. The compound of any one of claims 203 to 206, wherein B1And B4Each of which is independently

208. The compound of claim 207, wherein B1Is that

209. The compound of any one of claims 203 to 208, wherein C1And C2Each of which is independently

210. The compound of claim 209, wherein C1Is that

211. The compound of any one of claims 203 to 210, wherein B2Is NRN。

212. The compound of any one of claims 203 to 210, wherein B2Is optionally substituted C1-C4An alkyl group.

213. The compound of any one of claims 203 to 212, wherein f is 0.

214. The compound of any one of claims 203 to 212, wherein f is 1.

215. The compound of any one of claims 203 to 214, wherein g is 1.

216. The compound of any one of claims 203 to 215, wherein h is 0.

217. The compound of any one of claims 203 to 215, wherein h is 1.

218. The compound of any one of claims 203 to 217, wherein i is 0.

219. The compound of any one of claims 203 to 218, wherein j is 0.

220. The compound of any one of claims 203 to 219, wherein k is 0.

221. The compound of any one of claims 203 to 220, wherein the linker has In the structure of (a) to (b),

wherein

x is 1, 2, 3, 4, 5, 6, 7 or 8:

y is 1, 2, 3 or 4;

Rxis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Ryis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group; and is

W is O or SRWWherein R iswIs H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group.

222. The compound of any one of claims 203 to 221, wherein the linker has the structure of:

223. The compound of any one of claims 203 to 221, wherein the linker hasThe structure of (1).

224. The compound of any one of claims 2 to 202, wherein the linker has the structure of formula V:

A1-(E1)-(F1)-(C3)m-(E3)n-(F2)o1-(F3)o2-(E2)p-A2，

formula V

Wherein

A1Is a bond between the linker and a;

A2is a bond between B and the linker;

each of m, n, o1, o2, and p is independently 0 or 1;

E1and E2Is independently O, S, NRNOptionally substituted C1-10Alkylene, optionally substituted C2-10Alkenylene, optionally substituted C2-10Alkynylene, optionally substituted C2-C10Polyethylene glycol or optionally substituted C1-10A heteroalkylene group;

E3is optionally substituted C1-C6Alkylene, optionally substituted C1-C6Heteroalkylene, O, S or NRN：

Each RNIndependently is H, optionallySubstituted C1-4Alkyl, optionally substituted C2-4Alkenyl, optionally substituted C2-4Alkynyl, optionally substituted C2-6Heterocyclyl, optionally substituted C6-12Aryl or optionally substituted C1-7A heteroalkyl group;

C3is carbonyl, thiocarbonyl, sulfonyl or phosphoryl; and is

F1、F2And F3Each of which is independently optionally substituted C3-C10Carbocyclylene, optionally substituted C2-10Heterocyclylene radical, optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

225. The compound of claim 224, wherein the linker has the structure of formula Va:

A1-(E1)-(F1)-(C3)m-(E2)p-A2。

Formula Va

226. The compound of claim 224, wherein the linker has the structure of formula Vb:

A1-(E1)-(F1)-(E2)p-A2。

formula Vb

227. The compound of claim 224, wherein the linker has the structure of formula Vc:

A1-(E1)-(F1)-A2。

formula Vc

228. The compound of claim 224, wherein the linker has the structure of formula Vd:

A1-(E1)-(F1)-(C3)m-(F2)o1-A2。

formula Vd

229. The compound of claim 224, wherein the linker has the structure of formula Ve:

A1-(E1)-(F1)-(E3)n-(F2)o1-(E2)p-A2。

formula Ve

230. The compound of claim 224, wherein the linker has the structure of formula Vf:

A1-(E1)-(F1)-(C3)m-(E3)n-(F2)o1-(E2)p-A2。

formula Vf

231. The compound of claim 224, wherein the linker has the structure of formula Vg:

A1-(E1)-(F1)-(E3)n-(F2)o1-A2，

formula Vg

232. The compound of any one of claims 224 to 231, wherein E1And E2Each of which is independently NRNOptionally substituted C1-10Alkylene, optionally substituted C2-C10Polyethylene glycol or optionally substituted C1-10A heteroalkylene group.

233. The compound of any one of claims 224 to 232, wherein E3Is optionally substituted C1-C6Alkylene, O, S or NRN。

234. The compound of claim 233, wherein E3Is optionally substituted C1-C6An alkylene group.

235. The compound of claim 233, wherein E3Is optionally substituted C1-C3An alkylene group.

236. The compound of claim 233, wherein E3Is that Wherein a is 0, 1, 2, 3, 4 or 5.

237. The compound of claim 233, wherein E3Is that

238. The compound of claim 233, wherein E3Is O.

239. The compound of any one of claims 224 to 238, wherein each R isNIndependently is H or optionally substituted C1-4An alkyl group.

240. The compound of claim 239, wherein each R isNIndependently is H or methyl.

241. The compound of any one of claims 224 to 240, wherein E1Is that Wherein a is 0, 1, 2, 3, 4 or 5.

242. The compound of claim 241, wherein E1Is that

243. The compound of claim 242, wherein E1Is that

244. The compound of any one of claims 224 to 243, wherein E1Is that

Wherein

b is 0, 1, 2, 3, 4, 5 or 6:

Rais H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Rbis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group; and is

RcIs H, optionally substituted C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,Optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group.

245. The compound of claim 244, wherein E 1Is that

246. The compound of claim 245, wherein E1Is that

247. The compound of claim 246, wherein E1Is that

248. The compound of claim 247, wherein E1Is that

249. The compound of any one of claims 244 to 248, wherein RaIs HOr a methyl group.

250. The compound of claim 249, wherein RaIs H.

251. The compound of claim 249, wherein RaIs methyl.

252. The compound of any one of claims 224 to 251, wherein E2Is O, NRW、

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:

Rdis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Reis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Rfis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Rgis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionallySubstituted C3-C6A carbocyclic group; and is

W is O or NRwWherein R iswIs H or optionally substituted C1-C6An alkyl group.

253. The compound of claim 252, wherein E 2Is O,

254. The compound of any one of claims 224 to 253, wherein F1、F2Or F3Each of which is independently optionally substituted C3-C10A carbocyclylene group.

255. The compound of claim 254, wherein C is3-C10Carbocyclylene is monocyclic.

256. The compound of claim 254, wherein C is3-C10Carbocyclylene is polycyclic.

257. The compound of claim 256, wherein C is3-C10The carbocyclylene group is fused.

258. The compound of claim 256, wherein C is3-C10Carbocyclylene is spirocyclic.

259. The compound of claim 256, wherein C is3-C10The carbocyclylene group is bridged.

260. The compound of claim 259, wherein C is3-C10The carbocyclic radical being

261. The compound of claim 260, wherein C is3-C10The carbocyclic radical being

262. The compound of any one of claims 224 to 253, wherein F1、F2Or F3Each of which is independently optionally substituted C2-C6A heterocyclylene group.

263. The compound of claim 262, wherein said C is2-C6Heterocyclylene groups are monocyclic.

264. The compound of claim 263, wherein C is2-C6Heterocyclylene is

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 RhIndependently is2H. Halogen, optionally substituted C1-C6Alkyl, ORi2Or NRi3Ri4(ii) a Or two RhThe radicals, together with the carbon atoms to which they are each attached, combine to form optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group; or two RhThe radicals, together with the carbon atoms to which they are each attached, combine to form optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group;

Ri1is H or optionally substituted C1-C6An alkyl group;

Ri2is H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

265. the compound of claim 264, wherein C is2-C9Heterocyclylene is

266. The compound of claim 264 or 265, wherein each R ishIndependently is2H. Halogen, cyano, optionally substituted C1-C6Alkyl, ORi2Or NRi3Ri4。

267. The compound of claim 266, wherein each R ishIndependently is2H. F, methyl,

268. The compound of claim 267, wherein each RhIndependently F, methyl or NRi3Ri4。

269. The compound of any one of claims 264 to 268, wherein q1 is 0, 1, or 2.

270. The compound of any one of claims 264 to 269, wherein q2 is 0, 1, or 2.

271. The compound of any one of claims 264 to 270, wherein q3 is 0, 1, or 2.

272. The compound of any one of claims 264 to 271, wherein C is C2-C9Heterocyclylene is

273. The compound of claim 272, wherein C is2-C9Heterocyclylene is

274. The compound of claim 273, wherein said C is2-C9Heterocyclylene is

275. The compound of any one of claims 264 to 274, wherein F1Is that

276. The compound of any one of claims 264 to 275, wherein F2Is that

277. The compound of any one of claims 264 to 275, wherein F3Is that

278. The compound of claim 262, wherein said C is2-C6Heterocyclylene is polycyclic.

279. The compound of claim 278, wherein C is2-C6Heterocyclylene is bicyclic.

280. The compound of claim 278 or 279, wherein C is2-C6The heterocyclylene group is bridged.

281. The compound of claim 280, wherein C is2-C6Heterocyclylene is

282. The compound of claim 278 or 279, wherein C is2-C6The heterocyclylene group is fused.

283. The compound of claim 282, wherein said C is2-C9Heterocyclylene is

284. The compound of claim 283, wherein F1Is that

285. The compound of claim 283 or 284, wherein F2Is that

286. The compound of claim 278 or 279, wherein C is2-C6Heterocyclylene is spirocyclic.

287. The compound of claim 286, wherein C is2-C6Heterocyclylene is

288. The compound of claim 287, wherein F1Is that

289. The compound of claim 287 or 288, wherein F2Is that

290. Such asThe compound of any one of claims 287-289, wherein F3Is that

291. The compound of any one of claims 262-290, wherein said C2-C9The heterocyclylene group comprises a quaternary amine.

292. The compound of any one of claims 224 to 253, wherein F1、F2Or F3Each of which is independently optionally substituted C6-C10An arylene group.

293. The compound of claim 292, wherein said C is6-C10Arylene is

294. The compound of any one of claims 224 to 253, wherein F1、F2Or F3Each of which is independently optionally substituted C2-C9A heteroarylene group.

295. The compound of claim 294, wherein C is2-C9The heteroarylene group is

296. The compound of claim 295, wherein F 2Is that

297. The compound of claim 296, wherein F2Is that

298. The compound of any one of claims 224 to 297, C3Is that

299. The compound of claim 298, wherein C3Is that

300. The compound of any one of claims 224 to 299, wherein m is 1.

301. The compound of any one of claims 224 to 299, wherein m is 0.

302. The compound of any one of claims 224 to 301, wherein p is 1.

303. The compound of any one of claims 224 to 301, wherein p is 0.

304. The compound of any one of claims 224 to 303, wherein o1 is 1.

305. The compound of any one of claims 224 to 303, wherein o1 is 0.

306. The compound of any one of claims 224 to 305, wherein o2 is 1.

307. The compound of any one of claims 224 to 305, wherein o2 is 0.

308. The compound of any one of claims 224 to 307, wherein n is 1.

309. The compound of any one of claims 224 to 307, wherein n is 0.

310. The compound of any one of claims 224 to 309, wherein the linker has

The structure of (1).

311. The compound of any one of claims 224 to 309, wherein the linker has

The structure of (1).

312. The compound of any one of claims 224 to 309, wherein the linker has the structure of:

313. the compound of any one of claims 2 to 202, wherein the linker is optionally substituted C3-C10Carbocyclylene, optionally substituted C2-10Heterocyclylene radical, optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

314. The compound of claim 313, wherein the linker is optionally substituted C2-10Heterocyclylene radical

315. The compound of claim 312, wherein the linker has The structure of (1).

316. The compound of claim 315, wherein the linker hasThe structure of (1).

317. The compound of any one of claims 2 to 202, wherein the linker is absent.

318. 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.

319. The compound of any one of claims 2 to 317, wherein the compound has the structure of any one of compounds D1-D31 in table 2A, or a pharmaceutically acceptable salt thereof.

320. The compound of any one of claims 2-317, wherein the compound has the structure of any one of compounds D32-D184 in table 2B, or a pharmaceutically acceptable salt thereof.

321. The compound of any one of claims 2 to 317, wherein the compound has the structure of any one of compounds D185-D316 in table 2C, or a pharmaceutically acceptable salt thereof.

322. A pharmaceutical composition comprising a compound of any one of claims 1-321 and a pharmaceutically acceptable excipient.

323. A method of inhibiting the level of BRD9 in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1-321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

324. A method of inhibiting the activity of BRD9 in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1-321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

325. The method of claim 323 or 324, wherein the cell is a cancer cell.

326. The method of claim 325, wherein the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma, non-small cell lung cancer, gastric cancer, or breast cancer.

327. The method of claim 326, wherein the cancer is a sarcoma.

328. The method of claim 327, wherein the sarcoma is soft tissue sarcoma, synovial sarcoma, ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibrosarcoma, gastrointestinal stromal tumor, kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant phyllodes tumor, malignant peripheral schlemma, myxofibrosarcoma, or low-grade rhabdomyosarcoma.

329. The method of claim 328, wherein the sarcoma is synovial sarcoma.

330. A method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

331. A method of treating an SSl8-SSX fusion protein-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1-321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

332. A method of treating a BRD 9-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1-321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

333. The method of any one of claims 330-332, wherein the disorder is cancer.

334. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

335. The method of claim 333 or 334, wherein the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma, non-small cell lung cancer, gastric cancer, or breast cancer.

336. The method of claim 335, wherein the cancer is a sarcoma.

337. The method of claim 336, wherein the sarcoma is soft tissue sarcoma, synovial sarcoma, ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibrosarcoma, gastrointestinal stromal tumor, kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant phyllodes tumor, malignant peripheral schlemma, myxofibrosarcoma, or low-grade rhabdomyosarcoma.

338. The method of claim 337, wherein the sarcoma is synovial sarcoma.

339. The method of any one of claims 330-332, wherein the disorder is an infection.

340. A method of treating an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 321, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 322.

341. The method of claim 339 or 340, wherein the infection is a viral infection.

342. The method of claim 341, wherein the viral infection is an infection with a virus of the family retroviridae, hepadnaviridae, flaviviridae, adenoviridae, herpesviridae, papilloma virus, parvoviridae, polyomaviridae, paramyxoviridae, or togaviridae.

343. The method of claim 341 or 342, wherein the viral infection is kefen-cilris, neurofibromatosis, or meningioma multiplex.

Background

The disorder may be affected by BAF complexes. BRD9 is a component of BAF complexes. The present invention relates to useful compositions and methods for treating BAF complex-associated disorders, such as cancer and infections.

Disclosure of Invention

Bromodomain-containing protein 9(BRD9) is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1 or BRM-associated factor) complex, a SWI/SNF atpase chromatin remodeling complex, and belongs to the IV family of bromodomain-containing proteins. BRD9 is present in several SWI/SNF ATPase chromatin remodeling complexes and is upregulated in multiple cancer cell lines. Thus, agents that reduce the level and/or activity of BRD9 may provide novel methods for treating diseases and disorders, such as cancer and infections. The inventors found that depletion of BRD9 in cells resulted in depletion of SS18-SSX fusion protein in those cells. The SS18-SSX fusion protein was detected in more than 95% of synovial sarcoma tumors, and was usually the only cytogenetic abnormality in synovial sarcoma. Furthermore, there is evidence that BAF complexes are involved in cellular antiviral activity. Thus, agents (e.g., compounds) that degrade BRD9 can be used to treat disorders (e.g., cancer or infection) associated with BAF, BRD9, and/or SS 18-SSX.

The disclosure features compounds and methods useful for treating BAF-associated disorders (e.g., cancer or infection).

In one aspect, the disclosure features a compound having structural formula I:

wherein

R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6An alkenyl group,Optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

Z1is CR2Or N;

R2is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

X1is N or CH, and X2Is C-R7(ii) a Or X1Is C-R7And X2Is N or CH;

R7is optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;

X3is N or CH;

X4is N or CH;

g is optionally substituted C3-C10Carbocyclyl, C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group; or a pharmaceutically acceptable salt thereof.

In some embodiments, R1Is H, optionally substituted C 1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group. In some embodiments, R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl or optionally substituted C3-C10A carbocyclic group. In some embodiments, R1Is H, optionally substituted C1-C6Alkyl or optionally substituted C3-C10A carbocyclic group.

In some embodiments, R1Is H. In some embodiments, R1Is optionally substituted C1-C6An alkyl group. In some embodiments, R1Is optionally substituted C2-C6An alkenyl group. In some embodiments, R1Is optionally substituted C3-C10A carbocyclic group.

In some embodiments, optionally substituted C1-C6Alkyl is C1-C6A perfluoroalkyl group.

In some embodiments, R1Is that

In some embodiments, R1Is that

In some embodiments, R1Is that

In some embodiments, R1Is H, In some embodiments, R1Is that In some embodiments, R1Is H,

In some embodiments, R1Is H,

In some embodiments, R1Is H,

In some embodiments, R1Is H or

In some embodiments, R1Is H. In some embodiments, R1Is that

In some embodiments, Z1Is CR2. In some embodiments, Z1Is N.

In some embodiments, R 2Is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl or optionally substituted C6-C10And (4) an aryl group.

In some embodiments, R2Is H, halogen or optionally substituted C1-C6An alkyl group.

In some embodiments, R2Is H, F or

In some embodiments, R2Is H. In some embodiments, R2Is F. In some embodiments, R2Is that

In some embodiments, R7Is optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Alkyl, optionally substituted C1-C6A heteroalkyl group, an optionally substituted carbocyclyl group having 3 to 6 atoms, or an optionally substituted heterocyclyl group having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Alkoxy or optionally substituted amino. In some embodiments, R7Is an optionally substituted sulfone or an optionally substituted sulfonamide.

In some embodiments, R7Is optionally substituted C1-C6Alkyl or optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C 1-C6Heteroalkyl groups or optionally substituted heterocyclic groups having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group.

In some embodiments, R7Is optionally substituted C1-C6An alkyl group. In some embodiments, R7Is a taskOptionally substituted C1-C6A heteroalkyl group. In some embodiments, R7Is optionally substituted C1-C6An alkoxy group. In some embodiments, R7Is an optionally substituted amino group. In some embodiments, R7Is an optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R7Is an optionally substituted heterocyclic group having 3 to 6 atoms. In some embodiments, R7Is an optionally substituted sulfone. In some embodiments, R7Is an optionally substituted sulfonamide.

In some embodiments, R7Is optionally substituted C1-C3An alkyl group. In some embodiments, R7Is optionally substituted C1-C3A heteroalkyl group.

In some embodiments, R7Is that

In some embodiments, R7is-NR3R4OR-OR4Wherein R is3Is H or optionally substituted C1-C6Alkyl, and R4Is optionally substituted C1-C6An alkyl group.

In some embodiments, R7is-NR3R4. In some embodiments, R7is-OR4。

In some embodiments, R 3Is H. In some embodiments, R3Is optionally substituted C1-C6An alkyl group.

In some embodiments, R3Is H, and R4Is methyl. In some embodiments, R3Is methyl, and R4Is methyl.

In some embodiments, R7Is thatIn some embodiments, R7Is that

In some embodiments, R7Is an optionally substituted carbocyclyl having 3 to 6 atoms or an optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R7Is an optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R7Is an optionally substituted heterocyclic group having 3 to 6 atoms.

In some embodiments, R7Is a carbocyclic group having 3 to 6 atoms or a heterocyclic group having 3 to 6 atoms. In some embodiments, R7Is a carbocyclic group having 3 to 6 atoms. In some embodiments, R7Is a heterocyclic group having 3 to 6 atoms.

In some embodiments, R7Is that

In some embodiments, R7Is that

In some embodiments, R7Is that

In some embodiments, R7Is that

In some embodiments, R7Is thatIn some embodiments, R7Is that In some embodiments, R7Is that In some embodiments, R 7Is that In some embodiments, R7Is that

In some embodiments, X1Is N, and X2Is C-R7. In some embodiments, X1Is CH, and X2Is C-R7. In some embodiments, X1Is C-R7And X2Is N. In some embodiments, X1Is C-R7And X2Is CH.

In some embodiments, X1Is N or CH, and X2Is C-NR3R4、C-OR4、Or X1Is C-NR3R4、C-OR4、And X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4、 Or X1Is C-NR3R4、 And X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4OrOr X1Is C-NR3R4OrOpening and X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4OrOr X1Is C-NR3R4OrAnd X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4OrOr X1Is C-NR3R4OrAnd X2Is N or CH.

In some embodiments, R7is-NR3R4、-OR4Or an optionally substituted heterocyclic group having 3 to 6 atoms.

In some embodiments, X1Is N, and X2Is C-NR3R4. In some embodiments, X1Is C-NR3R4And X2Is N. In some embodiments, X1Is N, and X2Is C-OR4. In some embodiments, X 1Is C-OR4And X2Is N.

In some embodiments, R3Is H. In some embodiments, R3Is optionally substituted C1-C6An alkyl group.

In some embodiments, R3Is that In some embodiments, R3Is thatIn some embodiments, R3Is thatIn some embodiments, R3Is a methyl group, an ethyl group,

In some embodiments, R4Is that In some embodiments, R4Is thatIn some embodiments, R4Is thatIn some embodiments, R4Is a methyl group, an ethyl group,

In some embodiments, X3Is N. In some embodiments, X3Is CH.

In some embodiments, X4Is N. In some embodiments, X4Is CH.

In some embodiments, X3Is N, and X4Is N.

In some embodiments, X3Is N, and X4Is CH.

In some embodiments, X3Is CH, and X4Is N.

In some embodiments, X3Is CH, and X4Is CH.

In some embodiments, G is optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group. In some embodiments, G isOptionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group.

In some embodiments, G is optionally substituted C3-C10A carbocyclic group. In some embodiments, G is optionally substituted C 6-C10And (4) an aryl group. In some embodiments, G is optionally substituted C2-C9A heterocyclic group. In some embodiments, G is optionally substituted C2-C9A heteroaryl group.

In some embodiments, G is

Wherein

RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments of the present invention, the substrate is,RG1、RG2、RG3、RG4and RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C 2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, F, Cl,

In some embodiments, R G1、RG2、RG3、RG4And RG5Each of which is independently H, F,

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, F, Cl,

In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is thatAnd R isG5Is H. In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is H; and R isG5Is thatIn some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is Cl or F; and R isG5Is H. In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is H; and R isG5Is H. In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is thatAnd R isG5Is H.

In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heterocyclic group. In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heteroaryl group.

In some embodiments, G is Wherein R isG6Is H or optionally substituted C1-C6An alkyl group. In some embodiments, G is Wherein R isG6Is H or optionally substituted C 1-C6An alkyl group.

In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9Heterocyclyl or optionally substituted C2-C9A heteroaryl group.

In some embodiments, G is Wherein R isG6Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, RG6Is H,

In some embodiments, RG6Is H or

In some embodiments, RG6Is H.

In some embodiments, RG1H, F, In some embodiments, RG1Is H.

In some embodiments, RG2H, F, In some embodiments, RG2Is H.

In some embodiments, RG3H, F, In some embodiments, RG3Is H.

In some embodiments, RG4H, F, In some embodiments, RG4Is H.

In some embodiments, RG5H, F, In some embodiments, RG5Is H.

In some embodiments, RG1、RG2、RG3、RG4And RG5Is H. In some embodiments of the present invention, the substrate is,RG1、RG2、RG3、RG4and RG5Two or more of which are H. In some embodiments, RG1、RG2、RG3、RG4And RG5Three or more of which are H. In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is H.

In some embodiments, G is

Wherein

RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C 6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substitutedC1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, F, Cl, In some embodiments, RG8Is that

In some embodiments, G is

In some embodiments, RG7Is H; rG8Is thatRG9Is H; and R isG11Is H.

In some embodiments, G is

Wherein

RG12、RG13And RG14Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C 3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG12And RG14Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG12、RG13And RG14Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or RG12And RG14Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, the compound of formula I has the structure of formula Ia:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ib:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ic:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Id:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ie:

wherein R is5And R6Each of which is independently H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group; or R5And R6Together with the nitrogen to which each is attached, to form optionally substituted C2-C9A heterocyclic group; or a pharmaceutical preparation thereofThe above acceptable salts.

In some embodiments, the compound of formula I has the structure of formula If:

wherein R is5And R6Each of which is independently H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group; or R5And R6Together with the nitrogen to which each is attached, to form optionally substituted C2-C9A heterocyclic group; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ig:

Wherein R is5And R6Each of which is independently H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group; or R5And R6Together with the nitrogen to which each is attached, to form optionally substituted C2-C9A heterocyclic group; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ih:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ij:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ik:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Im:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula I have the structure of formula In:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Io:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ip:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Iq:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I has the structure of formula Ir:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one of compounds B1-B6 in table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds B1-B3 and B6 in table 1, or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features a compound having the structure of any one of compounds B1-B6 in table 1, or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features a compound having the structure of any one of compounds B1-B3 and B6 in table 1, or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features a compound having the structure of any one of compounds B4 and B5 in table 1, or a pharmaceutically acceptable salt thereof.

TABLE 1 Compounds of the present disclosure B1-B6

In one aspect, the disclosure features a compound having the structure of formula II:

A-L-B

In the formula II, the compound is shown in the specification,

wherein

L is a linker;

b is a degradation moiety; and is

A has the structure of formula III:

wherein

R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

Z1is CR2Or N;

R2is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

X1is N or CH, and X2Is C-R7"; or X1Is C-R7", and X2Is N or CH;

R7"isOptionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;

R7' is H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

X3is N or CH;

X4is N or CH;

g' isOptionally substituted C3-C10Carbocyclyl, C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

g' is optionally substituted C3-C10Carbocyclylene, C2-C9Heterocyclylene radical, optionally substituted C 6-C10Arylene or optionally substituted C2-C9A heteroarylene group; and is

A1Is the bond between a and the linker,

wherein G' isOr R7"isOr a pharmaceutically acceptable salt thereof.

In some embodiments, R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group. In some embodiments, R1Is H, optionally substitutedC of (A)1-C6Alkyl, optionally substituted C2-C6Alkenyl or optionally substituted C3-C10A carbocyclic group. In some embodiments, R1Is H, optionally substituted C1-C6Alkyl or optionally substituted C3-C10A carbocyclic group.

In some embodiments, R1Is H. In some embodiments, R1Is optionally substituted C1-C6An alkyl group. In some embodiments, R1Is optionally substituted C2-C6An alkenyl group. In some embodiments, R1Is optionally substituted C3-C10A carbocyclic group.

In some embodiments, optionally substituted C1-C6Alkyl is C1-C6A perfluoroalkyl group.

In some embodiments, R1Is that

In some embodiments, R1Is that

In some embodiments, R1Is that

In some embodiments, R1Is H, In some embodiments, R1Is that In some embodiments, R1Is H,

In some embodiments, R1Is H,

In some embodiments, R 1Is H,

In some embodiments, R1Is H or

In some embodiments, R1Is H. In some embodiments, R1Is that

In some embodiments, Z1Is CR2. In some embodiments, Z1Is N.

In some embodiments, R2Is H, halogenOptionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl or optionally substituted C6-C10And (4) an aryl group.

In some embodiments, R2Is H, halogen or optionally substituted C1-C6An alkyl group.

In some embodiments, R2Is H, F or

In some embodiments, R2Is H. In some embodiments, R2Is F. In some embodiments, R2Is that

In some embodiments, R7Is optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Alkyl, optionally substituted C1-C6A heteroalkyl group, an optionally substituted carbocyclyl group having 3 to 6 atoms, or an optionally substituted heterocyclyl group having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Alkoxy or optionally substituted amino. In some embodiments, R 7"is an optionally substituted sulfone or an optionally substituted sulfonamide.

In some embodiments, R7Is optionally substituted C1-C6Alkyl or optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Heteroalkyl groups or optionally substituted heterocyclic groups having 3 to 6 atoms. In some embodiments, R7Is optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group.

In some embodiments, R7Is optionally substituted C1-C6An alkyl group. In some embodiments, R7Is optionally substituted C1-C6A heteroalkyl group. In some embodiments, R7Is optionally substituted C1-C6An alkoxy group. In some embodiments, R7"is an optionally substituted amino group. In some embodiments, R7"is an optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R7"is an optionally substituted heterocyclic group having 3 to 6 atoms. In some embodiments, R7"is an optionally substituted sulfone. In some embodiments, R7"is an optionally substituted sulfonamide.

In some embodiments, R7Is optionally substituted C1-C3An alkyl group. In some embodiments, R7Is optionally substituted C1-C3A heteroalkyl group.

In some embodiments, R7"is

In some embodiments, R7"is-NR3R4OR-OR4Wherein R is3Is H or optionally substituted C1-C6Alkyl, and R4Is optionally substituted C1-C6An alkyl group.

In some embodiments, R7"is-NR3R4. In some embodiments, R7"is-OR4。

In some embodiments, R3Is H. In some embodiments, R3Is optionally substituted C1-C6An alkyl group.

In some embodiments, R3Is H, and R4Is methyl. In some embodiments, R3Is methyl, and R4Is methyl.

In some embodiments, R7"isIn some embodiments, R7"is

In some embodiments, R7"is an optionally substituted carbocyclyl having 3 to 6 atoms or an optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R7"is an optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R7"is an optionally substituted heterocyclic group having 3 to 6 atoms.

In some embodiments, R7"is a carbocyclic group having 3 to 6 atoms or a heterocyclic group having 3 to 6 atoms. In some embodiments, R7"is a carbocyclic group having 3 to 6 atoms. In some embodiments, R 7"is a heterocyclic group having 3 to 6 atoms.

In some embodiments, R7"is

In some embodiments, R7"is

In some embodiments, R7"is

In some embodiments, R7"is

In some embodiments, R7"is In some embodiments, R7"is In some embodiments, R7"is In some embodiments, R7"isIn some embodiments, R7"is

In some embodiments, X1Is N, and X2Is C-R7". In some embodiments, X1Is CH, and X2Is C-R7". In some embodiments, X1Is C-R7", and X2Is N. In some embodiments, X1Is C-R7", and X2Is CH.

In some embodiments, X1Is N or CH, and X2Is C-NR3R4、C-OR4、Or X1Is C-NR3R4、C-OR4、And X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4、 Or X1Is C-NR3R4、 And X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4OrOr X1Is C-NR3R4OrOpening and X2Is N or CH. In some embodiments, X1Is N or CH, and X2Is C-NR3R4OrOr X1Is C-NR3R4OrAnd X2Is N or CH. In some embodiments, X1Is N or CH, and X 2Is C-NR3R4OrOr X1Is C-NR3R4OrAnd X2Is N or CH.

In some embodiments, R7"is-NR3R4、-OR4Or an optionally substituted heterocyclic group having 3 to 6 atoms.

In some embodiments, X1Is N, and X2Is C-NR3R4. In some embodiments, X1Is C-NR3R4And X2Is N.

In some embodiments, R3Is H. In some embodiments, R3Is optionally substituted C1-C6An alkyl group.

In some embodiments, R3Is that In some embodiments, R3Is thatIn some embodiments, R3Is thatIn some embodiments, R3Is a methyl group, an ethyl group,

In some embodiments, R4Is that In some embodiments, R4Is thatIn some embodiments, R4Is thatIn some embodiments, R4Is a methyl group, an ethyl group,

In some embodiments, X3Is N. In some embodiments, X3Is CH.

In some embodiments, X4Is N. In some embodiments, X4Is CH.

In some embodiments, X3Is N, and X4Is N.

In some embodiments, X3Is N, and X4Is CH.

In some embodiments, X3Is CH, and X4Is N.

In some embodiments, X3Is CH, and X4Is CH.

In some embodiments, G' is

In some embodiments, G' is optionally substituted C3-C10Carbocyclylene or optionally substituted C2-C9A heterocyclylene group. In some embodiments, G' is optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

In some embodiments, G' is optionally substituted C3-C10A carbocyclylene group. In some embodiments, G' is optionally substituted C6-C10An arylene group. In some embodiments, G' is optionally substituted C2-C9A heterocyclylene group. In some embodiments, G' is optionally substituted C2-C9A heteroarylene group.

In some embodiments, G' is

Wherein

RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclic, hydroxy, thiol or optionally substitutedAn amino group; or RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to form And isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

In some embodiments, RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

In some embodiments, R G1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

In some embodiments, RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

In some embodiments, RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1、F、Cl、

In some embodiments, RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1、F、

In some embodiments, RG1′、RG2′、RG3′、RG4' and RG5' Each of which is independently H, A1、F、Cl、

In some embodiments, RG3' is a1。

In some embodiments, RG1' is H; rG2' isRG3' is a1；RG4' isAnd R isG5' is H. In some embodiments, R G1' is H; rG2' isRG3' is a1；RG4' is H; and R isG5' isIn some embodiments, RG1' is H; rG2' isRG3' is a1；RG4' is Cl or F; and R isG5' is H. In some embodiments, RG1' is H; rG2' isRG3' is a1；RG4' is H; and R isG5' is H. In some embodiments, RG1' is H; rG2' isRG3' is a1；RG4' isAnd R isG5' is H.

In some embodiments, RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A1Is substituted in which RG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution. In some embodiments, RG1' and RG2′、RG2' and RG3′、RG3' and RG4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A1Is substituted in which RG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

In some casesIn an embodiment, G' is Wherein R isG6' is H, A1Or optionally substituted C1-C6An alkyl group. In some embodiments, G' is Wherein R isG6' is H, A1Or optionally substituted C1-C6An alkyl group.

In some embodiments, RG1' and RG2′、RG2' and RG3′、RG3' and R G4' and/or RG4' and RG5Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl or optionally substituted C2-C9Heteroaryl, any of which is optionally substituted by A1Is substituted in which RG1′、RG2′、RG3′、RG4' and RG5One of' is A1Or is orQuilt A1And (4) substitution.

In some embodiments, G' is Wherein R isG6' is H, A1Or optionally substituted C1-C6An alkyl group.

In some embodiments, RG6' is H, A1、

In some embodiments, RG6' is H, A1Or

In some embodiments, RG6' is H or A1。

In some embodiments, RG6' is H. In some embodiments, RG6' is a1。

In some embodiments, RG1' is H, A1、F、 In some embodiments, RG1' is H.

In some embodiments, RG2' is H, A1、F、 In some embodiments, RG2' is H.

In some embodiments, RG3' is H, A1、F、 In some embodiments, RG3' is H.

In some embodiments, RG4' is H, A1、F、 In some embodiments, RG4' is H.

In some embodiments, RG5' is H, A1、F、 In some embodiments, RG5' is H.

In some embodiments, RG1′、RG2′、RG3′、RG4' andRG5one or more of' is H. In some embodiments, R G1′、RG2′、RG3′、RG4' and RG5Two or more of' are H. In some embodiments, RG1′、RG2′、RG3′、RG4' and RG5Three or more of are H.

In some embodiments, RG1' is a1. In some embodiments, RG2' is a1. In some embodiments, RG3' is a1. In some embodiments, RG4' is a1. In some embodiments, RG5' is a1. In some embodiments of the present invention, the substrate is,quilt A1And (4) substitution.

In some embodiments, G' is

Wherein

RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG7' and RG8′、RG8' and RG9′、RG9' and RG10' and/or RG10' and RG11Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C 2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG7′、RG8′、RG9′、RG10' and RG11One of' is A1(ii) a OrQuilt A1And (4) substitution.

In some embodiments, RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group, a hydroxyl group,A thiol or an optionally substituted amino group; or RG7' and RG8′、RG8' and RG9′、RG9' and RG10' and/or RG10' and RG11Are combined with the carbon atom to which each is attached to formOpening and closingIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG7′、RG8′、RG9′、RG10' and RG11One of' is A1(ii) a OrQuilt A1And (4) substitution.

In some embodiments, RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C 3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG7' and RG8′、RG8' and RG9′、RG9' and RG10' and/or RG10' and RG11Are combined with the carbon atom to which each is attached to formAnd isIs optionalSubstituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG7′、RG8′、RG9′、RG10' and RG11One of' is A1(ii) a OrQuilt A1And (4) substitution.

In some embodiments, RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

In some embodiments, RG7′、RG8′、RG9′、RG10' and RG11' Each of which is independently H, A1、F、Cl、 In some embodiments, RG8' is

In some embodiments, G' is

In some embodiments, RG7' is H; rG8' isRG9' is a1(ii) a And R isG11' is H.

In some embodiments, G' is

Wherein

RG12′、RG13' and RG14' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C 6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG12' and RG14Are combined with the carbon atom to which each is attached to formAnd isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG12′、RG13' and RG14One of' is A1(ii) a OrQuilt A1And (4) substitution.

In some embodiments, RG12′、RG13' and RG14' Each of which is independently H, A1Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG12' and RG14Are combined with the carbon atom to which each is attached to form And isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9Heterocyclyl, any of which is optionally substituted by A1Is substituted in which RG12′、RG13' and RG14One of' is A1(ii) a OrQuilt A1And (4) substitution.

In some casesIn embodiments, R7"is

In some embodiments, R7' is H, optionally substituted C1-C6Alkyl or optionally substituted C3-C10A carbocyclic group. In some embodiments, R7' is H or optionally substituted C1-C6An alkyl group.

In some embodiments, R7' is H, In some embodiments, R7' is H orIn some embodiments, R7' is H. In some embodiments, R7' is

In some embodiments, G' is optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group. In some embodiments, G' is optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group.

In some embodiments, G' is optionally substituted C3-C10A carbocyclic group. In some embodiments, G is optionally substituted C6-C10And (4) an aryl group. In some embodiments, G is optionally substituted C2-C9A heterocyclic group. In some embodiments, G' is optionally substituted C2-C9A heteroaryl group.

In some embodiments, G' is

Wherein

RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclic ringRadical, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or R G1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, F, Cl,

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, F,

In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which is independently H, F, Cl,

In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is thatAnd R isG5Is H. In some embodiments, R G1Is H; rG2Is thatRG3Is thatRG4Is H; and R isG5Is thatIn some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is Cl or F; and R isG5Is H. In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is H; and R isG5Is H. In some embodiments, RG1Is H; rG2Is thatRG3Is thatRG4Is thatAnd R isG5Is H.

In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5With the carbon atoms to which each is attachedTogether form an optionally substituted C2-C9A heterocyclic group. In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heteroaryl group.

In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heterocyclic group. In some embodiments, RG1And RG2、RG2And RG3、RG3And RG4And/or RG4And RG5Together with the carbon atom to which each is attached form optionally substituted C2-C9A heteroaryl group.

In some embodiments, G' is Wherein R isG6Is H or optionally substituted C1-C6An alkyl group. In some embodiments, G' is Wherein R isG6Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, G' is Wherein R isG6Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, RG6Is H,

In some embodiments, RG6Is H or

In some embodiments, RG6Is H.

In some embodiments, RG1H, F, In some embodiments, RG1Is H.

In some embodiments, RG2H, F, In some embodiments, RG2Is H.

In some embodiments, RG3H, F, In some embodiments, RG3Is H.

In some embodiments, RG4H, F, In some embodiments, RG4Is H.

In some embodiments, RG5H, F, In some embodiments, RG5Is H.

In some embodiments, RG1、RG2、RG3、RG4And RG5Is H. In some embodiments, RG1、RG2、RG3、RG4And RG5Two or more of which are H. In some embodiments, RG1、RG2、RG3、RG4And RG5Three or more of which are H. In some embodiments, RG1、RG2、RG3、RG4And RG5Each of which isOne is H.

In some embodiments, G' is

Wherein

RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C 3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclic radical, optionallySubstituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

In some embodiments, R G7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group; or RG7And RG8、RG8And RG9、RG9And RG10And/or RG10And RG11Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl or optionally substituted-C1-C3alkyl-C2-C5A heterocyclic group.

In some embodiments, RG7、RG8、RG9、RG10And RG11Each of which is independently H, F, Cl, In some embodiments, RG8Is that

In some embodiments, G' is

In some embodiments, RG7Is H; rG8Is thatRG9Is H; and R isG11Is H.

In some embodiments, G' is

Wherein

RG12、RG13And RG14Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C 2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, optionally substituted-C1-C3alkyl-C3-C6Carbocyclic ringRadical, optionally substituted-C1-C3alkyl-C2-C5Heterocyclyl, hydroxy, thiol, or optionally substituted amino; or RG12And RG14Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, RG12、RG13And RG14Each of which is independently H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or RG12And RG14Together with the carbon atom to which each is attached form optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, a has the structure of formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIId:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIe:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIg:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIh:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIj:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIk:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIm:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIn:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIo:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIp:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIq:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIr:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIs:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIt:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIu:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a has the structure of formula IIIv:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprises a Cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2) or a von Hippel-Lindau (VHL) ligand or a derivative or analog thereof.

In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprises a Cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2), or a von hippel-lindau ligand or a derivative or analog thereof.

In some embodiments, the degradation moiety comprises a structure of formula Y:

wherein

A2Is a bond between the degradation moiety and the linker;

v1 is 0, 1, 2, 3, 4 or 5;

u1 is 1, 2 or 3;

T1is a key or

T2Is that

R5AIs H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

each RJ1Independently is halogen, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

JAabsent, is O, optionally substituted amino, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group; and is

J is absent, is optionally substituted C3-C10Carbocyclylene, optionally substituted C6-C10Arylene, optionally substituted C2-C9Heterocyclylene or optionally substituted C2-C9A heteroarylene group; or a pharmaceutically acceptable salt thereof.

In some embodiments, T2Is thatIn some embodiments, T2Is thatIn some embodiments, T2Is thatIn some embodiments, T2Is that

In some embodiments, the structure of formula Y has the structure of formula Y1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, T1Is a bond. In some embodiments, T1Is that

In some embodiments, the structure of formula Y has the structure of formula Y2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula Y has a structure of formula Z:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, u1 is 1. In some embodiments, u1 is 2. In some embodiments, u1 is 3.

In some embodiments, the structure of formula Z has the structure of formula AA 0:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula Z has the structure of formula AB:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula Z has a structure of formula AC:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J isAIs absent. In some embodiments, J isAIs optionally substituted C1-C6An alkyl group. In some embodiments, J isAIs optionally substituted C1-C6A heteroalkyl group. In some embodiments, J isAIs O or optionally substituted amino.

In some embodiments, J isAIs that

In some embodiments, the structure of formula AA0 has the structure of formula AA 0:

or a pharmaceutically acceptable salt thereof.

In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0. In some embodiments, v1 is 1. In some embodiments, v1 is 2. In some embodiments, v1 is 3.

In some embodiments, the structure of formula AA has the structure of formula AA 1:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula AB has the structure of formula AB 1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula AC has the structure of formula AC 1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J is absent. In some embodiments, J is optionally substituted C3-C10Carbocyclylene or optionally substituted C6-C10An arylene group. In some embodiments, J is optionally substituted C2-C9Heterocyclylene or optionally substituted C2-C9A heteroarylene group.

In some embodiments, J is an optionally substituted heterocyclylene. In some embodiments, J is optionally substituted C6-C10An arylene group.

In some embodiments, J is

In some embodiments, the structure of formula AA has the structure of formula AA 2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula AA has the structure of formula AA 3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula AA has the structure of formula AA 4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, RA5Is H or optionally substituted C1-C6An alkyl group. In some embodiments, RA5Is optionally substituted C 1-C6A heteroalkyl group.

In some embodiments, RA5Is H or methyl. In some embodiments, RA5Is H. In some embodiments, RA5Is methyl. In some embodiments, RA5Is that

In some embodiments, the structure of formula AA has the structure of formula a:

wherein

Y1Is that

RA5Is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RA6is H or optionally substituted C1-C6An alkyl group; and R isA7Is H or optionally substituted C1-C6An alkyl group; or RA6And RA7Combined together with the carbon atom to which each is bound to formOptionally substituted C3-C6Carbocyclyl or optionally substituted C2-C5A heterocyclic group; or RA6And RA7Together with the carbon atom to which each is bound, form an optionally substituted C3-C6Carbocyclyl or optionally substituted C2-C5A heterocyclic group;

RA8is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RA1、RA2、RA3and RA4Is independently H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, thiol, or optionally substituted amino; or R A1And RA2、RA2And RA3And/or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2Substitution; or a pharmaceutically acceptable salt thereof.

In some embodiments, RA1、RA2、RA3And RA4Is independently H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or RA1And RA2、RA2And RA3And/or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2Substitution; or a pharmaceutically acceptable salt thereof.

In some embodiments, RA1、RA2、RA3And RA4Is H, A 2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclic ringA group, a hydroxyl group, an optionally substituted amino group; or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

In some embodiments, RA1、RA2、RA3And RA4Is independently H, A2、F、Or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

In some embodiments, RA1Is A2. In some embodiments, RA2Is A2. In some embodiments, RA3Is A2. In some embodiments, RA4Is A2. In some embodiments, RA5Is A2。

In some embodiments, RA5Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, RA5Is H orIn some embodiments, RA5Is H. In some embodiments, RA5Is that

In some embodiments, Y is1Is thatIn some embodiments, Y is1Is thatIn some embodiments, Y is 1Is that

In some embodiments, RA6And RA7Each of which is independently H, F, Or RA6And RA7Combined together with the carbon atom to which each is bound to formIn some embodiments, RA6Is H, and RA7Is H.

In some embodiments, Y is1Is that In some embodiments, Y is1Is that In some embodiments, Y is1Is that

In some embodiments, the structure of formula a has the structure of formula a 1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 5:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 6:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 7:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula A8:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 9:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula a has the structure of formula a 10:

or a pharmaceutically acceptable salt thereof.

In some embodiments, wherein the structure of formula A is Or a derivative or analogue thereof.

In some embodiments, the structure of formula a is

In some embodiments, the structure of formula a is Or a derivative or analogue thereof.

In some embodiments of the present invention, the substrate is,is thatWherein R isA9Is H, A2Optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group.

In some embodiments, the structure of formula a is

In some embodiments, RA9Is H, A2Or optionally substituted C1-C6Alkyl, in some embodiments, RA9Is H, A2Or a methyl group. In some embodiments, R9AIs H. In some embodiments, R9AIs methyl. In some embodiments, RA9Is A2。

In some embodiments, the structure of formula a is

In some embodiments, the structure of formula AA has the structure of formula B:

wherein

RA5Is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RA1、RA2、RA3and RA4Is independently H, A 2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, thiol, or optionally substituted amino; or RA1And RA2、RA2And RA3And/or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C6-C10Aryl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heteroaryl or C2-C9Heterocyclyl, any of which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2Substitution; or a pharmaceutically acceptable salt thereof.

In some embodiments, RA1、RA2、RA3And RA4Is H, A2Halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted-O-C3-C6Carbocyclyl, hydroxy, optionally substituted amino; or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

In some embodiments, R A1、RA2、RA3And RA4Is independently H, A2、F、Or RA1And RA2、RA2And RA3Or RA3And RA4Combined together with the carbon atom to which each is attached to formAnd isIs optionally substituted C2-C9Heterocyclyl, which is optionally substituted by A2Is substituted in which RA1、RA2、RA3And RA4Is A2Or is orQuilt A2And (4) substitution.

In some embodiments, RA1Is A2. In some embodiments, RA2Is A2. In some embodiments, RA3Is A2. In some embodiments, RA4Is A2. In some embodiments, RA5Is A2。

In some embodiments, RA5Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, RA5Is H orIn some embodiments, RA5Is H. In some embodiments, RA5Is that

In some embodiments, the structure of formula B has a structure of formula B1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula B has a structure of formula B2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula B has a structure of formula B3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula B has a structure of formula B4:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention, the substrate is,the structure of formula B is In some embodiments, the structure of formula B is In some embodiments, the structure of formula B is

In some embodiments, the ubiquitin ligase binding moiety comprises a von hippel-lindau ligand.

In some embodiments, the von hippel-lindau ligand hasIn the structure of (a) to (b),

or a derivative or analogue thereof.

In some embodiments, the degradation moiety comprises a structure of formula C:

wherein

RB1Is H, A2Optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RB2is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RB3is A2Optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

RB4is H, optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

RB5is H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

v2 is 0, 1, 2, 3 or 4;

each RB6Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C 6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and is

RB7And RB8Each of which is independently H, halogen, optionally substituted C1-C6Alkyl or optionally substituted C6-C10An aryl group, a heteroaryl group,

wherein R isB1And RB3Is A2(ii) a Or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula C is Or a derivative or analogue thereof.

In some embodiments, the structure of formula C is

In some embodiments, the degrader moiety comprises the structure of formula D:

wherein

A2Is a bond between B and the linker;

RC1、RC2and RC7Each of which is independently H, optionally substituted C1-C6Alkyl or optionally substituted C1-C6A heteroalkyl group;

RC3is optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

RC5is optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

v3 is 0, 1, 2, 3 or 4;

each RC8Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C 1-C6Heteroalkyl, optionally substitutedSubstituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v4 is 0, 1, 2, 3 or 4; and is

Each RC9Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula D isOr a derivative or analogue thereof.

In some embodiments, the degrader moiety comprises the structure of formula E:

wherein

A2Is a bond between B and the linker;

RC10and RC11Each of which is independently H, optionally substituted C1-C6Alkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C6-C10Aryl, optionally substituted C1-C6Alkyl radical C3-C10Carbocyclyl or optionally substituted C1-C6Alkyl radical C6-C10An aryl group;

v5 is 0, 1, 2, 3 or 4;

each RC12Independently is halogen, optionally substituted C 1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v6 is 0, 1, 2, 3 or 4; and is

Each R21Independently is halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl, optionally substituted C2-C9Heteroaryl, optionally substituted C2-C6Alkenyl, optionally substituted C2-C6Heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of formula E is

Or a derivative or analogue thereof.

In some embodiments, the degrading moiety comprises the structure of formula FA:

wherein

Is thatOr by A2Substituted and substituted with one or more substituents independently selected from H, RFF1And oxo;

is a single or double bond;

u2 is 0, 1, 2 or 3;

A2is a bond between the degrader and the linker;

YFais CRFbRFc、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH 2；

YFbIs NH, NRFF1、CH2、CHRFF1、C(RFF1)2O or S;

YFcis CRFdRFe、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

RFb、RFc、RFdAnd RFeEach of which is independently H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxy, alkoxy, amino, -NH alkyl, or-N alkyl2；

Or RFbAnd RFcTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or RFdAnd RFeTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; and is

Or RFdAnd RFbTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

YFdand YFfIs independently CH2、CHRFF2、C(RFF2)2、C(O)、N、NH、NRFF3O, S or S (O);

YFeis linked to Y and contains 1 to 5 continuous carbon atoms forming a 3-to 8-membered ringFdAnd YFfA bond or a divalent moiety of (a),

wherein 1, 2 or 3 carbon atoms may be replaced by nitrogen, oxygen or sulfur atoms;

wherein one of the ring atoms is substituted by A2Substituted and the other ring atoms are independently selected from H and R by one or more FF1Substituted with a group of (1); and is

Wherein Y isFeThe consecutive atoms of (a) may be connected by a single or double bond;

each RFF1Independently is H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxy, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxy, or haloalkyl;

each RFF2Independently is alkyl, alkene, alkyne, halogen, hydroxy, 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), -NHSO2Alkyl, aryl, heteroaryl, and heteroaryl,

-N (alkyl) SO2Alkyl, -NHSO2Aryl, -N (alkyl) SO2Aryl, -NHSO2Alkenyl, -N (alkyl) SO2An alkenyl group,

-NHSO2Alkynyl, -N (alkyl) SO2Alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, -SH, -S alkyl, or haloAlkyl radicals; and is

RFF3Is alkyl, alkenyl, alkynyl, -C (O) H, -C (O) OH, -C (O) alkyl or-C (O) Oalkyl,

wherein if Y isFdOr YFfQuilt A2Substituted, then YFeIs a bond; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula FA has the structure of formula FA 1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety comprises the structure of formula FB:

wherein

Is thatOr by A2Substituted and substituted with one or more substituents independently selected from H, RFF1And oxo;

A2is a bond between the degrader and the linker;

YFais CRFbRFc、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

YFbAnd YFgEach of which is independently NH, NRFF1、CH2、CHRFF1、C(RFF1)2O or S;

YFcis CRFdRFe、C＝O、C＝S、C＝CH2、SO2S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)2P (O) alkyl, P (O) OH, P (O) NH2；

RFb、RFc、RFd、RFe、RFfAnd RFgEach of which is independently H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxy, alkoxy, amino, -NH alkyl, or-N alkyl2；

Or RFbAnd RFcTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or RFdAnd RFeTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

Or RFfAnd RFgTogether with the carbon atom to which each is attached, form a 3-, 4-, 5-, or 6-membered spirocyclic carbocyclylene or 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or RFdAnd RFbTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

or RFdAnd RFfTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

or RFbAnd RFgTaken together with the carbon atoms to which each is attached to form a 1, 2, 3 or 4 carbon bridged ring;

YFdand YFfIs independently CH2、CHRFF2、C(RFF2)2、C(O)、N、NH、NRFF3O, S or S (O);

YFeis linked to Y and contains 1 to 5 continuous carbon atoms forming a 3-to 8-membered ringFdAnd YFfA bond or a divalent moiety of (a),

wherein 1, 2 or 3 carbon atoms may be replaced by nitrogen, oxygen or sulfur atoms;

wherein one of the ring atoms is substituted by A2Substituted and the other ring atoms are independently selected from H and R by one or moreFF1Substituted with a group of (1); and is

Wherein Y isFeThe consecutive atoms of (a) may be connected by a single or double bond;

each RFF1Independently is H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxy, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxy, or haloalkyl;

Each RFF2Independently is alkyl, alkene, alkyne, halogen, hydroxy, 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), -NHSO2Alkyl, aryl, heteroaryl, and heteroaryl,

-N (alkyl) SO2Alkyl, -NHSO2Aryl, -N (alkyl) SO2Aryl, -NHSO2Alkenyl, -N (alkyl) SO2An alkenyl group,

-NHSO2Alkynyl, -N (alkyl) SO2Alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, -SH, -S alkyl, or haloalkyl; and is

RFF3Is alkyl, alkenyl, alkynyl, -C (O) H, -C (O) OH, -C (O) alkyl or-C (O) Oalkyl,

wherein if Y isFdOr YFfQuilt A2Substituted, then YFeIs a bond; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula FB has the structure of formula FB 1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety comprises the structure of formula F1:

wherein A is2Is a bond between the degrader and the linker; and R isF1Is absent or is O; or a pharmaceutically acceptable salt thereof.

In some embodiments, R F1Is absent. In some embodiments, RF1Is O.

In some embodiments, the structure of formula F1 is

In some embodiments, the degradation moiety comprises the structure of formula F2:

wherein A is2Is a bond between the degrader and the linker; and Y is2Is CH2Or NH; or a pharmaceutically acceptable salt thereof.

In some embodiments, Y is2Is NH. In some embodiments, Y is2Is CH2。

In some embodiments, the structure of formula F2 is

In some embodiments, the degradation moiety comprises a structure of formula G:

wherein A is2Is a bond between the degrader and the linker; and Y is3Is CH2Or NH; or a pharmaceutically acceptable salt thereof.

In some embodiments, Y is3Is NH. In some embodiments, Y is3Is CH2。

In some embodiments, the structure of formula G is

Such degraded portions may also be included in, for example, WO 2017/197036; WO 2019/204354; WO 2019/236483; WO 2020/010177; and the structures found in WO2020/010227, the structures of which are incorporated herein by reference.

In some embodiments, the linker has the structure of formula IV:

A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2

formula IV

Wherein

A1Is a bond between the linker and A;

A2is a bond between B and the linker;

B1、B2、B3and B4Each of which is independently optionally substituted C 1-C2Alkylene, optionally substituted C1-C3Heteroalkylidene, O, S, S (O)2Or NRN；

Each RN is independently H, optionally substituted C1-4Alkyl, optionally substituted C2-4Alkenyl, optionally substituted C2-4Alkynyl, optionally substituted C2-6A heterocyclic group,Optionally substituted C6-12Aryl or optionally substituted C1-7A heteroalkyl group;

C1and C2Each of which is independently carbonyl, thiocarbonyl, sulfonyl or phosphoryl;

f. each of g, h, i, j, and k is independently 0 or 1; and is

D is optionally substituted C1-10Alkylene, optionally substituted C2-10Alkenylene, optionally substituted C2-10Alkynylene, optionally substituted C2-6Heterocyclylene radical, optionally substituted C6-12Arylene, optionally substituted C2-C10Polyethylene glycol or optionally substituted C1-10Heteroalkylene, or A1-(B1)f-(C1)g-(B2)h-is connected to- (B)3)i-(C2)j-(B4)k-A2The chemical bond of (1).

In some embodiments, B1、B2、B3And B4Each of which is independently optionally substituted C1-C4Alkylene, optionally substituted C1-C4Hetero alkyl radicals or NRN。

In some embodiments, each R isNIndependently is H or optionally substituted C1-C4An alkylene group.

In some embodiments, each R isNIndependently is H or methyl.

In some embodiments, B1And B4Each of which is independently

In some embodiments, B1Is that

In some embodiments, C 1And C2Each of which is independently

In some embodiments, C1Is that

In some embodiments, B2Is NRN. In some embodiments, B2Is optionally substituted C1-C4An alkylene group.

In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, j is 0. In some embodiments, k is 0.

In some embodiments, the linker has In the structure of (a) to (b),

wherein

x is 1, 2, 3, 4, 5, 6, 7 or 8;

y is 1, 2, 3 or 4;

Rxis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Ryis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group; and is

W is O or NRwWherein R iswIs H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group.

In some embodiments, the linker has The structure of (1).

In some embodiments, RxIs H or optionally substituted C1-C6An alkyl group. In some embodiments, R yIs H or optionally substituted C1-C6An alkyl group. In some embodiments, RwIs H or optionally substituted C1-C6An alkyl group.

In some embodiments, RxIs H or methyl. In some embodiments, RyIs H or methyl. In some embodiments, RwIs H or methyl.

In some embodiments, the linker has

The structure of (1).

In some embodiments, the linker hasThe structure of (1).

In some embodiments, the linker has The structure of (1).

In some embodiments, the linker has the structure of formula V:

A1-(E1)-(F1)-(C3)m-(E3)n-(F2)o1-(F3)o2-(E2)p-A2，

formula V

Wherein

A1Is a bond between the linker and A;

A2is a bond between B and the linker;

each of m, n, o1, o2, and p is independently 0 or 1;

E1and E2Is independently O, S, NRNOptionally substituted C1-10Alkylene, optionally substituted C2-10Alkenylene, optionally substituted C2-10Alkynylene, optionally substituted C2-C10Polyethylene glycol or optionally substituted C1-10A heteroalkylene group;

E3is optionally substituted C1-C6Alkylene, optionally substituted C1-C6Heteroalkylene, O, S or NRN；

Each RNIndependently is H, optionally substituted C1-4Alkyl, optionally substituted C2-4Alkenyl, optionally substituted C2-4Alkynyl, optionally substituted C2-6Heterocyclyl, optionally substituted C6-12Aryl or optionally substituted C 1-7A heteroalkyl group;

C3is carbonyl, thiocarbonyl, sulfonyl or phosphoryl; and is

F1、F2And F3Each of which is independently optionally substituted C3-C10Carbocyclylene, optionally substitutedSubstituted C2-10Heterocyclylene radical, optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

In some embodiments, the linker has the structure of formula Va:

A1-(E1)-(F1)-(C3)m-(E2)p-A2。

formula Va

In some embodiments, the linker has the structure of formula Vb:

A1-(E1)-(F1)-(E2)p-A2。

formula Vb

In some embodiments, the linker has the structure of formula Vc:

A1-(E1)-(F1)-A2。

formula Vc

In some embodiments, the linker has the structure of formula Vd:

A1-(E1)-(F1)-(C3)m-(F2)o1-A2。

formula Vd

In some embodiments, the linker has a structure of formula Ve:

A1-(E1)-(F1)-(E3)n-(F2)o1-(E2)p-A2。

formula Ve

In some embodiments, the linker has a structure of formula Vf:

A1-(E1)-(F1)-(C3)m-(E3)n-(F2)o1-(E2)p-A2。

formula Vf

In some embodiments, the linker has the structure of formula Vg:

A1-(E1)-(F1)-(E3)n-(F2)o1-A2，

formula Vg

In some embodiments, E1And E2Each of which is independently NRNOptionally substituted C1-10Alkylene, optionally substituted C2-C10Polyethylene glycol or optionally substituted C1-10A heteroalkylene group.

In some embodiments, E3Is optionally substituted C1-C6Alkylene, O, S or NRN；

In some embodiments, E3Is optionally substituted C1-C6An alkylene group. In some embodiments, E 3Is optionally substituted C1-C3An alkylene group. In some embodiments, E3Is O, S or NRN。

In some embodiments, E3Is C1-C6An alkylene group. In some embodiments, E3Is C1-C3An alkylene group. In some embodiments, E3Is O.

In some embodiments, E3Is that Wherein a is 0, 1, 2, 3, 4 or 5.

In some embodiments, E3Is that

In some embodiments, each R isNIndependently is H or optionally substituted C1-4An alkyl group.

In some casesIn embodiments, each R isNIndependently is H or methyl.

In some embodiments, E1Is that Wherein a is 0, 1, 2, 3, 4 or 5.

In some embodiments, E1Is that Wherein a is 0, 1, 2, 3, 4 or 5.

In some embodiments, E1Is that In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E1Is that

Wherein

b is 0, 1, 2, 3, 4, 5 or 6;

Rais H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Rbis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group; and is

RcIs H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group.

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, RaIs H or optionally substituted C1-C6An alkyl group. In thatIn some embodiments, RbIs H or optionally substituted C1-C6An alkyl group. In some embodiments, RcIs H or optionally substituted C1-C6An alkyl group.

In some embodiments, RaIs H or methyl. In some embodiments, RbIs H or methyl. In some embodiments, RcIs H or methyl.

In some embodiments, b is 0, 1, 2, or 3. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3.

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E1Is that

In some embodiments, E2Is O, NRw、

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;

Rdis H, optionally substituted C1-C6Alkyl, optionally substituted C 1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Reis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Rfis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Rgis H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group; and is

W is O or NRwWherein R iswIs H or optionally substituted C1-C6An alkyl group.

In some embodiments, E2Is O, NRw、

In some embodiments, RdIs H or optionally substituted C1-C6An alkyl group. In some embodiments, ReIs H or optionally substituted C1-C6An alkyl group. In some embodiments, RfIs H or optionally substituted C1-C6An alkyl group. In some embodiments, RgIs H or optionally substituted C1-C6An alkyl group. In some embodiments, RwIs H or optionally substituted C1-C6An alkyl group.

In some embodiments, RdIs H or methyl. In some embodiments, ReIs H or methyl. In some embodiments, RfIs H or methyl. In some embodiments, RgIs H or methyl. In some embodiments, RwIs H or methyl.

In some embodiments, E2Is that

In some embodiments, E2Is O,

In some embodiments, F1、F2Or F3Each of which is independently optionally substituted C3-C10A carbocyclylene group.

In some embodiments, said C3-C10Carbocyclylene is monocyclic. In some embodiments, said C3-C10Carbocyclylene is polycyclic.

In some embodiments, said C3-C10Carbocyclylene is bicyclic.

In some embodiments, said C3-C10The carbocyclylene group is bridged. In some embodiments, said C3-C10The carbocyclylene group is fused. In some embodiments, said C3-C10Carbocyclylene is spirocyclic.

In some embodiments, said C3-C10The carbocyclic radical being

In some embodiments, F2Is that

In some embodiments, said C3-C10The carbocyclic radical being

In some embodiments, F1Is that

In some implementationsIn scheme F1、F2Or F3Each of which is independently optionally substituted C2-C9A heterocyclylene group.

In some embodiments, said C2-C9Heterocyclylene groups are monocyclic. In some embodiments, said C2-C9Heterocyclylene is polycyclic.

In some embodiments, said C2-C9Heterocyclylene is bicyclic.

In some embodiments, said C2-C9The heterocyclylene group is bridged. In some embodiments, said C2-C9The heterocyclylene group is fused. In some embodiments, said C 2-C9Heterocyclylene is spirocyclic.

In some embodiments, said C2-C9Heterocyclylene groups include quaternary amines.

In some embodiments, said C2-C9Heterocyclylene is

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 RhIndependently is2H. Halogen, optionally substituted C1-C6Alkyl, ORi2Or NRi3Ri4(ii) a Or two RhThe radicals, together with the carbon atoms to which they are each attached, combine to form optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group; or two RhThe radicals, together with the carbon atoms to which they are each attached, combine to form optionally substituted C3-C10Carbocyclic radicals or optionally substitutedC2-C9A heterocyclic group;

Ri1is H or optionally substituted C1-C6An alkyl group;

Ri2is H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C6A carbocyclic group;

Ri3is H or optionally substituted C1-C6An alkyl group; and is

Ri4Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, each R ishIndependently is halogen, optionally substituted C1-C6Alkyl, ORi2Or NRi3Ri4. In some embodiments, Ri1Is H or optionally substituted C1-C6An alkyl group. In some embodiments, Ri2Is H or optionally substituted C1-C6An alkyl group. In some embodiments, Ri3Is H or optionally substituted C 1-C6An alkyl group. In some embodiments, Ri4Is H or optionally substituted C1-C6An alkyl group.

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, each R ishIndependently is halogen, optionally substituted C1-C6Alkyl, ORi2Or NRi3Ri4. In some embodiments, each R ishIndependently is halogen, optionally substituted C1-C6Alkyl or NRi3Ri4。

In some embodiments, each R ishIndependently is2H. Halogen, cyano, optionallySubstituted C1-C6Alkyl, ORi2Or NRi3Ri4. In some embodiments, two R arehThe radicals, together with the carbon atoms to which they are each attached, combine to form optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group. In some embodiments, two R arehThe radicals, together with the carbon atoms to which they are each attached, combine to form optionally substituted C3-C10Carbocyclyl or optionally substituted C2-C9A heterocyclic group.

In some embodiments, each R ishIndependently is2H. F, methyl,

In some embodiments, each R ishIndependently F, methyl or NRi3Ri4。

In some embodiments, q1 is 0, 1, or 2. In some embodiments, q1 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2.

In some embodiments, q2 is 0, 1, or 2. In some embodiments, q2 is 0. In some embodiments, q2 is 1. In some embodiments, q2 is 2.

In some embodiments, q3 is 0, 1, or 2. In some embodiments, q3 is 0. In some embodiments, q3 is 1. In some embodiments, q3 is 2.

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F2Is that In some embodiments, F2Is that

In some embodiments, F3Is that In some embodiments, F3Is that

In some embodiments, Ri1Is H or methyl. In some embodiments, Ri2Is H or methyl. In some embodiments, Ri3Is H or methyl. In some embodiments, Ri4Is H or methyl.

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, said C2-C9Heterocyclylene is

In some embodiments, F 1Is that

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F2Is that

In some embodiments, said C2-C9The heterocyclic radical is

In some embodiments, said C2-C9The heterocyclic radical is

In some embodiments, said C2-C9The heterocyclic radical is

In some embodiments, said C2-C9The heterocyclic radical is

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F1Is that

In some embodiments, F2Is that

In some embodiments, F2Is that

In some embodiments, F2Is that

In some embodiments, F2Is that

In some embodiments, F3Is that

In some embodiments, F1、F2Or F3In (1)Each is independently optionally substituted C6-C10An arylene group.

In some embodiments, said C6-C10Arylene is

In some embodiments, F1、F2Or F3Each of which is independently optionally substituted C2-C9A heteroarylene group.

In some embodiments, said C2-C9The heteroarylene group is

In some embodiments, F2Is thatIn some embodiments, F2Is that

In some embodiments, C3Is thatIn some embodiments, C 3Is that

In some embodiments, m is 1. In some embodiments, p is 1.

In some embodiments, the linker has

The structure of (1).

In some embodiments, the linker has

The structure of (1).

In some embodiments, the linker has the structure:

in some embodiments, the linker is absent.

In some embodiments, the linker is optionally substituted C3-C10Carbocyclylene, optionally substituted C2-10Heterocyclylene radical, optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

In some embodiments, the linker is optionally substituted C3-C10Carbocyclylene or optionally substituted C2-10A heterocyclylene group. In some embodiments, the linker is optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group.

In some embodiments, the linker is optionally substituted C2-10A heterocyclylene group.

In some embodiments, said C2-C9Heterocyclylene groups are monocyclic. In some embodiments, said C2-C9Heterocyclylene is polycyclic.

In some embodiments of the present invention, the substrate is,said C is2-C9Heterocyclylene is bicyclic.

In some embodiments, said C2-C9The heterocyclylene group is bridged. In some embodiments, said C 2-C9The heterocyclylene group is fused. In some embodiments, said C2-C9Heterocyclylene is spirocyclic.

In some embodiments, the linker has The structure of (1).

In some embodiments, the linker has The structure of (1).

In some embodiments, the compound has the structure of any one of compounds D1-D31 in table 2A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of compound D32-D184 in table 2B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D185-D316 in table 2C, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one of compounds D1, D7, D15-D21, D23, and D27-D30 in table 2A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D32-D42, D46, D48-D63, D65-D73, D75-D83, D85-D87, D89-D93, D95-D116, D118, D120-D164, D166-D168, D170, D171, D173, D174, D176-D178, D180, D182, and D184 in table 2B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D185-D190, D192-D204, D248, D254-D258, D260, D262-D269, D271-D280, D284, D286-D291, and D293-D316 in table 2C, or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features compounds D1-D31 in table 2A or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features compounds D32-D184 in table 2B, or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features compounds D185-D316 in table 2C or a pharmaceutically acceptable salt thereof.

TABLE 2A. Compounds of the present disclosure D1-D31

TABLE 2B. Compounds D32-D184 of the present disclosure

TABLE 2℃ Compounds D185-D316 of the present disclosure

In another aspect, the disclosure features a pharmaceutical composition that includes any of the foregoing compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In one aspect, the disclosure features a method of inhibiting the level and/or activity of BRD9 in a cell, the method including contacting the cell with an effective amount of any one of the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the disclosure features a method of reducing the level and/or activity of BRD9 in a cell, the method including contacting the cell with an effective amount of any one of the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In some embodiments, the cell is a cancer cell.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibrosarcoma, gastrointestinal stromal tumor, kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or ewing's sarcoma), non-small cell lung cancer (e.g., squamous carcinoma or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

In one aspect, the disclosure features a method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the foregoing compounds or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the BAF complex-associated disorder is cancer. In some embodiments, the BAF complex-associated disorder is an infection.

In another aspect, the disclosure features a method of treating a SS18-SSX fusion protein-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the SS18-SSX fusion protein-related disorder is cancer. In some embodiments, the SS18-SSX fusion protein-related disorder is an infection. In some embodiments of any of the foregoing methods, the SS18-SSX fusion protein is

SS18-SSX1 fusion protein, SS18-SSX2 fusion protein or SS18-SSX4 fusion protein.

In another aspect, the disclosure features a method of treating a BRD 9-associated disorder in a subject in need thereof, the method including administering to the subject an effective amount of any one of the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the BRD 9-associated disorder is cancer. In some embodiments, the BRD 9-associated disorder is an infection.

In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, particularly burkitt's lymphoma and non-hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcomas, including ewing's sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelial tumors, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pinealoblastoma, meningioma, meningiosarcoma, fibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that can be treated using the disclosed compounds according to the invention include, for example, acute myelogenous leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical cancer, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone marrow cancer, intestinal cancer, brain stem glioma, breast cancer, tris (estrogen, progestin, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progestin, and HER-2 are negative), single negative (one of estrogen, progestin, and HER-2 are negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, cancer with a combination of two or more thereof, and combinations of two or more thereof, Estrogen receptor positive breast cancer, metastatic breast cancer, luminal a breast cancer, luminal B breast cancer, Her2 negative breast cancer, Her2 positive or negative breast cancer, progestin receptor positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, skin lymphoma, skin melanoma, diffuse astrocytoma, Ductal Carcinoma In Situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma multiforme (GBM), Glioma, hairy cell leukemia, head and neck cancer, angioendothelioma, hodgkin lymphoma, hypopharynx cancer, Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC), Inflammatory Breast Cancer (IBC), intestinal cancer, intrahepatic bile duct cancer, invasive/invasive breast cancer, islet cell cancer, maxillofacial cancer, kaposi sarcoma, kidney cancer, larynx cancer, leiomyosarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, merkel cell, mesenchymal chondrosarcoma, mesenchymal phylloma, mesothelioma metastatic breast cancer, metastatic melanoma metastatic cervical squamous carcinoma, mixed glioma, monogerm layer teratoma, oral cancer mucus cancer, mucosal melanoma, squamous cell carcinoma, mixed glioma, single germ layer teratoma, oral cancer, mucosal carcinoma, cervical carcinoma, squamous cell carcinoma of the head carcinoma of head carcinoma, or head carcinoma, head carcinoma of head carcinoma, or head carcinoma of head carcinoma, or head carcinoma of head carcinoma, or head carcinoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, eye melanoma, oligodendroglioma, oral cancer (oral cancer), oral cancer (oral cavity cancer), oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian carcinoma ovarian germ cell tumor, primary peritoneal ovarian cancer, primary funo-mesenchymal tumor, Paget's disease, pancreatic cancer, papillary cancer, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, hairy cell astrocytoma, pinecone tumor, pineblastoma, pituitary cancer, primary Central Nervous System (CNS) lymphoma, Prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, Small Cell Lung Cancer (SCLC), small intestine cancer, spinal cord cancer (spinal cancer), spinal cord cancer (spinal cord cancer), squamous cell cancer, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureter cancer, urethral cancer, uterine adenocarcinoma, uterine carcinoma, uterine sarcoma, vaginal cancer, vulval cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell lymphoma, cervical cancer, and cervical cancer, Precursor B-cell lymphoma, large B-cell lymphoma, burkitt's lymphoma, B-cell ALL, philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic Marginal Zone Lymphoma (SMZL); large B cell lymphoma in blood vessels; primary effusion lymphoma; or lymphomatoid granulomatosis; b cell prolymphocytic leukemia; undifferentiated splenic lymphoma/leukemia, diffuse splenic erythroid small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, bone solitary plasmacytoma; extraosseous plasmacytoma; primary cutaneous follicular central lymphoma, large B-cell lymphoma rich in T cells/histiocytes, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL for the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL (legged), ALK + large B-cell lymphoma, plasmablast lymphoma; large B-cell lymphoma that occurs in HHV 8-associated multicenter castleman's disease; an undifferentiated B-cell lymphoma characterized between diffuse large B-cell lymphomas, or an undifferentiated B-cell lymphoma characterized between diffuse large B-cell lymphomas and classical Hodgkin's lymphoma.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibrosarcoma, gastrointestinal stromal tumor, kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or ewing's sarcoma), non-small cell lung cancer (e.g., squamous carcinoma or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

In some embodiments, the infection is a viral infection (e.g., by a virus of the family Retroviridae, such as lentiviruses (e.g., Human Immunodeficiency Virus (HIV) and delta retroviruses (e.g., human T-cell leukemia Virus I (HTLV-I), human T-cell leukemia Virus II (HTLV-II)); the family hepadnaviridae (e.g., Hepatitis B Virus (HBV)), the family Flaviviridae (e.g., Hepatitis C Virus (HCV)), the family adenoviridae (e.g., human adenovirus)), the family herpesviridae (e.g., Human Cytomegalovirus (HCMV), Epstein-Barr Virus, herpes simplex Virus 1(HSV-1), herpes simplex Virus 2(HSV-2), human herpes Virus 6(HHV-6), herpes Virus K, CMV, varicella-zoster Virus), the family Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1)); parvoviridae (e.g., parvovirus B19); polyomaviridae (e.g., JC virus and BK virus); paramyxoviridae (e.g., measles virus); or togaviridae (e.g., rubella virus)). In some embodiments, the disease condition is keffin-Siris (Coffin Siris), neurofibromatosis (e.g., NF-1, NF-2, or schwannomas), or multiple meningiomas. In one aspect, the disclosure features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds, or a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutical compositions.

In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, particularly burkitt's lymphoma and non-hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcomas, including ewing's sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelial tumors, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pinealoblastoma, meningioma, meningiosarcoma, fibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that can be treated using the disclosed compounds according to the invention include, for example, acute myelogenous leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical cancer, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone marrow cancer, intestinal cancer, brain stem glioma, breast cancer, tris (estrogen, progestin, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progestin, and HER-2 are negative), single negative (one of estrogen, progestin, and HER-2 are negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, cancer with a combination of two or more thereof, and combinations of two or more thereof, Estrogen receptor positive breast cancer, metastatic breast cancer, luminal a breast cancer, luminal B breast cancer, Her2 negative breast cancer, Her2 positive or negative breast cancer, progestin receptor positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, skin lymphoma, skin melanoma, diffuse astrocytoma, Ductal Carcinoma In Situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma multiforme (GBM), Glioma, hairy cell leukemia, head and neck cancer, angioendothelioma, hodgkin lymphoma, hypopharynx cancer, Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC), Inflammatory Breast Cancer (IBC), intestinal cancer, intrahepatic bile duct cancer, invasive/invasive breast cancer, islet cell cancer, maxillofacial cancer, kaposi sarcoma, kidney cancer, larynx cancer, leiomyosarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, merkel cell, mesenchymal chondrosarcoma, mesenchymal phylloma, mesothelioma metastatic breast cancer, metastatic melanoma metastatic cervical squamous carcinoma, mixed glioma, monogerm layer teratoma, oral cancer mucus cancer, mucosal melanoma, squamous cell carcinoma, mixed glioma, single germ layer teratoma, oral cancer, mucosal carcinoma, cervical carcinoma, squamous cell carcinoma of the head carcinoma of head carcinoma, or head carcinoma, head carcinoma of head carcinoma, or head carcinoma of head carcinoma, or head carcinoma of head carcinoma, or head carcinoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, eye melanoma, oligodendroglioma, oral cancer (oral cancer), oral cancer (oral cavity cancer), oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian carcinoma ovarian germ cell tumor, primary peritoneal ovarian cancer, primary funo-mesenchymal tumor, Paget's disease, pancreatic cancer, papillary cancer, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, hairy cell astrocytoma, pinecone tumor, pineblastoma, pituitary cancer, primary Central Nervous System (CNS) lymphoma, Prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, Small Cell Lung Cancer (SCLC), small intestine cancer, spinal cord cancer (spinal cancer), spinal cord cancer (spinal cord cancer), squamous cell cancer, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureter cancer, urethral cancer, uterine adenocarcinoma, uterine carcinoma, uterine sarcoma, vaginal cancer, vulval cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell lymphoma, cervical cancer, and cervical cancer, Precursor B-cell lymphoma, large B-cell lymphoma, burkitt's lymphoma, B-cell ALL, philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic Marginal Zone Lymphoma (SMZL); large B cell lymphoma in blood vessels; primary effusion lymphoma; or lymphomatoid granulomatosis; b cell prolymphocytic leukemia; undifferentiated splenic lymphoma/leukemia, diffuse splenic erythroid small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, bone solitary plasmacytoma; extraosseous plasmacytoma; primary cutaneous follicular central lymphoma, large B-cell lymphoma rich in T cells/histiocytes, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL for the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL (legged), ALK + large B-cell lymphoma, plasmablast lymphoma; large B-cell lymphoma that occurs in HHV 8-associated multicenter castleman's disease; an undifferentiated B-cell lymphoma characterized between diffuse large B-cell lymphomas, or an undifferentiated B-cell lymphoma characterized between diffuse large B-cell lymphomas and classical Hodgkin's lymphoma.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibrosarcoma, gastrointestinal stromal tumor, kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or ewing's sarcoma), non-small cell lung cancer (e.g., squamous carcinoma or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

In another aspect, the disclosure features a method for treating a viral infection in a subject in need thereof. The method comprises administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutically acceptable salt thereof or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection by: retroviridae, such as lentiviruses (e.g., Human Immunodeficiency Virus (HIV) and delta retroviruses (e.g., human T cell leukemia Virus I (HTLV-I), human T cell leukemia Virus II (HTLV-II)); hepadnaviridae (e.g., Hepatitis B Virus (HBV)); Flaviviridae (e.g., Hepatitis C Virus (HCV)); Adenoviridae (e.g., human adenovirus); Herpesviridae (e.g., Human Cytomegalovirus (HCMV)), Epstein-Barr Virus, herpes simplex Virus 1(HSV-1), herpes simplex Virus 2(HSV-2), human herpes Virus 6(HHV-6), herpes Virus K.SubCMV, varicella-zoster Virus); Oncoviridae (e.g., human papilloma Virus (HPV, HPV E1)); parvoviridae (e.g., parvoviridae B19); Polytumoridae (e.g., JC virus and BK) Paramyxoviridae (E); or togaviridae (e.g., rubella virus)).

In another embodiment of any of the foregoing methods, the method further comprises administering to the subject another anti-cancer therapy (e.g., a chemotherapeutic or cytotoxic agent or radiation therapy).

In particular embodiments, the other anti-cancer therapy is: chemotherapeutic or cytotoxic agents (e.g., doxorubicin or ifosfamide), differentiation-inducing agents (e.g., retinoic acid, vitamin D, cytokines), hormonal agents, immunological agents, or anti-angiogenic agents. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposide, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, docetaxel, paclitaxel, and the like,

Cisplatin). A list of additional compounds with anticancer activity can be found in l.brunton, b.chabner and b.knollman (ed.). Goodman and Gilman's The pharmaceutical Basis of Therapeutics, twelfth edition, 2011, McGraw Hill company, New York, NY.

In particular embodiments, the compound of the invention and the additional anti-cancer therapy and any of the foregoing compounds or pharmaceutical compositions are each administered within 28 days (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 day) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hour; or simultaneously) of each other in amounts that are effective to treat the subject together.

Chemical terminology

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

For any of the following chemical definitions, the numbers following the atomic symbols represent the total number of atoms of the element in question that are present in the particular chemical moiety. It is to be understood that other atoms, such as hydrogen atoms or substituents as described herein, may be present as desired to satisfy the valency of the atoms. For example, unsubstituted C2Alkyl has the formula-CH2CH3. When used with groups as defined herein, reference to the number of carbon atoms includes the divalent carbons in acetal and ketal groups, but does not include the carbonyl carbons in acyl, ester, carbonate or carbamate groups. References to the number of oxygen, nitrogen or sulfur atoms in a heteroaryl group include only those atoms that form part of a heterocyclic ring.

The phrase "optionally substituted X" (e.g., optionally substituted alkyl) is intended herein to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) itself is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted," with or without the term "optionally" preceding, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (e.g., any of the substituents or groups described herein). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that is substantially unchanged when subjected to conditions that allow for the production, detection, and in certain embodiments, recovery, purification, and use of the compound for one or more of the purposes disclosed herein.

As used herein, the term "aliphatic" refers to a saturated or unsaturated straight chain,Branched or cyclic hydrocarbons. "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporate each of these definitions. In one embodiment, "aliphatic" is used to denote those aliphatic groups having 1 to 20 carbon atoms. The aliphatic chain may be, for example, mono-, di-, tri-or polyunsaturated, or alkynyl. The unsaturated aliphatic group may be in the cis or trans configuration. In one embodiment, the aliphatic group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1-C2、C1-C3、C1-C4、C1-C5Or C1-C6. The specified ranges as used herein represent aliphatic groups having each member of the range described as an independent species. For example, the term C as used herein1-C6Aliphatic means a straight or branched alkyl, alkenyl or alkynyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as an independent species. For example, the term C as used herein 1-C4Aliphatic means a straight or branched alkyl, alkenyl or alkynyl group having 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that result in the formation of a stabilizing moiety.

As used herein, the term "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom, such as an amine, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom, in place of a carbon atom in the chain. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. "heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amides, polyamides, polylactides, polyglycolides, thioethers, ethers, alkyl-heterocycle-alkyl, -O-alkyl, and alkyl-O-haloalkyl.

The term "acyl" as used herein, means hydrogen or alkyl attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., carboxyaldehyde groups), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbons.

The term "alkyl" as used herein refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms). An "alkylene" is a divalent alkyl group.

The term "alkenyl" as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). "alkenylene" is a divalent alkenyl group.

The term "alkynyl", as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon triple bond and having from 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). "alkynylene" is a divalent alkynyl group.

As used herein, the term "amino" means-N (R)N1)2Wherein each R isN1Independently H, OH, NO2、N(RN2)2、SO2ORN2、SO2RN2、SORN2N-protecting group, alkyl, alkoxy, aryl, arylalkylAlkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other acyl groups described herein), where these are listed as RN1Each of the groups may be optionally substituted; or two RN1Combine to form an alkylene or heteroalkylene group, and wherein each RN2Independently H, alkyl or aryl. The amino group of the compounds described herein can be an unsubstituted amino group (i.e., -NH)2) Or substituted amino (i.e., -N (R)N1)2)。

As used herein, the term "aryl" refers to an aromatic mono-or multicyclic group of, for example, 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, indanyl, and 1H-indenyl.

As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, such as C)1-C6Alkyl radical C6-C10Aryl radical, C1-C10Alkyl radical C6-C10Aryl or C1-C20Alkyl radical C6-C10Aryl) such as benzyl and phenethyl. In some embodiments, each of the alkyl and aryl groups can be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective group.

As used herein, the term "azido" refers to-N3A group.

As used herein, the term "bridged cyclic group" refers to a bridged polycyclic group of 5 to 20 atoms containing 1 to 3 bridges. Bridged ring groups include bridged carbocyclyl (e.g., norbornyl) and bridged heterocyclyl (e.g., 1, 4-diazabicyclo [2.2.2] octane).

As used herein, the term "cyano" denotes a-CN group.

As used herein, the term "carbocyclyl" refers to a non-aromatic C wherein the ring is formed from carbon atoms3-C12Monocyclic or polycyclic (e.g., bicyclic or tricyclic) structures. Carbocyclyl structures include cycloalkyl (e.g., cyclohexyl) and unsaturated carbocyclyl groups: (For example, cyclohexenyl). Polycyclic carbocyclic groups include spirocyclic, bridged, and fused carbocyclic groups. "carbocyclylene" is a divalent carbocyclyl.

As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monovalent mono-or multicyclic group having 3 to 10, preferably 3 to 6, carbon atoms. This term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

As used herein, the term "halo" or "halogen" refers to a fluoro (fluoro), chloro (chloro), bromo (bromo), or iodo (iodo) group.

The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced with nitrogen, oxygen, or sulfur. In some embodiments, heteroalkyl groups may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. Examples of heteroalkyl groups are "alkoxy", as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy); and "alkylamino", as used herein, alkylamino means alkylamino

-N (alkyl) RNaWherein R isNaIs H or alkyl (e.g., methylamino). "Heteroalkylene" is a divalent heteroalkyl group.

The term "heteroalkenyl" as used herein refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, a heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for an alkenyl group. An example of a heteroalkenyl group is "alkenyloxy," which, as used herein, refers to alkenyl-O-. "Heteroalkenylene" is a divalent heteroalkenyl group.

The term "heteroalkynyl" as used herein refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen or sulfur. In some embodiments, heteroalkynyl may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynyloxy," which, as used herein, refers to alkynyl-O-. "Heteroalkynyl" is divalent heteroalkynyl.

As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic structure of 5 to 12 atoms having at least one aromatic ring containing 1, 2 or 3 ring atoms selected from nitrogen oxide and sulfur, wherein the remaining ring atoms are carbon. One or two ring carbon atoms of a heteroaryl group may be substituted with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl and thiazolyl. A "heteroarylene" is a divalent heteroaryl.

As used herein, the term "heteroarylalkyl" denotes an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are 7 to 30 carbons (e.g., 7 to 16 carbons or 7 to 20 carbons, such as C)1-C6Alkyl radical C2-C9Heteroaryl group, C1-C10Alkyl radical C2-C9Heteroaryl or C1-C20Alkyl radical C2-C9Heteroaryl). In some embodiments, each of the alkyl and heteroaryl groups can be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective group.

As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) group of 3 to 12 atoms having at least one non-aromatic ring containing 1, 2, 3, or 4 ring atoms selected from N, O or S, and no aromatic ring containing any N, O or S atoms. Polycyclic heterocyclic groups include spiro heterocyclic groups, bridged heterocyclic groups, and fused heterocyclic groups. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1, 3-dioxanyl. "Heterocyclylene" is a divalent heterocyclic radical.

As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl. Exemplary unsubstituted heterocyclylalkyl groups are 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, such as C)1-C6Alkyl radical C2-C9Heterocyclic group, C1-C10Alkyl radical C2-C9Heterocyclyl or C1-C20Alkyl radical C2-C9A heterocyclic group). In some embodiments, each of the alkyl and heterocyclyl groups may be further substituted by 1, 2, 3, or 4 substituents as defined herein for the respective group.

As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an-OH group.

As used herein, the term "hydroxy" denotes an-OH group.

As used herein, the term "imine" means ═ NRNGroup, wherein RNIs for example H or alkyl.

As used herein, the term "N-protecting group" refers to those groups intended to protect amino groups from undesirable reactions during synthesis. Commonly used N-protecting Groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3 rd edition (John Wiley & Sons, New York, 1999). N-protecting groups include, but are not limited to, acyl, aroyl, or carbamoyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; a carbamate-forming group such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3, 4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylcarbamoyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3, 4-methoxybenzyloxycarbonyl, 3, 5-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3, 4-nitrobenzyloxycarbonyl, 3, 5-methoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl, Ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups, such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, the term "nitro" means-NO2A group.

As used herein, the term "oxo" denotes an ═ O group.

As used herein, the term "thiol" denotes an-SH group.

The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, typically 1 to 4 substituents will be present unless otherwise indicated. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, wherein a substituent comprises any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluorine), hydroxy, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH)2Or mono or dialkylamino), azido, cyano, nitro, oxo, sulfonyl, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups can also be substituted with alkyl (unsubstituted and substituted, such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

The compounds described herein (e.g., compounds of the invention) can have one or more asymmetric carbon atoms and can exist as optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are paired stereoisomers, the mirror images of which are non-superimposable, the most common reason being that they contain asymmetrically substituted carbon atoms which act as chiral centers. "enantiomer" refers to one of a pair of molecules that are mirror images of each other and that do not overlap. Diastereomers are stereoisomers that are unrelated to mirror images, the most common reason being that they contain two or more asymmetrically substituted carbon atoms and represent the configuration of the substituent around one or more chiral carbon atoms. Enantiomers of compounds can be prepared, for example, by separating the enantiomers from the racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. One skilled in the art can readily determine the appropriate technique and/or method to isolate an enantiomer of a compound described herein from a racemic mixture. "racemate" or "racemic mixture" refers to a compound containing two enantiomers, wherein such mixture does not exhibit optical activity; i.e. they do not rotate the plane of the polarized light. "geometric isomers" refers to isomers that differ in the orientation of the substituent atoms associated with a carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic ring system. The atoms (other than H) on each side of the carbon-carbon double bond may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents on the same side) configuration. "R", "S", "R", "E", "Z", "cis" and "trans" represent configurations relative to the core molecule. Some of the disclosed compounds may exist as atropisomeric forms. Atropisomers are stereoisomers that arise due to the hindered rotation about a single bond, wherein the rotating steric strain barrier is high enough to allow separation of conformers. The compounds described herein (e.g., compounds of the invention) can be prepared as individual isomers or resolved from mixtures of isomers by isomer-specific synthesis. Conventional resolution techniques include formation of the free base salt of each isomer of the isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), formation of the acid form salt of each isomer of the isomer pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), formation of the ester or amide of each isomer of the isomer pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolution of the isomeric mixture of the starting material or the final product using various well-known chromatographic methods. When the disclosed compounds are named or depicted by structure stereochemistry, the named or depicted stereoisomer is at least 60, 70, 80, 90, 99, or 99.9 wt% relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60, 70, 80, 90, 99, or 99.9% optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60, 70, 80, 90, 99, or 99.9% weight pure. Percent optical purity is the ratio of the weight of an enantiomer relative to the weight of the enantiomer plus the weight of its optical isomer. Diastereoisomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereoisomers. When the disclosed compounds are named or depicted by structure stereochemistry, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. Percent purity in terms of mole fraction is the ratio of moles of an enantiomer to moles of enantiomer plus the moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of moles of a diastereomer to moles of a diastereomer plus moles of its isomer. When the disclosed compounds are named or depicted by structure without indicating stereochemistry and have at least one chiral center, it is to be understood that the name or structure encompasses any enantiomer of the compound that is free of the corresponding optical isomer, racemic mixtures of the compound, or mixtures that are enriched in one enantiomer relative to its corresponding optical isomer. When the disclosed compounds are named or depicted by structure without indication of stereochemistry and have two or more chiral centers, it is understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free of other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers in which one diastereomer is enriched relative to the other diastereomer or diastereomers. The present invention includes all of these forms.

The compounds of the present disclosure also include all isotopes of atoms occurring in the intermediates or final compounds. "isotope" refers to atoms having the same number of atoms but different mass numbers resulting from different numbers of neutrals in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

Unless otherwise specified, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I and125I. isotopically-labelled compounds (e.g. with3H and14c-labeled compounds) may be suitable for use in compound or substrate tissue distribution assays. Tritiated (i.e., a tritiated compound) may be used for ease of preparation and detectability3H) And carbon-14 (i.e.14C) An isotope of (1). In addition, the metal can be doped with a metal such as deuterium (i.e.,2H) may provide certain therapeutic advantages resulting from better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced with2H or3H instead of, or with one or more carbon atoms replaced by 13C-or14C-enriched carbon substitution. Such as15O、13N、11C and18the positron emitting isotope of F is suitable for use in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for the compounds of the invention described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

As known in the art, many chemical entities can take a variety of different solid forms, such as amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention may be used in any such form, including in any solid form. In some embodiments, the compounds described or depicted herein may be provided or used in the form of a hydrate or solvate.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Definition of

In this application, unless the context clearly dictates otherwise, (i) the term "a" or "an" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and/or"; and (iii) the terms "comprising" and "including" can be understood to encompass a listing of components or steps by item, whether present by themselves or with one or more other components or steps.

As used herein, the terms "about" and "approximately" refer to values within 10% above or below the value being described. For example, the term "about 5 nM" means the range of 4.5 to 5.5 nM.

As used herein, the term "administering" refers to administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

As used herein, the term "adult soft tissue sarcoma" refers to sarcomas that typically develop in the soft tissues of the body in adolescent and adult subjects (e.g., subjects at least 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 years of age). Non-limiting examples of adult soft tissue sarcomas include, but are not limited to, synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, cutaneous fibrosarcoma, liposarcoma, smooth muscle sarcoma, angiosarcoma, kaposi's sarcoma, lymphangiosarcoma, malignant peripheral nerve sheath/nerve fibrosarcoma, extraosseous chondrosarcoma, extraosseous osteosarcoma, extraosseous mucoid chondrosarcoma, and extraosseous mesenchymal chondrosarcoma.

As used herein, the term "antisense" refers to a nucleic acid comprising a polynucleotide that is sufficiently complementary to all or part of a gene, primary transcript, or processed mRNA to interfere with the expression of an endogenous gene (e.g., BRD 9). "complementary" polynucleotides are those that are capable of base pairing according to the standard Watson-Crick (Watson-Crick) complementarity rules. Specifically, the purine will base pair with a pyrimidine to form a combination of adenine (G: C) paired with cytosine and adenine (A: T) (in the case of DNA) paired with thymine or adenine (A: U) (in the case of RNA) paired with uracil. It will be appreciated that even if two polynucleotides are not fully complementary to each other, they may hybridize to each other, so long as each polynucleotide has at least one region that is substantially complementary to each other.

The term "antisense nucleic acid" includes single-stranded RNA as well as double-stranded DNA expression cassettes that can be transcribed to produce antisense RNA. An "active" antisense nucleic acid is an antisense RNA molecule that is capable of selectively hybridizing to a primary transcript or mRNA encoding a polypeptide having at least 80% sequence identity (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity or greater) to the targeted polypeptide sequence (e.g., a BRD9 polypeptide sequence). The antisense nucleic acid can be complementary to the entire coding strand, or to only a portion thereof. In some embodiments, the antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence. The term "coding region" refers to a region of a nucleotide sequence that contains codons that are translated into amino acid residues. In some embodiments, the antisense nucleic acid molecule is antisense to a "non-coding region" of the coding strand of the nucleotide sequence. The term "non-coding region" refers to 5 'and 3' sequences flanking the coding region that are not translated into amino acids (i.e., also referred to as 5 'and 3' untranslated regions). The antisense nucleic acid molecule may be complementary to the entire coding region of an mRNA, or may be antisense to only a portion of the coding or non-coding region of an mRNA. For example, the antisense oligonucleotide may be complementary to a region surrounding the translation initiation site. The antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length.

As used herein, the term "BAF complex" refers to BRG1 or HRBM-related factor complex in human cells.

As used herein, the term "BAF complex-associated disorder" refers to a disorder caused or affected by the level and/or activity of BAF complexes.

As used herein, the terms "GBAF complex" and "GBAF" refer to SWI/SNF atpase chromatin remodeling complexes in human cells. GBAF complex subunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B, BICRA, bical, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2, SMARCD3, and SS 18. The term "cancer" refers to conditions caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, the term "BRD 9" refers to bromodomain-containing protein 9, which is a component of the BAF (BRG1 or BRM-related factor) complex, a SWI/SNF atpase chromatin remodeling complex, and belongs to the IV family of bromodomain-containing proteins. BRD9 is encoded by the BRD9 gene, which has the nucleic acid sequence set forth in SEQ ID NO: 1, listed in the table. The term "BRD 9" also refers to natural variants of wild-type BRD9 protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity or greater) to the amino acid sequence of wild-type BRD9 (which is set forth in SEQ ID NO: 2).

As used herein, the term "BRD 9-related disorder" refers to a disorder caused by or affected by the level and/or activity of BRD 9. The term "cancer" refers to conditions caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, "combination therapy" or "administration in combination" refers to the administration of two (or more) different agents or treatments to a subject as part of a defined treatment regimen for a particular disease or disorder. The treatment regimen defines the dose and administration period of each agent such that the effects of the individual agents on the subject overlap. In some embodiments, the delivery of two or more agents is simultaneous or concurrent, and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescription regimen. In some embodiments, the combined administration of two or more agents or treatments results in a reduction in symptoms or other parameters associated with the disorder that is greater than the reduction observed with one agent or treatment delivered alone or in the absence of the agent. The effects of the two treatments may be partially additive, fully additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be accomplished by any suitable route including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent in combination can be administered by intravenous injection, while a second therapeutic agent in combination can be administered orally.

"compounds of the invention" and similar terms as used herein, whether or not specifically indicated, refer to compounds that are useful for treating BAF-related disorders (e.g., cancer or infection) described herein, including, for example, compounds of formula I or formula II (e.g., compounds of table 2A, table 2B, and table 2C), as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof. One skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, and tautomers) or isotopic forms (e.g., where one or more atoms have been replaced with a different isotope of an atom, such as hydrogen for deuterium). Unless otherwise indicated or clear from context, the depicted structures are understood to represent any such isomeric or isotopic form, either individually or in combination. The compounds described herein can be asymmetric (e.g., have one or more stereogenic centers). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are meant. The compounds of the present disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ═ N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are encompassed in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be separated as mixtures of isomers or as separate isomeric forms. In some embodiments, one or more compounds described herein may exist in different tautomeric forms. It will be clear from the context that, unless explicitly excluded, reference to such compounds encompasses all such tautomeric forms. In some embodiments, the tautomeric form results from a single bond exchanging with an adjacent double bond and concomitantly accompanying proton migration. In certain embodiments, the tautomeric form can be a proton tautomer, which is an isomeric protonated state having the same empirical formula and total charge as the reference form. Examples of moieties having proton tautomeric forms are keto-enol pairs, amide-imidic acid pairs, lactam-lactam pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms, wherein a proton may occupy two or more positions in a heterocyclic ring system, such as 1H-and 3H-imidazole; 1H-, 2H-and 4H-1, 2, 4-triazole; 1H-and 2H-isoindoles; and 1H-and 2H-pyrazoles. In some embodiments, tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric form results from acetal tautomerism.

As used herein, the term "degradation agent" refers to a small molecule compound comprising a degradation moiety, wherein the compound interacts with a protein (e.g., BRD9) in a manner that results in degradation of the protein, e.g., binding of the compound reduces the level of the protein, e.g., in a cell or subject, by at least 5%.

As used herein, the term "degradation moiety" refers to a moiety whose binding results in the degradation of a protein (e.g., BRD 9). In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes a protein (e.g., BRD 9).

By "determining the level of a protein" is meant detecting the protein or the mRNA encoding the protein, either directly or indirectly, by methods known in the art. "directly determining" refers to performing a process (e.g., performing an assay or test on a sample, or "analyzing a sample" as the term is defined herein) to obtain a physical entity or value. "indirectly determining" refers to receiving a physical entity or value from a party or source (e.g., a third party laboratory that directly obtains the physical entity or value). Methods for measuring protein levels generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), Radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, Liquid Chromatography (LC) -mass spectrometry, minicytosis, microscopy, Fluorescence Activated Cell Sorting (FACS), and flow cytometry, as well as protein property-based assays, including, but not limited to, enzymatic activity or interaction with other protein partners. Methods for measuring mRNA levels are known in the art.

As used herein, the terms "effective amount," "therapeutically effective amount," and "sufficient amount" of an agent that reduces the level and/or activity of BRD9 (e.g., in a cell or subject) as described herein refer to an amount sufficient to produce a beneficial or desired result (including a clinical result) when administered to a subject, including a human, and thus an "effective amount" or synonym thereof, is dependent on the context in which it is used. For example, in the context of treating cancer, it is the amount of agent that reduces the level and/or activity of BRD9 that is sufficient to achieve a therapeutic response, as compared to the response obtained without administration of an agent that reduces the level and/or activity of BRD 9. The amount of a given agent that will correspond to such an amount to reduce the level and/or activity of BRD9 described herein will vary depending on various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and/or weight) or host being treated, etc., but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a "therapeutically effective amount" of an agent that reduces the level and/or activity of BRD9 of the present disclosure is an amount that produces a beneficial or desired result in a subject, as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and/or activity of BRD9 of the present disclosure can be readily determined by one of ordinary skill in the art by routine methods known in the art. The dosage regimen may be adjusted to provide the optimum therapeutic response.

As used herein, the term "inhibitor" refers to any agent that reduces the level and/or activity of a protein (e.g., BRD 9). Non-limiting examples of inhibitors include small molecule inhibitors, degradants, antibodies, enzymes, or polynucleotides (e.g., siRNA).

The term "inhibitory RNA agent" refers to an RNA or analog thereof that has sufficient sequence complementarity with a target RNA to direct RNA interference. Examples also include DNA that can be used to prepare RNA. RNA interference (RNAi) refers to a sequence-specific or selective process by which a target molecule (e.g., a target gene, protein, or RNA) is down-regulated. In general, interfering RNA ("iRNA") is a double-stranded short interfering RNA (sirna), short hairpin RNA (shrna), or single-stranded microrna (mirna) that results in the catalytic degradation of a particular mRNA, and may also be used to reduce or inhibit gene expression.

"level" refers to the level of a protein or mRNA encoding the protein as compared to a reference. The reference may be any useful reference as defined herein. "reduction" or "increase" in the level of a protein refers to a reduction or increase in the level of a protein as compared to a reference (e.g., a reduction or increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more; a reduction or increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100% or about 200%, a reduction or increase of less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold or less; or an increase of more than about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 4-fold, or less than a reference, About 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). The level of protein can be expressed as mass/volume (e.g., g/dL, mg/mL, μ g/mL, ng/mL) or as a percentage of total protein or mRNA in the sample.

The terms "miRNA" and "microrna" refer to RNA agents, preferably single stranded agents, of about 10-50 nucleotides in length, preferably between about 15-25 nucleotides, which are capable of directing or mediating RNA interference. Naturally occurring mirnas are produced by Dicer from stem-loop precursor RNAs (i.e., pre-mirnas). The term "Dicer" as used herein includes Dicer as well as any Dicer ortholog or homolog capable of processing dsRNA structures into siRNA, miRNA, siRNA-like or miRNA-like molecules. The term microrna ("miRNA") may be used interchangeably with the term "small-order RNA" ("stRNA") based on the fact that naturally occurring mirnas have been found to be expressed in a temporal manner (e.g., during development).

By "modulating the activity of a BAF complex" is meant altering the level of or associated with an activity associated with a BAF complex (e.g., GBAF). The level of BAF complex activity can be measured using any method known in the art, for example, kadoc et al, Cell 153: 71-85(2013), the methods of which are incorporated herein by reference.

"percent (%) sequence identity" with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for the purpose of determining percent identity of nucleic acid or amino acid sequences can be accomplished in a variety of ways within the ability of those skilled in the art, for example using publicly available computer software such as BLAST, BLAST-2, or Megalign software. One skilled in the art can determine appropriate parameters for aligning the sequences, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared. For example, the percent sequence identity value can be generated using the sequence comparison computer program BLAST. By way of illustration, the percentage of sequence identity of a given nucleic acid or amino acid sequence a to, with, or against a given nucleic acid or amino acid sequence B (which may alternatively be said to mean that the given nucleic acid or amino acid sequence a has or comprises a certain percentage of sequence identity to, with, or against a given nucleic acid or amino acid sequence B) is calculated as follows:

100X (fraction X/Y)

Wherein X is the number of nucleotides or amino acids scored as identical matches in an alignment of a and B by a sequence alignment program (e.g., BLAST), and wherein Y is the total number of nucleic acids in B. It will be understood that when the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not be equal to the percent sequence identity of B to A.

As used herein, "pharmaceutically acceptable excipient" refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound) and has substantially non-toxic and non-inflammatory properties in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Exemplary excipients include, but are not limited to: butylated Hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crospovidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin a, vitamin E, vitamin C, and xylitol.

The term "pharmaceutically acceptable salt" as used herein refers to any pharmaceutically acceptable salt of any compound described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: berge et al, j. pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: properties, Selection, and Use, (edited by p.h. stahl and c.g. wermuth), Wiley-VCH, 2008. Salts may be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

The compounds described herein may have ionizable groups so as to enable the preparation of pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or in the case of the acidic forms of the compounds described herein, the salts may be prepared from inorganic or organic bases. Typically, the compounds are prepared as pharmaceutically acceptable salts or are used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, sulfate, salicylate, and the like, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

As used herein, the term "pharmaceutical composition" means a composition that contains a compound described herein formulated with a pharmaceutically acceptable excipient and is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. The pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, caplets, soft capsules, or syrups); for topical administration (e.g., in the form of a cream, gel, lotion, or ointment); for intravenous administration (e.g., in the form of a sterile solution without a particulate plug and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

By "reducing the activity of BRD 9" is meant reducing the level of or associated with the activity associated with BRD 9. A non-limiting example of inhibiting the activity of BRD9 is reducing the level of BAF complexes (e.g., GBAF) in a cell. The level of activity of BRD9 can be measured using any method known in the art. In some embodiments, the agent that decreases the activity of BRD9 is a small molecule BRD9 inhibitor. In some embodiments, the agent that reduces the activity of BRD9 is a small molecule BRD9 degrader.

By "reducing the level of BRD 9" is meant reducing the level of BRD9 in a cell or subject. The level of BRD9 can be measured using any method known in the art.

"reference" refers to any useful reference for comparing protein or mRNA levels. The reference may be any sample, standard curve or level used for comparison purposes. The reference may be a normal reference sample or a reference standard or level. A "reference sample" can be, for example, a control, e.g., a predetermined negative control value, such as a "normal control" or a previous sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not suffering from a disease; a sample from a subject diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any of those described herein) at a known normal concentration. "reference standard or level" refers to a value or number derived from a reference sample. A "normal control value" is a predetermined value indicative of a non-disease state, e.g., a value expected in a healthy control subject. Typically, the normal control value is expressed as a range ("between X and Y"), a high threshold ("not higher than X"), or a low threshold ("not lower than X"). For a particular biomarker, a subject having a measurement value within a normal control value is generally referred to as "within normal limits" for that biomarker. A normal reference standard or level can be a normal subject who has never suffered a disease or disorder (e.g., cancer); a value or number obtained from a subject who has been treated with a compound described herein. In preferred embodiments, the reference sample, standard or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage and overall health. A standard curve of the level of purified protein (e.g., any of those described herein) within a normal reference range may also be used as a reference.

The terms "short interfering RNA" and "siRNA" (also referred to as "small interfering RNA") refer to an RNA agent, preferably a double-stranded agent, of about 10-50 nucleotides in length, the strand optionally having an overhang comprising, for example, 1, 2, or 3 overhanging nucleotides (or nucleotide analogs) capable of directing or mediating RNA interference. Naturally occurring sirnas are produced from longer dsRNA molecules (e.g., greater than 25 nucleotides in length) by the RNAi machinery of the cell (e.g., Dicer or a homolog thereof).

As used herein, the term "shRNA" refers to an RNA agent having a stem-loop structure comprising first and second regions of complementary sequence that are sufficiently complementary in degree and orientation to allow base pairing to occur between the regions, the first and second regions being linked by a loop region that results from a lack of base pairing between nucleotides (or nucleotide analogs) within the loop region.

As used herein, the term "subject" refers to any organism to which a composition according to the invention may be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). The subject may seek or require treatment, be receiving treatment, will receive treatment, or be a human or animal under the care of a trained professional for a particular disease or condition.

As used herein, the term "SS 18-SSX fusion protein-related disorder" refers to a disorder caused by or affected by the level and/or activity of SS18-SSX fusion protein.

As used herein, the terms "treatment", "treating" or "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease or to achieve a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; a reduced extent of the disorder, condition, or disease; the status of the condition, disorder or disease is stable (i.e., not worsening); delay in onset or slowing of progression of the condition, disorder or disease; amelioration or palliation (whether partial or complete) of the condition, disorder or disease state; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or amelioration of a condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes an extended survival compared to the expected survival in the absence of treatment.

As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally occurring, synthetic and semi-synthetic analogs of the compounds, peptides, proteins or other substances described herein. Variants or derivatives of the compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the original material.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Drawings

Figure 1 is a series of graphs showing the effect of specific guide rnas (sgrnas) targeting BRD9 BAF complex subunits on synovial sarcoma cell growth. The Y-axis indicates the drop-out rate. The X axis indicates the nucleotide position of the BRD9 gene. Grey boxes indicate the range of negative control sgrnas in the screen. The SYO1 cell line carries the SS18-SSX2 fusion protein. The breaking point connecting the N-terminal region of SS18 to the C-terminal region of SSX2 is indicated by a black line in its respective figure. Linear protein sequences are shown with BRD9 PFAM domains annotated from the PFAM database.

Figure 2 is an image showing dose-dependent depletion of BRD9 levels in synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrading agent.

Figure 3 is a graph showing sustained inhibition of BRD9 levels in synovial sarcoma cell line (SYO1) over 72 hours in the presence of a BRD9 degrading agent.

Fig. 4 is a graph showing sustained inhibition of BRD9 levels in both cell lines (293T and SYO1) over 5 days in the presence of a BRD9 degrading agent.

Fig. 5 is a graph showing sustained inhibition of BRD9 levels in synovial sarcoma cell lines (SYO1 and Yamato) within 7 days in the presence of a BRD9 degrading agent compared to levels in cells treated with CRISPR agents.

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

Figure 7 is an image showing the effect on cell growth of two cell lines (SYO1 and G401) in the presence of a BRD9 degrading agent.

FIG. 8 is an image showing the effect on cell growth of three synovial sarcoma cell lines (SYO1, HS-SY-II and ASKA) in the presence of BRD9 degradant, a BRD9 binding agent and an E3 ligase binding agent.

Figure 9 is an image showing the effect on cell growth of three non-synovial sarcoma cell lines (RD, HCT116 and Calu6) in the presence of a BRD9 degradant, a BRD9 binding agent and an E3 ligase binding agent.

Figure 10 is a graph showing the percentage of SYO1 in various cell cycle phases after 8 or 13 days of treatment with DMSO, 200nM of compound 1, or 1 μ M of compound 1.

Figure 11 is a series of contour plots showing the percentage of SYO1 cells in each cell cycle phase after 8 days of treatment with DMSO, 200nM compound 1, 1 μ M compound 1, or 200nM lenalidomide. The values corresponding to each contour plot are found in the table below.

Figure 12 is a series of contour plots showing the percentage of SYO1 cells in each cell cycle phase after 13 days of treatment with DMSO, 200nM compound 1, 1 μ M compound 1, or 200nM lenalidomide. The values corresponding to each contour plot are found in the table below.

Figure 13 is a series of contour plots showing the percentage of early and late apoptosis SYO1 cells after 8 days of treatment with DMSO, 200nM compound 1, 1 μ M compound 1, or 200nM lenalidomide. The values corresponding to each contour plot are found in the table below.

FIG. 14 is a diagram showing the proteins present in the BAF complex comprising SS18-SSX fusion protein.

Detailed Description

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

Compound (I)

The compounds described herein reduce the level of activity associated with BRD9 or associated downstream effects, or reduce the level of BRD9 in a cell or subject. Exemplary compounds described herein have a structure according to formula I or formula II.

Formula I is:

wherein

R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

Z1is CR2Or N;

R2is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

X1is N or CH, and X2Is C-R7(ii) a Or X1Is C-R7And X2Is N or CH;

R7is optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamideAn optionally substituted carbocyclyl having 3 to 6 atoms or an optionally substituted heterocyclyl having 3 to 6 atoms;

X3is N or CH;

X4is N or CH;

g is optionally substituted C3-C10Carbocyclyl, C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group; or a pharmaceutically acceptable salt thereof.

Formula II is:

A-L-B

in the formula II, the compound is shown in the specification,

wherein

L is a linker;

b is a degradation moiety; and is

A has the structure of formula III:

wherein

R1Is H, optionally substituted C1-C6Alkyl, optionally substituted C2-C6Alkenyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C 3-C10A carbocyclic group;

Z1is CR2Or N;

R2is H, halogen, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C3-C10Carbocyclyl, optionally substituted C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

X1is N or CH, and X2Is C-R7"; or X1Is C-R7", and X2Is N or CH;

R7"isOptionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl, optionally substituted C1-C6Alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;

R7' is H, optionally substituted C1-C6Alkyl, optionally substituted C1-C6Heteroalkyl or optionally substituted C3-C10A carbocyclic group;

X3is N or CH;

X4is N or CH;

g' isOptionally substituted C3-C10Carbocyclyl, C2-C9Heterocyclyl, optionally substituted C6-C10Aryl or optionally substituted C2-C9A heteroaryl group;

g' is optionally substituted C3-C10Carbocyclylene, C2-C9Heterocyclylene radical, optionally substituted C6-C10Arylene or optionally substituted C2-C9A heteroarylene group; and is

A1Is the bond between a and the linker,

wherein G' isOr R7"isOr a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one of compounds B1-B6 in table 1 or a pharmaceutically acceptable salt thereof

In some embodiments, the compound has the structure of any one of compounds D1-D31 in table 2A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D32-D184 in table 2B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D185-D316 in table 2C, or a pharmaceutically acceptable salt thereof.

Other embodiments and exemplary methods for the production of these compounds are described herein.

Pharmaceutical use

The compounds described herein are useful in the methods of the invention, and while not being bound by theory, it is believed that their desired effect may be exerted by their ability to modulate the level, state and/or activity of BAF complexes, for example by inhibiting the activity or level of BRD9 protein in cells within BAF complexes in mammals.

One aspect of the present invention relates to methods of treating a disorder associated with 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 produce one or more (e.g., two or more, three or more, four or more) of: (a) reducing tumor size, (b) reducing the rate of tumor growth, (c) increasing tumor cell death, (d) decreasing tumor progression, (e) decreasing the number of metastases, (f) decreasing metastasis rate, (g) decreasing tumor recurrence, (h) increasing subject survival, and (i) increasing progression-free survival of the subject.

Treating cancer can result in a reduction in the size or volume of the 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 the size prior to treatment. Tumor size can be measured by any repeatable measurement means. For example, the size of a tumor can be measured as the diameter of the tumor.

Treatment of cancer may further result in a reduction in tumor numbers. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of tumors can be measured by any repeatable measurement means, for example, by counting tumors that are visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50 x).

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

Treatment of cancer may result in an increase in the average survival time of a population of subjects treated according to the invention compared to an untreated population of subjects. For example, the average survival time increases by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of a population can be measured by any repeatable means. The increase in the mean survival time of a population can be measured, for example, by calculating the mean survival length of the population after starting treatment with a compound described herein. The increase in the mean survival time of a population can also be measured, for example, by calculating the mean length of survival of the population after completion of the first round of treatment with a pharmaceutically acceptable salt described herein.

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

Combination therapy

The methods of the invention can be used alone or in combination with additional therapeutic agents (e.g., other agents that treat cancer or symptoms associated with cancer) or in combination with other types of therapies to treat cancer. In combination therapy, the dosage of one or more therapeutic compounds may be reduced from the standard dosage when administered alone. For example, dosages can be determined empirically for drug combinations and permutations, or can be derived by isobologram analysis (e.g., Black et al, Neurology 65: S3-S6 (2005)). In such cases, the dosages of the compounds in the combination should provide a therapeutic effect.

In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful for treating 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 ureas, methylhydrazine derivatives, adrenocortical suppressants, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin releasing hormone analogs. Also included are 5-fluorouracil (5-FU), Leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa (benzodopa), carboquone, mitodopa, and ulidopa; ethyleneimine and methylmelamine including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; polyacetyl (especially bullatacin and bullatacin ketone); camptothecin (including the synthetic analog topotecan); bryostatins; a sponge statin; CC-1065 (including Their aldorexin, kazelaixin and bizelaixin synthetic analogs); nostoc (especially nostoc 1 and nostoc 8); dolastatin; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); (ii) coprinus atramentarius alkali; alcohol of coral tree; spongistatin (spongistatin); nitrogen mustards, such as chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, neonebixin, benzene mustard cholesterol, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorourethrin, fotemustine, lomustine, nimustine and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ II and calicheamicin ω II (see, e.g., Agnew, chem. intl. ed Engl. 33: 183-186 (1994)); daptomycin, including daptomycin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostamycin chromophore and related tryptophane diyne antibiotic chromophore), aclacinomycin, actinomycin, antromycin, azalomycin, azaserine, bleomycin, actinomycin C, carubicin, carminomycin, carzinomycin, tryptomycin, dactinomycin, daunomycin, ditobicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, sisomicin, mitomycin (e.g., mitomycin C), mycophenolic acid, noramycin, olivomycin, pelomycin, pofiomycin, puromycin, trirubicin, roxobicin, streptonigrin, streptozotocin, tubercidin, ubenimex, setastatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thioguanine; pyrimidine analogues, e.g. ancitabine, azacitidine, 6-azauridine, carmoisolFluorine, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as carpoterone, drotandrosterone propionate, epitioandrostanol, meiandrane, testolactone; anti-adrenergic agents, such as aminoglutethimide, mitotane, troostitan; folic acid replenisher such as folinic acid; acetic acid glucurolactone; an aldehydic phosphoramide glycoside; (ii) aminolevulinic acid; eniluracil; amsacrine; betrebuche; a bisantrene group; edatrexae; defu famine; colchicine; diazaquinone; eflornithine; ammonium etiolate; an epothilone; etoglut; gallium nitrate; a hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanol; diamine nitracridine (nitrarine); pentostatin; methionine; pirarubicin; losoxanthraquinone; podophyllinic acid; 2-ethyl hydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); lezoxan; rhizomycin (rhizoxin); a texaphyrin; a germanium spiroamine; alternarionic acid; a tri-imine quinone; 2, 2', 2 "-trichlorotriethylamine; trichothecene toxins (particularly T-2 toxin, verrucosin A, bacillocin A and serpentine); uratan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gatifloxacin (gacytosine); cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g.Paclitaxel (Bristol-Myers squirb Oncology, Princeton, NJ),Albumin-engineered paclitaxel nanoparticle formulations without cremophor (American Pharmaceutical Partners, Schaumberg, IL) anddocetaxel (Rhone-Poulenc Rorer, Antony, France);chlorambucil;gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;vinorelbine; nuoantot; (ii) teniposide; edatrexae; daunomycin; aminopterin; (ii) Hirodad; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and a pharmaceutically acceptable salt, acid or derivative of any of the foregoing. Two or more chemotherapeutic agents may be used in a mixture for administration in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in salvz et al, proc.am.soc.clin.oncol.18: 233a (1999) and Douillard et al, Lancet 355 (9209): 1041 ion 1047(2000)

In some embodiments, the second therapeutic agent is a therapeutic agent that is a biological agent for cancer treatment, such as a cytokine (e.g., an interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumabIn some embodiments, the biologic is an immunoglobulin-based biologic, such as 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 to cancer. Such agents include(rituximab);(daclizumab);(basiliximab);(palivizumab);(infliximab);(trastuzumab);(gemtuzumab ozomicin);(alemtuzumab);(ibritumomab tiuxetan);(adalimumab);(omalizumab);(tositumomab-I-131);(efletuzumab);(cetuximab);(bevacizumab);(natalizumab);(toclizumab);(panitumumab);(ranibizumab);(eculizumab);(pertuzumab pegylation);(golimumab); (kanamantimab);(Ultecumab);(ofatumumab);(denosumab);(Movizumab);(ranibizumab);(belimumab);(ipilimumab);(bentuximab vildagliptin);(pertuzumab);(ado-trastuzumab emtansine); and(obituzumab). Antibody-drug conjugates are also included.

The second agent may be a therapeutic agent that is not a drug therapy. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical resection of tumor tissue.

The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of the checkpoint is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the inhibitor of the checkpoint is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the inhibitor of a checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of the checkpoint is an agent, such as an antibody, that interacts with a ligand of the checkpoint protein. In some embodiments, the inhibitor of the checkpoint is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., an anti-CTLA 4 antibody or fusion protein, such as ipilimumab @ Or tremelimumab).In some embodiments, the inhibitor of the checkpoint is an inhibitor of PD-1 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., nivolumab @Pimumab-pidilizumab/CT-011). In some embodiments, the inhibitor of a checkpoint is an inhibitor of PDL1 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., MPDL3280A/RG 7446; MEDI 4736; MSB 0010718C; BMS 936559). In some embodiments, the inhibitor of a checkpoint is an inhibitor of PDL2 (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) (e.g., PDL2/Ig fusion protein, such as AMP 224). In some embodiments, the inhibitor of a 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 ligand, or a combination thereof.

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

In any combination embodiment described herein, the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately before or after the second therapeutic agent, 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 16 hours, up to 17 hours, up to 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.

Pharmaceutical composition

The pharmaceutical compositions described herein are preferably formulated as pharmaceutical compositions for administration to a human subject in a biocompatible form suitable for in vivo administration.

The compounds described herein may be used in the form of the free base, as salts, solvates and in prodrug form. All forms are within the methods described herein. As will be appreciated by those skilled in the art, in accordance with the methods of the present invention, the described compounds, or salts, solvates, or prodrugs thereof, may be administered to a patient in a variety of forms depending on the route of administration selected. The compounds described herein can 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, epithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

The compounds described herein may be administered orally, for example, with an inert diluent or with an ingestible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the compounds described herein may be combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups and wafers. The compounds described herein may also be administered parenterally. Solutions of the compounds described herein may 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 normal conditions of storage and use, these formulations may contain preservatives to prevent microbial growth. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2012, 22 nd edition) and The United States pharmacy published in 2018: the National Formulary (USP 41 NF 36). 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 it can be readily injected via a syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in sterile form in single or multiple dose form in a sealed container, which may take the form of a cartridge or refill for an atomising device. Alternatively, the sealed container may be an integral dispensing device, such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve intended to be discarded after use. When the dosage form comprises an aerosol dispenser, it will contain a propellant which may be a compressed gas (e.g. compressed air) or an organic propellant (e.g. fluorochlorohydrocarbon). Aerosol dosage forms may also take the form of pump atomizers. Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, or tragacanth, gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories with conventional suppository bases such as cocoa butter. The compounds described herein can be administered intratumorally, e.g., in the form of an intratumoral injection. Intratumoral injection is direct injection into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional or systemic administration may also be appropriate. The compounds described herein may advantageously be contacted by administering to the tumor an injection or multiple injections, e.g., spaced at about 1cm intervals. In the case of surgery, the invention may be used preoperatively, for example to subject inoperable tumors to resection. Continuous administration may also be employed where appropriate, for example, by implanting a catheter into the tumor or tumor vasculature.

As described herein, the compounds described herein can be administered to an animal (e.g., a human) alone or in combination with a pharmaceutically acceptable carrier, in proportions determined by the solubility and chemical nature of the compound, the chosen route of administration, and standard pharmaceutical practice.

Dosage form

The dosage of a compound described herein and/or a composition comprising a compound described herein can vary depending on a number of factors, such as the pharmacodynamic properties of the compound; the mode of administration; age, health, and weight of the recipient; the nature and extent of the symptoms; frequency of treatment and type of concurrent treatment (if any); and the clearance of the compound in the animal to be treated. One skilled in the art can determine the appropriate dosage based on the factors described above. The compounds described herein may be administered initially in suitable dosages, which may be adjusted as needed in accordance with the clinical response. In general, satisfactory results are obtained when the compounds described herein are administered to humans at daily doses (measured as solids), for example, between 0.05mg and 3000 mg. Dosage ranges include, for example, between 10-1000mg (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 1000mg of the compound is administered.

Alternatively, the weight of the patient may be used to calculate the dose amount. For example, the dose of the compound or pharmaceutical composition thereof administered to the patient can be in the range of 0.1-100mg/kg (e.g., 0.1-50mg/kg (e.g., 0.25-25 mg/kg)). In exemplary non-limiting embodiments, the dose can be in the range of 0.5-5.0mg/kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0mg/kg) or 5.0-20mg/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).

Medicine box

The invention also features a kit that includes (a) a pharmaceutical composition that includes 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 for performing any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising 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 having instructions for performing any of the methods described herein.

Examples

Example 1-high Density tiled sgRNA screening for human BAF Complex subunits in synovial sarcoma cell line SY01

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

The procedure is as follows: for high density sgRNA tiling, a sgRNA library for BAF complex subunits was custom synthesized in Cellecta (Mountain View, CA). The DNA sequences encoding sgrnas targeting BRD9 used in this screen are listed in table 3. Both negative and positive control sgrnas are included in the library. The negative control consisted of 200 sgrnas that did not target the human genome. Positive controls were sgrnas targeting essential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1, PCNA, POLR2L, RPL9, and SF3 A3). The DNA sequences encoding all positive and negative control sgrnas are listed in table 4. Procedures for virus production, Cell infection and sgRNA screening have been previously described (Tsouthern 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. Log2 of the ratio between counts at day 24 and day 1 post infection (defined as the withdrawal ratio) was calculated. For the negative control sgrnas, 2.5 and 97.5 percentiles of log2 exit ratios for all non-targeted sgrnas were calculated and considered as background (grey boxes in the figure). The protein domain is obtained from the PFAM region defined for UNIPROT identifier Q9H8M 2.

As a result: as shown in fig. 1, targeted inhibition of GBAF complex component BRD9 by sgRNA resulted in growth inhibition of SYO1 synovial sarcoma cell line. Sgrnas directed against other components of the BAF complex resulted in increased cell proliferation, inhibition of cell growth, or no effect on SYO1 cells. These data indicate that targeting individual subunits of the GBAF complex represents a therapeutic strategy for the treatment of synovial sarcoma.

Table 3: BRD9 sgRNA library

Table 4: control sgRNA library

Example 2-BRD9 degradant depletes BRD9 protein

The following example demonstrates the depletion of BRD9 protein in synovial sarcoma cells treated with BRD9 degradant.

The procedure is as follows: for the indicated doses and time points, cells were degraded with DMSO or BRD9 degradation agent compound 1 (also known as dBRD9), see Remillard et al, angelw.chem.int.ed.engl.56 (21): 5738-5743 (2017); see structure of compound 1 below).

The whole cell extracts were fractionated by SDS-PAGE and transferred to a polyvinylidene fluoride membrane using a transfer device according to the manufacturer's protocol (Bio-Rad). After incubation with 5% skim milk for 60 minutes in TBST (10mM Tris (pH 8.0), 150mM NaCl, 0.5% Tween 20), the membranes were incubated with antibodies against BRD9 (1: 1,000, B ethyl laboratory A303-781A), GAPDH (1: 5,000, Cell Signaling Technology) and/or MBP (1: 1,000, BioRad) Incubate overnight. The membrane was washed 3 times for 10 minutes each and incubated for at least 1 hour with anti-mouse or anti-rabbit antibodies conjugated with horseradish peroxidase (HRP, FIGS. 2-3) or IRDye (FIG. 4, 1: 20,000, LI-COR). Blots were washed 3 times with TBST and developed using ECL system (fig. 2-3) or scanned on Odyssey CLx imaging system (fig. 4) according to the manufacturer's protocol.

As a result: treatment of SYO1 synovial sarcoma cells with BRD9 degradant compound 1 resulted in dose-dependent (figure 2) and time-dependent (figure 3) depletion of BRD9 in the cells. Furthermore, as shown in figure 4, depletion of BRD9 by compound 1 was repeated in a non-synovial sarcoma cell line (293T) and could last for at least 5 days.

Example 3 inhibition of growth of synovial cell lines by BRD9 inhibitor and BRD9 degradant

The following examples demonstrate that BRD9 degradants and inhibitors selectively inhibit the growth of synovial sarcoma cells.

The procedure is as follows:

cells were treated with indicated concentrations of DMSO or BRD9 degradant compound 1 and proliferation from day 7 to day 14 was monitored by measuring confluency over time using the IncuCyte live cell assay system (figure 5). Growth media and compounds were refreshed every 3-4 days.

Cells were seeded into 12-well plates and treated with DMSO, 1 μ M BRD9 inhibitor Compound 2 (also known as BI-7273, see Martin et al, J Med chem.59 (10): 4462-.

The number of cells was optimized for each cell line. Growth media and compounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T and HS-SY-II cells were fixed and stained on day 11. ASKA cells were fixed and stained on day 23. Dyeing is carried out by: incubate with crystal violet solution (0.5g crystal violet, 27mL 37% formaldehyde, 100mL 10X PBS, 10mL methanol, 863 dH20 to 1L) for 30 min, then wash 3 times with water and dry the plate at room temperature for at least 24 h. The plate was then scanned on an Odyssey CLx imaging system (fig. 6).

Cells were seeded into 96-well ultra-low cluster plates (Costar, #7007) in 200 μ Ι of complete medium and treated with the indicated doses of DMSO, staurosporine, or BRD9 degradant compound 1 on day 2 (fig. 7). Media and compounds were changed every 5 days and cell colonies were imaged on day 14.

As a result: as shown in figures 5, 6 and 7, treatment of synovial sarcoma cell lines (SYO1, Yamato, HS-SY-II and ask) with BRD9 inhibitor compound 2 or BRD9 degradant compound 1 resulted in inhibition of cell growth, but not in inhibition of growth of non-synovial control cancer cell lines (293T, A549, G401).

Example 4-Selective inhibition of growth of synovial cell lines by BRD9 degradant and BRD9 binding agent

The following examples demonstrate that BRD9 degradants and binding agents selectively inhibit the growth of synovial sarcoma cells.

The procedure is as follows: cells were seeded into 6-or 12-well plates and treated daily with indicated concentrations of BRD9 degradant (compound 1), bromodomain BRD9 binding agent (compound 2), E3 ligase binding agent (lenalidomide), DMSO, or staurosporine (positive control for cell killing). The number of cells was optimized for each cell line. Growth medium was refreshed every 5 days. By day 14, the medium was removed, the cells were washed with PBS, and stained with 500 μ L of a 0.005% (w/v) crystal violet solution in 25% (v/v) methanol at room temperature for at least 1 hour. The plate was then scanned on an Odyssey CLx imaging system.

As a result: 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 cell growth, but did not result in inhibition of growth of non-synovial control cancer cell lines (RD, HCT116, and Calu 6). Overall, compound 1 showed the most significant growth inhibition in all synovial cell lines.

Example 5 inhibition of cell growth in synovial sarcoma cells

The following example shows that BRD 9-degrading agents inhibit cell growth and induce apoptosis in synovial sarcoma cells.

The procedure is as follows: SYO1 cells were treated with DMSO, 200nM or 1 μ M BRD9 degradant (Compound 1) or 200nM E3 ligase binding agent (lenalidomide) for 8 or 13 days. Compounds were refreshed every 5 days. Using Click-iTTMThe Plus EdU flow cytometry assay (Invitrogen) performed cell cycle analysis. Apoptosis assays were performed using the annexin V-FITC apoptosis detection kit (Sigma A9210). The assay was performed according to the manufacturer's protocol.

As a result: as shown in figures 10-13, treatment with compound 1 for 8 or 13 days resulted in a decrease in cells in the S phase of the cell cycle compared to DMSO and lenalidomide. Treatment with compound 1 for 8 days also resulted in an increase in the number of early and late apoptotic cells compared to DMSO control.

Example 6-SS18-SSX1-BAF composition

The following example illustrates the identification of BRD9 as a component of a BAF complex containing SS 18-SSX.

The procedure is as follows: lentiviral integration was used to generate a stable 293T cell line expressing HA-SS18SSX 1. BAF complexes containing SS18-SSX1 were subjected to affinity purification and subsequent mass spectrometry analysis revealed SS18-SSX1 interacting proteins.

As a result: as shown in FIG. 14, the BAF complex comprising SS18-SSX fusion protein also includes BRD 9. 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 4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-6- (methylamino) -1, 2-dihydro-2, 7-naphthyridin-1-one (Compound B1)

To 6-chloro-4- [4- [ (dimethylamino) methyl group at room temperature]-3, 5-dimethoxyphenyl]A stirred mixture of-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (100mg, 0.26mmol, 1.0 equiv.) and methylamine hydrochloride (174.08mg, 2.58mmol, 10.0 equiv.) in DMSO (3mL) was added K2CO3(890.82mg, 6.45mmol, 25.0 equiv.). Mixing the obtained mixture inStirred for 16 hours and then allowed to cool to room temperature. The solid was filtered off and the crude solution was purified by preparative HPLC (conditions: Xbridge Shield RP18 OBD column 30 x 150mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 40 mL/min; gradient: 18% B to 18% B in 2 min; 254/220 nm; Rt: 7.43 min) to give 4- [4- [ (dimethylamino) methyl ] amino]-3, 5-dimethoxyphenyl]-2-methyl-6- (methylamino) -1, 2-dihydro-2, 7-naphthyridin-1-one (27mg, 26%).1H NMR (400MHz, methanol-d 4) Δ 9.08(s, 1H), 7.40(s, 1H), 6.74(s, 2H), 6.44(s, 1H), 3.88(s, 6H), 3.69(s, 2H), 3.58(s, 3H), 2.88(s, 3H), 2.33(s, 6H). LCMS (ESI) m/z: [ M + H ] ]+＝383.20。

EXAMPLE 8 preparation of 6- (dimethylamino) -4-14- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (Compound B2)

To 6-chloro-4- [4- [ (dimethylamino) methyl group at room temperature]-3, 5-dimethoxyphenyl]A stirred mixture of-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (77.6mg, 0.20mmol, 1.0 equiv.) and dimethylamine hydrochloride (163.14mg, 2.0mmol, 10.0 equiv.) in DMF (6mL) was added TEA (404.91mg, 4.0mmol, 20.0 equiv.). Mixing the obtained mixture inStirred for 16 hours and then allowed to cool to room temperature. The solid was filtered off and the filtrate was purified by preparative HPLC using the following conditions (2# SHIMADZU (HPLC-01)): column, X Bridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH)3H2O) and ACN (10% phase B to 70% in 8 min); 23mg (27%) of 6- (dimethylamino) -4- [4- [ (dimethylamino) methyl ] methyl as a brown solid were obtained]-3, 5-dimethoxyphenyl]-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one.1H NMR (400MHz, methanol-d 4) Δ 9.15(s, 1H), 7.43(s, 1H), 6.77(s, 2H), 6.52(s, 1H), 3.89(s, 6H), 3.70(s, 2H), 3.59(s, 3H), 3.12(s, 6H), 2.34(s, 6H). LCMS (ESI) m/z: [ M + H ] ]+＝397.40。

EXAMPLE 9 preparation of 4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-7- (methylamino) -1, 2-dihydro-2, 6-naphthyridin-1-one (Compound B3)

To 7-chloro-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]Solution of-2-methyl-1, 2-dihydro-2, 6-naphthyridin-1-one (50mg, 0.13mmol, 1.0 equiv.) and methylamine hydrochloride (87.0mg, 1.29mmol, 10.0 equiv.) in solvent DMSO (2mL) was added K2CO3(445.4mg, 3.22mmol, 25.0 equiv.). The obtained solution is mixed inStirring was continued overnight. After cooling, the solid was filtered off and the crude solution was passed through preparative HPLC (conditions: Xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 30% B to 80% B in 8 minutes; 220 nm; rt: 7.8 min) to give 4- [4- [ (dimethylamino) methyl group as a yellow solid]-3, 5-dimethoxyphenyl]-2-methyl-7- (methylamino) -1, 2-dihydro-2, 6-naphthyridin-1-one (15.5mg, 31%).1H NMR (300MHz, methanol-d 4) δ 8.53(d, J ═ 0.9Hz, 1H), 7.24(d, J ═ 0.9Hz, 1H), 7.09(s, 1H), 6.76(s, 2H), 3.88(s, 6H), 3.67(d, J ═ 11.1Hz, 5H), 2.97(s, 3H), 2.31(s, 6H). LCMS: (ES, m/z): [ M + H ] ]+＝383.30。

EXAMPLE 10 preparation of 6-amino-4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (Compound B4) and 7-amino-4- (4- ((dimethylamino) methyl) -3, 5-dimethoxyphenyl) -2-methyl-2, 6-naphthyridin-1 (2H) -one (Compound B5)

Step 1: preparation of 4-bromo-6-chloro-N-methylpyridine-3-carboxamide (i10-2)

To a solution of 4-bromo-6-chloropyridine-3-carboxylic acid (2.0g, 8.46mmol, 1.0 equiv.), methylamine hydrochloride (0.63g, 9.30mmol, 1.1 equiv.), and DIEA (3.28g, 25.38mmol, 3.0 equiv.) in DCM (20mL) was added HATU (4.82g, 12.69mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred for an additional 1 hour. The reaction was then washed with water (20m x 2) and the organic layer was concentrated in vacuo to give a yellow slurry. The product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝249。

Step 2: preparation of 6-chloro-4- [ (E) -2-ethoxyvinyl ] -N-methylpyridine-3-carboxamide (i10-3)

To 4-bromo-6-chloro-N-methylpyridine-3-carboxamide (1.0g, 4.0mmol, 1 eq.) and 2- [ (E) -2-ethoxyvinyl]-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.95g, 4.81mmol, 1.2 equiv.) in dioxane (10mL) and H 2Solution in O (2mL) with addition of Cs2CO3(3.92g, 12.03mmol, 3.0 equiv.) and Pd (dppf) Cl2·CH2Cl2(0.35g, 0.48mmol, 0.12 equiv.). The mixture is put under nitrogen atmosphereStirred for 2 hours and the reaction mixture was diluted with water and extracted with ethyl acetate over Na2SO4Dried and concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (20: 1) to give 6-chloro-4- [ (E) -2-ethoxyvinyl) as an off-white solid]-N-methylpyridine-3-carboxamide (680mg, 57%). LCMS (ESI) m/z: [ M + H ]]+＝241。

And step 3: 6-chloro-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (i10-4)

To a 20mL pressure tube at room temperature was added 6-chloro-4- [ (E) -2-ethoxyvinyl group]-N-methylpyridine-3-carboxamide (680mg, 2.83mmol, 1.0 equiv.) and TFA (5mL, 67.32mmol, 23.83 equiv.) the reaction was stirred atStirring was continued overnight. The resulting mixture was concentrated in vacuo to give 6-chloro-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (580mg, crude) as a dark yellow solid.The product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝195。

And 4, step 4: preparation of 4-bromo-6-chloro-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (i10-5)

To a stirred mixture of 6-chloro-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (580mg, 2.98mmol, 1.0 equiv.) in DMF (10mL) was added NBS (583.46mg, 3.28mmol, 1.1 equiv.) at room temperature and the resulting mixture was stirred for 2 hours. The reaction mixture was diluted with DCM (50mL) and washed with water (3 × 50 mL). Subjecting the organic layer to Na 2SO4Dried and concentrated under vacuum. The crude product was purified by flash silica chromatography eluting with 0% to 80% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to give 4-bromo-6-chloro-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one as a yellow solid (899mg, 88%). LCMS (ESI) m/z: [ M + H ]]+＝273。

And 5: preparation of 6-chloro-4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (i10-6)

To 4-bromo-6-chloro-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (843mg, 3.08mmol, 1.0 equiv.) and [4- [ (dimethylamino) methyl]-3, 5-dimethoxyphenyl]Boric acid (736.88mg, 3.08mmol, 1.0 equiv.) in dioxane (40mL) and H2Solution in O (4mL) with addition of Cs2CO3(3.01g, 9.25mmol, 3.0 equiv.) and Pd (dppf) Cl2·CH2Cl2(302.04mg, 0.37mmol, 0.12 equiv.). In thatAfter stirring under nitrogen for 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetateAnd (4) extracting. Subjecting the organic layer to Na2SO4Dried and then concentrated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 0% to 80% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to give 6-chloro-4- [4- [ (dimethylamino) methyl ] amino as a yellow solid ]-3, 5-dimethoxyphenyl]-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (670mg, 51%). LCMS (ESI) m/z: [ M + H ]]+＝388。

Step 6: preparation of 6-amino-4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (Compound B4)

To 6-chloro-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one (232mg, 060mmol, 1.0 equiv.) and NH4A stirred mixture of Cl (479.94mg, 8.97mmol, 15.0 equiv.) in DMSO (10mL) was added K2CO3(2.07g, 14.95mmol, 25.0 equiv.). Mixing the obtained mixture inStirring was continued overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, over Na2SO4Dried and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (conditions: X Select CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase, water (0.1% FA) and ACN (7% phase B retained over 7 min); detector, UV) to yield 3.4mg (1.54%) of 6-amino-4- [4- [ (dimethylamino) methyl ] methyl as an off-white solid]-3, 5-dimethoxyphenyl]-2-methyl-1, 2-dihydro-2, 7-naphthalen-pyridin-1-one.1H NMR (400MHz, methanol-d 4) Δ 9.04(s, 1H), 7.44(s, 1H), 6.84(s, 2H), 6.54(s, 1H), 4.34(s, 2H), 3.97(s, 6H), 3.59(s, 3H), 2.85(s, 6H). LCMS (ESI) m/z: [ M + H ] ]+＝369.25。

Preparation of 7-amino-4- (4- ((dimethylamino) methyl) -3, 5-dimethoxyphenyl) -2-methyl-2, 6-naphthyridin-1 (2H) -one (Compound B5)

Compound B5 was prepared in a similar manner as described above for compound B4.1H NMR (300MHz, methanol-d 4) δ 8.39(s, 1H), 7.65(d, J ═ 2.2Hz, 1H), 7.23(s, 1H), 6.89(s, 2H), 4.42(s, 2H), 3.98(s, 6H), 3.64(s, 3H), 2.92(s, 6H). LCMS (ESI) m/z: [ M + H ]]+＝369.25。

EXAMPLE 11 preparation of 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] -N, N-dimethylacetamide carboxylic acid (Compound B6 carboxylic acid)

To [ (8- [4- [ (dimethylamino) methyl group)]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino]A stirred mixture of acetic acid (60.0mg, 0.141mmol, 1.00 equiv.) and dimethylamine hydrochloride (17.2mg, 0.211mmol, 1.50 equiv.) in DMF (2.00mL) was added DIEA (54.6mg, 0.422mmol, 3.00 equiv.). The mixture was stirred at room temperature for 5 min, then PyBOP (146.43mg, 0.281mmol, 2.00 eq) was added. After stirring at room temperature for 2 hours, the reaction mixture was passed through preparative HPLC (conditions: Sun Fire C18 OBD Prep column, 5 μm, 19mm X250 mm; mobile phase, water (0.1% FA) and ACN (10% phase B to 31% in 11 min). This gave 2- [ (8- [4- [ (dimethylamino) methyl ] ester as a dark yellow solid]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino]-N, N-dimethylacetamide; formic acid (10.9mg, 17.7%).1H NMR (300MHz, methanol-d 4) Δ 8.51(br s, 0.5H, FA), 8.50(s, 1H), 7.37(s, 1H), 7.16(s, 1H), 6.92(s, 2H), 4.92(s, 2H), 4.37(s，2H)，3.95(s，6H)，3.65(s，3H)，3.36(s，6H)，3.05(d，J＝5.5Hz，6H)。LCMS(ESI)m/z：[M+H]+＝454.20。

EXAMPLE 12 preparation of 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] oxy ] pentyl) azetidine-3-carboxamide (Compound D1)

Step 1: preparation of 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde (i12-2)

To 4-bromo-6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (400.00mg, 1.42mmol, 1.00 equiv.) in dioxane (10.00mL) and H2To a solution of O (1.00mL) were added 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (500mg, 1.70mmol, 1.2 equiv.), Pd (dppf) Cl 2(100.0mg, 0.14mmol, 0.1 equiv.) and Cs2CO3(1.39g, 4.14mmol, 3 equiv.). The obtained solution is mixed inThe mixture was stirred under nitrogen for 1 hour. The crude product was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (10: 1) to give 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl as a pale yellow solid]-2, 6-dimethoxybenzaldehyde (416.8mg, 119.03%). LCMS (ESI) m/z: [ M + H ]]+＝367.4。

Step 2: preparation of methyl 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidine-3-carboxylate (i12-3)

To 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl group]-2, 6-dimethoxybenzaldehyde (331.00mg, 0.901mmol, 1.00 equiv.) in MeOH (10.00mL) methyl azetidine-3-carboxylate hydrochloride (163.88mg, 1.081mmol, 1.2 equiv.) and NaBH3CN (169.85mg, 2.703mmol, 3 equiv.). The resulting solution was stirred at room temperature for 1 hour. The crude mixture was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (10: 1) to give 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a pale yellow solid ]-2, 6-dimethoxyphenyl]Methyl) azetidine-3-carboxylic acid methyl ester (279mg, 66.38%). LCMS (ESI) m/z: [ M + H ]]+＝466.5。

And step 3: preparation of 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidine-3-carboxylic acid (i12-4)

To 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) azetidine-3-carboxylic acid methyl ester (140.00mg, 0.300mmol, 1.00 equiv.) in MeOH (3.00mL) and H2To a solution in O (3.00mL) was added LiOH (71.87mg, 3.001mmol, 10.00 equiv). The resulting solution was stirred at room temperature for 3 hours. The crude mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (conditions: column, C18 silica gel; mobile phase, aqueous HCl, 10% to 70% gradient over 35 min; detector, UV 254 nm). This gives 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid]-2, 6-dimethoxyphenyl]Methyl) azetidine-3-carboxylic acid (120mg, 88.37%). LCMS (ESI) m/z：[M+H]+＝452.5。

And 4, step 4: preparation of 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] oxy ] pentyl) azetidine-3-carboxamide (Compound D1 carboxylic acid)

To 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) azetidine-3-carboxylic acid (50.00mg, 0.110mmol, 1.00 equiv.) and 4- [ (5-aminopentyl) oxy]-2- (2, 6-dioxopiperidin-3-yl) -2, 3-dihydro-1H-isoindole-1, 3-dione (39.71mg, 0.110mmol, 1.00 equiv.) in DMF (1.50mL) DIEA (42.84mg, 0.331mmol, 3.00 equiv.) and PyBOP (86.25mg, 0.166mmol, 1.50 equiv.) were added. The resulting solution was stirred at room temperature for 1 hour. The crude product (50mg) was passed through preparative HPLC (conditions: SunFire C18 OBD Prep column,5 μm, 19mm X250 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 11% B to 27% B in 18 minutes; 254 nm; rt: 16.87 min) to yield 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) as a pale yellow solid]-2, 6-dimethoxyphenyl]Methyl) -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl]Oxy radical]Pentyl) azetidine-3-carboxamide formate (13.5 mg).1H NMR (300MHz, acetonitrile-d 3) δ 9.12(s, 1H), 8.17(s, 0.3H, FA), 7.76(dd, J ═ 8.5, 7.3Hz, 1H), 7.53-7.28(m, 3H), 6.79(s, 2H), 6.65(s, 1H), 6.53(s, 1H), 4.99(dd, J ═ 12.1, 5.4Hz, 1H), 4.26(s, 2H), 4.23-4.15(m, 2H), 4.15-4.03(m, 2H), 4.04-3.92(m, 2H), 3.87(s, 6H), 3.52(s, 3H), 3.42(t, J ═ 8.1Hz, 1H), 3.34H), 3.7H, d, c -3.12(m，3H)，3.10(s，6H)，2.86-2.62(m，3H)，2.21-2.07(m，1H)，1.88-1.76(m，2H)，1.63-1.50(m，4H)。LCMS(ESI)m/z：[M+H]+＝452.45。

EXAMPLE 13 preparation of 4- ((((((S) -1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) azetidin-2-yl) methyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound D2)

Step 1: preparation of tert-butyl (S) -2- ((2, 2, 2-trifluoroacetylamino) methyl) azetidine-1-carboxylate (i13-2)

To a solution of (2S) -tert-butyl 2- (aminomethyl) azetidine-1-carboxylate (900.00mg, 4.832mmol, 1.00 equiv.) and trifluoroacetic anhydride (1.522g, 7.248mmol, 1.5 equiv.) in THF (9.00mL) was added TEA (977.92mg, 9.664mmol, 2 equiv.). The obtained solution is mixed inStirred for 12 hours. The resulting solution was diluted with EtOAc. The resulting mixture was washed with water (3 × 50mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was applied to a silica gel column with ethyl EA/PE (15: 85) to give (2S) -2- [ (2, 2, 2-trifluoroacetamido) methyl ] amino as a yellow oil]Azetidine-1-carboxylic acid tert-butyl ester (1.27g, 93.11%). LCMS (ESI) m/z: [ M + H ]]+＝283。

Step 2: preparation of (S) -tert-butyl 2- ((2, 2, 2-trifluoro-N-methylacetamido) methyl) azetidine-1-carboxylate (i13-3)

To (2S) -2- [ (2, 2, 2-trifluoroacetylamino) methyl group]A solution of azetidine-1-carboxylic acid tert-butyl ester (1.27g, 4.499mmol, 1.00 equiv.) and dimethyl sulfate (681.00mg, 5.399mmol, 1.2 equiv.) in acetone (15.00mL) was added K2CO3(621.83mg, 4.499mmol, 1 equiv.). The obtained solution is mixed inStirred for 12 hours. The resulting mixture was filtered and the filtrate was evaporated to dryness to give (2S) -2- [ (2, 2, 2-trifluoro-N-methylacetamido) methyl group as a yellow oil]Azetidine-1-carboxylic acid tert-butyl ester (1.64g, crude), which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝297。

And step 3: preparation of (S) -N- (azetidin-2-ylmethyl) -2, 2, 2-trifluoro-N-methylacetamide (i13-4)

Reacting (2S) -2- [ (2, 2, 2-trifluoro-N-methylacetamido) methyl]A solution of azetidine-1-carboxylic acid tert-butyl ester (1.64g, 5.535mmol, 1.00 equiv.) and TFA (3.50mL, 47.121mmol, 8.51 equiv.) in DCM (16.00mL) was dissolved inStirred for 1 hour. The mixture was concentrated to give N- [ (2S) -azetidin-2-ylmethyl as a brown oil]2, 2, 2-trifluoro-N-methylacetamide (2.08g, crude), which was used without further purification. LCMS (ESI) m/z: [ M + H ] ]+＝197。

And 4, step 4: preparation of (S) -N- ((1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) azetidin-2-yl) methyl) -2, 2, 2-trifluoro-N-methylacetamide (i13-5)

To 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl group]-2, 6-dimethoxybenzaldehyde (620.00mg, 1.688mmol, 1.00 equiv.) and N- [ (2S) -azetidin-2-ylmethyl]-2, 2, 2-trifluoro-N-methylacetamide (496.57mg, 2.531mmol, 1.50 equiv.) in DMF (5.00mL, 64.609mmol, 38.29 equiv.) NaBH (OAc)3(715.31mg, 3.375mmol, 2 equiv.). The obtained solution is mixed inStirred for 1 hour. The mixture was concentrated to give the crude product, which was purified by passage through a column with MeOH]Purification by chromatography on silica gel eluted with DCM (4.2: 95.8) to give N- [ [ (2S) -1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] as a dark yellow solid]-2, 6-dimethoxyphenyl]Methyl) azetidin-2-yl]Methyl radical]-2, 2, 2-trifluoro-N-methylacetamide (436mg, 47.18%). LCMS (ESI) m/z: [ M + H ]]+＝548。

And 5: preparation of (S) -4- (3, 5-dimethoxy-4- ((2- ((methylamino) methyl) azetidin-1-yl) methyl) phenyl) -6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1 (2H) -one (6)

Reacting N- [ [ (2S) -1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) azetidin-2-yl]Methyl radical]-2, 2, 2-trifluoro-N-methylacetamide (400.00mg, 0.730mmol, 1.00 equiv.) and NH3·H2A solution of O (2.00mL, 51.361mmol, 70.31 equiv.) in DMF (4.00mL, 12.922mmol, 196.55 equiv.) was preparedStirred for 12 hours. The resulting solution was concentrated to give a crude product of 4- (3, 5-dimethoxy-4- [ [ (2S) -2- [ (methylamino) methyl ] as a brown solid]Azetidine-1-radical]Methyl radical]Phenyl) -6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (458mg), which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝452。

Step 6: preparation of 4- (S) -1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) azetidin-2-yl) methyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound D2)

4- (3, 5-dimethoxy-4- [ [ (2R) -2- [ (methylamino) methyl group)]Azetidin-1-yl]Methyl radical]Phenyl) -6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (100.00mg, 0.221mmol, 1.00 eq) and 2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindole-4-carbaldehyde (63.39mg, 0.221mmol, 1.00 eq) were dissolved in MeOH (2.00 mL). Then NaBH is added 3CN (69.58mg, 1.107mmol, 5 equiv.) was added to the mixture and the resulting solution was addedStirred for 1 hour. Without any additional work-up, the mixture was passed through a preparative HPLC (conditions: SunFire C18 OBD Prep column,5 μm, 19mm X250 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 9% B to 19% B in 15 minutes; 254 nm; rt: 17.67 min) to give 4- (((((S) -1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) azetidin-2-yl) methyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione as a yellow solid (20.4mg, 12.76%).1H NMR (400MHz, methanol-d 4) δ 9.05(s, 1H), 8.00-7.74(m, 3H), 7.51(d, J ═ 6.9Hz, 1H), 6.88(d, J ═ 5.4Hz, 2H), 6.60(d, J ═ 4.5Hz, 1H), 5.26-5.05(m，1H)，4.64(dd，J＝12.8，10.2Hz，1H)，4.53(dd，J＝12.8，5.7Hz，1H)，4.27-4.08(m，4H)，3.93(d，J＝10.8Hz，6H)，3.59(d，J＝2.1Hz，3H)，3.16(s，6H)，3.10(s，2H)，2.95-2.80(m，1H)，2.80-2.58(m，3H)，2.32(dd，J＝15.9，2.4Hz，4H)，2.19-2.08(m，1H)。LCMS(ESI)m/z：[M+H]+＝722.20。

EXAMPLE 14 preparation of 4- ([ [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidin-3-yl ] (methyl) amino ] methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D3 carboxylic acid)

Step 1: preparation of 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde (i14-2)

To a solution of 4-bromo-6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (1.80g, 6.380mmol, 1.00 equiv.) and 4-formyl-3, 5-dimethoxyphenylboronic acid (1.34g, 6.380mmol, 1.00 equiv.) in 1, 4-dioxane and water was added CS2CO3(4.16g, 12.760mmol, 2.00 equiv.) and Pd (dppf) Cl2(0.47g, 0.638mmol, 0.10 equiv.). In thatAfter stirring under nitrogen for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (1: 1) to give 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a grey solid]-2, 6-dimethoxybenzaldehyde (1.5g, 57.59%). LCMS (ESI) m/z: [ M + H ]]+＝368。

Step 2: preparation of N- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidin-3-yl ] -N-methylcarbamic acid tert-butyl ester (i14-3)

To 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl group]A stirred mixture of-2, 6-dimethoxybenzaldehyde (100.00mg, 0.272mmol, 1.00 equiv.) and N- (azetidin-3-yl) -N-methylcarbamic acid tert-butyl ester hydrochloride (90.93mg, 0.408mmol, 1.50 equiv.) in MeOH was added NaBH in portions 3CN (34.21mg, 0.544mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (20: 1) to give N- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as an off-white solid]-2, 6-dimethoxyphenyl]Methyl) azetidin-3-yl]-N-methylcarbamic acid tert-butyl ester (103mg, 65.46%). LCMS (ESI) m/z: [ M + H ]]+＝538。

And step 3: 4- (3, 5-dimethoxy-4- ((3- (methylamino) azetidin-1-yl) methyl) phenyl) -6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1 (2H) -one (i14-44)

To tert-butyl-N- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) azetidin-3-yl]A stirred solution of-N-methylcarbamate (100.00mg, 0.186mmol, 1.00 equiv.) in DCM (1.00mL) was added TFA (0.20mL, 2.693mmol, 14.48 equiv.). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was used in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝438。

And 4, step 4: preparation of 4- ([ [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidin-3-yl ] (methyl) amino ] methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D3 carboxylic acid)

To 4- (3, 5-dimethoxy-4- [ [3- (methylamino) azetidin-1-yl group]Methyl radical]A stirred mixture of phenyl) -6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (50.00mg, 0.114mmol, 1.00 eq) and 2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindole-4-carbaldehyde (65.42mg, 0.229mmol, 2.00 eq) in MeOH was added NaBH in portions3CN (14.36mg, 0.229mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative HPLC (conditions: XSelectCSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase, water (0.1% FA) and ACN (16% phase B to 26% in 8 min.; detector, UV). This gives 4- ([ [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid]-2, 6-dimethoxyphenyl]Methyl) azetidin-3-yl](methyl) amino group]Methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (2.8mg, 3.17%).1H NMR (400MHz, methanol-d 4) δ 9.16(d, J ═ 0.7Hz, 1H), 8.56(br s, 1H, FA), 7.90-7.79(m, 3H), 7.43(s, 1H), 6.85(s, 2H), 6.47(s, 1H), 5.14(dd, J ═ 12.3, 5.4Hz, 1H), 4.37(s, 2H), 4.06(s, 3H), 3.98-3.85(m, 9H), 3.59(s, 3H), 3.55-3.45(m1H), 3.11(s, 6H), 2.89-2.80(m, 1H), 2.77-2.66(m, 2H), 2.16(s, 3H), 2.14-2.07(m, 1H). LCMS (ESI) m/z: [ M + H ] ]+＝708.30。

EXAMPLE 15 preparation of- (2S) -1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) -N-methylazetidine-2-carboxamide (Compound D4 carboxylic acid)

Compound D4 was prepared in a similar manner to example 12. (2S) -1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) -N-methylazetidine-2-carboxamide was obtained as a pale yellow solid (9.1mg, 17.56%).1H NMR (400MHz, methanol-d 4) Δ 9.18-9.11(m, 1H), 8.54(s, 0.2H, FA), 7.93-7.52(m, 2H), 7.46-7.27(m, 2H), 6.85(s, 2H), 6.54-6.30(m, 1H), 5.34-4.94(m, 4H), 4.48-4.31(m, 2H), 4.03-3.79(m, 8H), 3.91(s, 3H), 3.14-2.93(m, 9H), 2.90-2.67(m, 4H), 2.60-2.38(m, 1H), 2.23-2.09(m, 1H). LCMS (ESI) m/z: [ M + H ]]+＝736.45。

Example 16 preparation of 1- [ [2, 6-dimethoxy-4- (2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) phenyl ] methyl ] -N- (4- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino ] butyl) azetidine-3-sulfonamide carboxylic acid (Compound D5 carboxylic acid)

Step 1: preparation of tert-butyl-N- [8- [ (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino ] octyl ] carbamate (i16-1)

Using a procedure similar to that described in example 7 and substituting tert-butyl N- (8-aminooctyl) carbamate (945mg, 3.867mmol), tert-butyl-N- [8- [ (5- [4- [ (dimethylamino) methyl ] was obtained as a yellow slurry]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino]Octyl radical]Carbamate (140mg, 82%). LCMS (ESI) m/z: [ M + H ]]+＝596。

Step 2: preparation of 6- [ (8-Aminooctyl) amino ] -4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-2, 7-naphthyridin-1-one (i16-2)

To tert-butyl-N- [8- [ (5- [4- [ (dimethylamino) methyl group)]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino]Octyl radical]A stirred mixture of carbamate (140mg, 0.235mmol, 1.00 equiv.) in dichloromethane (2.0mL) was added trifluoroacetic acid (0.50mL, 6.732mmol, 28.65 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid), 1% to 20% gradient over 20 minutes; detector, UV 254nm) to give 6- [ (8-aminooctyl) amino group as a yellow slurry ]-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]2-methyl-2, 7-naphthyridin-1-one (100mg, 80%). LCMS (ESI) m/z: [ M + H ]]+＝596。

And step 3: preparation of N- [8- [ (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino ] octyl ] -2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] acetamidocarboxylic acid (Compound D5 carboxylic acid)

Using a procedure analogous to that described in example 11 and using 6- [ (8-Aminooctyl) amino group]-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]-2-methyl-2, 7-naphthyridin-1-one (50.0mg, 0.101mmol, 1.00 equiv.) and [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] -ester]Oxy radical]Acetic acid (30.2mg, 0.091mmol, 0.90 equiv.) substitution to give N- [8- [ (5- [4- [ (dimethylamino) methyl ] as a white solid]-3, 5-dimethylOxy-phenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino]Octyl radical]-2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl]Oxy radical]Acetamidocarboxylic acid (6.2mg, 7%).1H NMR (400MHz, methanol-d 4) δ 9.05(d, J ═ 0.7Hz, 1H), 8.57(br s, 1H, FA), 7.81(dd, J ═ 8.4, 7.3Hz, 1H), 7.53(d, J ═ 7.3Hz, 1H), 7.46-7.38(m, 2H), 6.83(s, 2H), 6.40(s, 1H), 5.13(dd, J ═ 12.6, 5.5Hz, 1H), 4.76(s, 2H), 4.60(s, 3H), 4.23(s, 2H), 3.95(s, 6H), 3.57(s, 3H), 3.34-3.23(m, 2H), 2.93-2.81(m, 2H), 2.80-2.67(m, 6H), 2.57 (s, 3H), 1.34-3.23 (m, 2H), 2.93-2.81(m, 2H), 2.80-2.67(m, 19.7H), 1H), 1H, 33.54 (m, 1H). LCMS (ESI) m/z: [ M + H ] ]+＝810.45。

Example 17 preparation of 4- ((5- ((5- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) amino) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D6 carboxylic acid)

Step 1: preparation of 4- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -6- ((5-hydroxypentyl) amino) -2-methyl-2, 7-naphthyridin-1 (2H) -one (i17-2)

Similar procedure as described in example 7 was used and substituted with 6-chloro-4- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -2-methyl-2, 7-naphthyridin-1 (2H) -one (150.0mg, 0.387mmol, 1.00 equiv.) and 5-aminopentanol (39.8mg, 0.387mmol, 1.00 equiv.) to give 4- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -6- ((5-hydroxypentyl) amino) -2-methyl-2, 7-naphthyridin-1 (2H) -one (90mg, 51.4%) as a brown solid. LCMS (ESI) m/z: [ M + H ]]+＝455。

Step 2: preparation of methanesulfonic acid 5- ((5- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) amino) pentyl ester (i17-3)

In thatTo a solution of 4- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -6- ((5-hydroxypentyl) amino) -2-methyl-2, 7-naphthyridin-1 (2H) -one (90mg, 0.198mmol, 1.00 equiv.) and triethylamine (100.2mg, 0.990mmol, 5.00 equiv.) in dichloromethane (2.00mL) was added methanesulfonyl chloride (45.4mg, 0.396mmol, 2.00 equiv.) slowly. The reaction mixture is added in Stirred for 30 minutes and then slowly warmed to room temperature. The reaction was quenched with saturated sodium bicarbonate solution (50mL) and extracted with dichloromethane (50mL x 3). The organic layers were combined and washed with brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give methanesulfonic acid 5- ((5- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) amino) pentyl ester (80.0mg, 68.3%) as a brown solid. LCMS (ESI) m/z: [ M + H ]]+＝533。

And step 3: preparation of 4- ((5- ((5- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) amino) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D6 carboxylic acid)

To methanesulfonic acid 5- ((5- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) amino) pentyl ester (80.0mg, 0.150mmol, 1.00 eq) and 2- (2, 6-bisOxopiperidin-3-yl) -4-hydroxyisoindoline-1, 3-dione (41.2mg, 0.150mmol, 1.00 eq.) in DMF (2.00mL) was added K2CO3(41.5mg, 0.300mmol, 2.00 equiv.). Mixing the obtained mixture in Stirred for 4 hours. The resulting mixture was filtered and the filtrate was passed through preparative HPLC (column: SunAire C)18The column of the OBD Prep is provided,5 μm, 19mm x 250 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 11% B to 26% B in 10 minutes; 254 nm; rt: 8.78 min) to give 4- ((5- ((5- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) amino) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione as a pale yellow solid; formate (15.3mg, 11.6%). LCMS (ESI) m/z: [ M + H ]]+＝711.65。1H NMR (400MHz, methanol-d 4) δ 9.02(s, 1H), 8.56(br s, 0.6H, FA), 7.77(dd, J ═ 8.5, 7.3Hz, 1H), 7.43(dd, J ═ 11.8, 7.8Hz, 2H), 7.28(s, 1H), 7.16(s, 1H), 7.01(s, 1H), 5.98(s, 1H), 5.09(dd, J ═ 12.8, 5.4Hz, 1H), 4.22(t, J ═ 6.2Hz, 2H), 4.03(s, 2H), 3.88(s, 3H), 3.75(s, 3H), 3.56(s, 3H), 3.28(t, J ═ 6.6Hz, 2H), 2.93-2H), 2.93 (s, 2H), 1.82 (s, 1H), 1.81-2H), 1.64 (m-1.64 (m, 1H), 1.64-2H), 1.81H, 2H, 1.4.4.2H, 2H, 1H, 2H, 1.6H, 2H, 1.6H, 1H, 1.4, 2H, 1H, 2H, 1.9, 1H, 2H, 1H, 2H, 1H, 2H, 1H, and the like.

EXAMPLE 18 preparation of 1- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] pentyl) azetidine-3-carboxamide carboxylic acid (Compound D7 carboxylic acid)

Compound 7 was prepared in a similar manner to example 10 and example 12. 1- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl) is obtained as a yellow solid]Phenyl radical]Methyl) -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl)]Oxy radical]Pentyl) azetidine-3-carboxamide carboxylic acid (30mg, 30.6%).1H NMR (300MHz, methanol-d 4) δ 8.56(br s, 0.7H, FA), 8.51(d, J ═ 0.9Hz, 1H), 7.77(dd, J ═ 8.4, 7.4Hz, 1H), 7.44(dd, J ═ 7.9, 2.5Hz, 2H), 7.23(d, J ═ 0.9Hz, 1H), 7.10(s, 1H), 6.81(s, 2H), 5.10(dd, J ═ 12.4, 5.5Hz, 1H), 4.30-4.21(m, 3H), 4.02(d, J ═ 8.1Hz, 3H), 3.92(s, 6H), 3.64(s, 3H), 3.47(t, J ═ 8.2, 1H), 3.29.1H (3.1H), 3.63-3.75 (m, 3H), 3.3.3.8, 3.1H), 3.8.1H, 3.1H, 3.3.8, 3.3.3H, 3.8, 3.3H, 3.3.3H, 3.3.3.3.3.3, 3.3.3H, 3.07 (m, 3.3.3.1H), 3.3.3.3.3.3.3.3H), 3.3.3.3.3.3.3.3.3H, 3.3.3H, 3H, 3.3.3H, 3H, 3.3H, 3H, etc. (t, 3. LCMS (ESI) m/z: [ M + H ] ]+＝780.60。

EXAMPLE 19 preparation of N- [8- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] octyl ] -2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] acetamide (Compound D8)

Step 1: preparation of tert-butyl N- [8- [ (8-bromo-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] octyl ] carbamate (i19-2)

To a mixture of 4-bromo-7-chloro-2-methyl-2, 6-naphthyridin-1-one (100mg, 0.366mmol, 1.00 equiv.) and tert-butyl N- (8-aminooctyl) carbamate (268.1mg, 1.097mmol, 3.00 equiv.) in DMSO (3.00mL) was added K2CO3(505.3mg, 3.656mmol, 10.00 equiv.). The obtained solution is mixed inStirred for 5 hours. The resulting solution was diluted with EtOAc (80 mL). The resulting mixture was washed with water (3 × 50 mL). The organic layer was concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1: 1). The fractions containing the desired compound were evaporated to dryness to give N- [8- [ (8-bromo-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] as a yellow solid]Octyl radical]Tert-butyl carbamate (50mg, 28.4%). LCMS (ESI) m/z: [ M + H ]]+＝483。

Step 2: preparation of tert-butyl N- [8- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] octyl ] carbamate (i19-3)

To N- [8- [ (8-bromo-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino group]Octyl radical]Tert-butyl carbamate (50.0mg, 0.104mmol, 1.00 equiv.) and 4- [ (dimethylamino) methyl]3, 5-Dimethoxyphenylboronic acid (37.2mg, 0.156mmol, 1.50 equiv.) in H2Cs was added to a solution of O (0.50mL) and dioxane (1.50mL)2CO3(67.7mg, 0.208mmol, 2.00 equiv.) and Pd (dppf) Cl2·CH2Cl2(7.60mg, 0.010mmol, 0.10 equiv.). The obtained solution is mixed inUnder N2Stirred under atmosphere for 1 hour. The resulting solution was diluted with EtOAc (50 mL). The resulting mixture was washed with water (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (30: 70). The fractions containing the desired compound were evaporated to dryness to give N- [8- [ (8- [4- [ (dimethylamino) methyl ] amino) methyl ] carbonyl as a yellow solid]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino]Octyl radical]Tert-butyl carbamate (30mg, 48.5%). LCMS (ESI) m/z: [ M + H ]]+＝596。

And step 3: preparation of 7- [ (8-aminooctyl) amino ] -4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-2, 6-naphthyridin-1-one (i 19-4).

To N- [8- [ (8- [4- [ (dimethylamino) methyl group) ]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino]Octyl radical]To a solution of tert-butyl carbamate (30mg, 0.050mmol, 1.00 equiv.) in DCM (2.00mL) was added TFA (2.00mL) and the resulting solution was addedStirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give 7- [ (8-aminooctyl) amino group as a yellow liquid]-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]2-methyl-2, 6-naphthyridin-1-one (35mg, crude) which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝496。

And 4, step 4: preparation of N- [8- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] octyl ] -2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] acetamide (Compound D8)

To [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] -group]Oxy radical]7- [ (8-Aminooctyl) amino group was added to a solution of acetic acid (24.1mg, 0.073mmol, 1.20 equiv.) and HATU (46.0mg, 0.121mmol, 2.00 equiv.) in DMF (2.00mL)]-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]2-methyl-2, 6-naphthyridin-1-one (30.0mg, 0.061mmol, 1.00 equiv.) and DIEA (39.1mg, 0.303mmol, 5.00 equiv.). The obtained solution is mixed in Stirred for 2 hours. Will be provided withThe crude product was purified by preparative HPLC (conditions: XSelect CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 20% B to 55% B in 8 min; 254 nm; Rt: 7.12 min) to give N- [8- [ (8- [4- [ (dimethylamino) methyl ] as a yellow solid]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino]Octyl radical]-2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl]Oxy radical]Acetamide (12mg, 24.5%).1H NMR (300MHz, methanol-d 4) δ 8.41(s, 1H), 7.80(dd, J ═ 8.4, 7.4Hz, 1H), 7.52(d, J ═ 7.3Hz, 1H), 7.43(d, J ═ 9.1Hz, 2H), 7.15(s, 1H), 6.90(s, 2H), 5.13(dd, J ═ 12.4, 5.4Hz, 1H), 4.77(s, 2H), 4.42(s, 2H), 3.98(s, 6H), 3.63(s, 3H), 3.40-3.35(m, 2H), 3.30-3.21(m, 2H), 2.92(s, 6H), 2.90-2.82(m, 1H), 2.80-2.65(m, 2H), 2.30-3.21 (m, 2H), 1.51-1H, 1.5.5H, 1H, and 1H. LCMS (ESI) m/z: [ M + H ]]+＝810.60。

EXAMPLE 20 preparation of N- (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] amino ] ethoxy) ethoxy ] propionamide (Compound D9)

Step 1: preparation of 3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) propionamide (i20-2)

Similar procedure as described in example 10, step 1 was used and substituted with 5- ([2- [2- (3, 3-dihydroxypropoxy) ethoxy ] ethyl ] amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (150mg, 0.344mmol, 1.00 equiv.) and ammonium chloride (24mg, 0.448mmol, 1.30 equiv.) to give 3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) propionamide (122mg, 81.5%) as a yellow solid. LCMS (ESI) m/z: [ M + H ] + -433.

Step 2: preparation of N- (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] amino ] ethoxy) ethoxy ] propanamide (Compound D9)

To 7-chloro-4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]-2-methyl-2, 6-naphthyridin-1-one (50mg, 0.129mmol, 1.00 equiv.) and 3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] -2-methyl-1, 6-dioxopiperidin-4-yl ]Amino group]Ethoxy) ethoxy]Solution of propionamide (55.8mg, 0.129mmol, 1 equivalent) in dioxane (4mL) was added tris (dibenzylideneacetone) dipalladium (0) (11.8mg, 0.013mmol, 0.10 equivalents), cesium carbonate (84.0mg, 0.258mmol, 2.0 equivalents) and Xantphos (14.9mg, 0.026mmol, 0.20 equivalents) and the resulting solution was dissolved in waterStirred for 3 hours. The mixture was filtered through a short pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (conditions: SunFire C18 OBD Prep column,5 μm, 19mm X250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL/min; gradient: 9B to 22B in 18 minutes; 254nm) to give N- (8- [4- [ (dimethylamino) methyl) carbonyl ] as a yellow solid]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] -piperidine derivative]Amino group]Ethoxy) ethoxy]Propionamide (6mg, 5.6%).1H NMR (300MHz, methanol-d 4) delta 8.82(s，1H)，8.64(s，1H)，7.40-7.30(m，2H)，6.89(s，2H)，6.86-6.76(m，2H)，4.99(dd，J＝12.4，5.4Hz，1H)，4.44(s，2H)，4.01(s，6H)，3.92(t，J＝5.7Hz，2H)，3.82-3.72(m，6H)，3.64(s，3H)，3.39(t，J＝5.0Hz，2H)，2.93(s，6H)，2.88-2.61(m，5H)，2.29-2.18(m，1H)。LCMS(ESI)m/z：[M+H]+＝784.50。

Example 21 preparation of 4- [ [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino ] ethoxy) ethyl ] amino ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D10 carboxylic acid)

Intermediate i-21-1 was prepared in a manner analogous to the preparation of i19-4 in example 19. To 6- ([2- [2- (2-aminoethoxy) ethoxy)]Ethyl radical]Amino) -4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]A stirred mixture of-2-methyl-2, 7-naphthyridin-1-one (100mg, 0.200mmol, 1.00 equiv.) and 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindole-1, 3-dione (55.3mg, 0.200mmol, 1.00 equiv.) in dimethylformamide (2mL) was added diisopropylethylamine (129.3mg, 1.001mmol, 5.00 equiv.). In thatAfter stirring overnight, the mixture was purified by preparative HPLC (conditions: Atlantis HILIC OBD column, 19X 150mm, 5 μm; mobile phase: A, water (0.1% formic acid) and B, acetonitrile (12% to 21% B in 9 min) to give 4- [ [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl ] amino)]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino]Ethoxy radical]Ethoxy) ethyl]Amino group]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (4mg, 2.5%).1H NMR (300MHz, methanol-d 4) δ 9.03(s, 1H), 8.57(br s, 0.83H, formic acid), 7.51(t, J ═ 7.8Hz, 1H), 7.40(s, 1H), 7.00(d, J ═ 7.8Hz, 2H), 6.83(s, 2H), 6.50(s, 1H), 4.96-4.90(m, 1H), 4..32(s，2H)，3.96(s，6H)，3.71-3.63(m，8H)，3.56(s，3H)，3.53-3.48(m，2H)，3.42(t，J＝5.2Hz，2H)，2.85(s，6H)，2.78-2.57(m，3H)，2.00(d，J＝9.2Hz，1H)。LCMS(ESI)m/z：[M+H]+＝756.45。

EXAMPLE 22 preparation of N- (5- (4- ((dimethylamino) methyl) -3, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) -3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propionamidocarboxylic acid (Compound D11 carboxylic acid)

Compound D11 was prepared in a similar manner to example 20. N- (5- [4- [ (dimethylamino) methyl) is obtained as a yellow solid]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] -piperidine derivative]Amino group]Ethoxy) ethoxy]Propionamidocarboxylic acid (8.1mg, 6.62%).1H NMR (300MHz, methanol-d 4) δ 9.10(s, 1H), 8.57(br s, 1H, FA), 8.45(s, 1H), 7.64(s, 1H), 7.34(dd, J ═ 8.6, 7.1Hz, 1H), 6.90-6.75(m, 4H), 4.86-4.82(m, 1H), 4.61(s, 1H), 4.33(s, 2H), 4.02(s, 6H), 3.94-3.84(m, 2H), 3.77-3.71(m, 6H), 3.65(s, 3H), 3.36(s, 1H), 2.85(s, 6H), 2.75-2.66(m, 3H), 2.63-2.54(m, 1H), 2.47-2.31(m, 1H), 1.73H, 1H). LCMS (ESI) m/z: [ M + H ]]+＝784.4。

Example 23 preparation of 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] pentyl) acetamidocarboxylic acid (Compound D12 carboxylic acid)

Step 1: preparation of tert-butyl 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] acetate (i22-1)

To a stirred solution of 4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (514mg, 1.344mmol, 1.00 eq) and tert-butyl 2-bromoacetate (393.2mg, 2.016mmol, 1.50 eq) in acetone was added cesium carbonate (875.8mg, 2.688mmol, 2.00 eq) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure. This gave tert-butyl 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] acetate (600mg, 89.9%) as a pale yellow solid. LCMS (ESI) m/z: [ M + H ] + ═ 497.2

Step 2: preparation of [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] acetic acid (i22-2)

To a stirred solution of tert-butyl 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] acetate (600mg, 1.208mmol, 1.00 eq) in dichloromethane was added trifluoroacetic acid (4mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The crude product was purified by preparative HPLC (conditions: MeCN/water 30%) to give [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] acetic acid as a pale yellow solid (450mg, 84.6%). LCMS (ESI) m/z: [ M + H ] + -441.

And step 3: preparation of 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino ] -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] pentyl) acetamidocarboxylic acid (Compound D12 carboxylic acid)

Using a procedure analogous to that described in example 11 and using [ (8- [4- [ (dimethylamino) methyl ]]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino]Acetic acid (100mg, 0.227mmol, 1.00 equiv.) and 4- [ (5-aminopentyl) oxy]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (122.4mg, 0.341mmol, 1.50 equivalents) to give 2- [ (8- [4- [ (dimethylamino) methyl ] as a yellow solid]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) (methyl) amino]-N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl)]Oxy radical]Pentyl) acetamidocarboxylic acid (80mg, 42.6%).1H NMR (300MHz, methanol-d 4) δ 8.56(s, 1H), 8.51(brs, 0.8H, formic acid), 7.78(dd, J ═ 8.6, 7.2Hz, 1H), 7.48-7.42(m, 2H), 7.25(s, 1H), 7.14(s, 1H), 6.89(s, 2H), 5.10(dd, J ═ 12.4, 5.4Hz, 1H), 4.82(s, 2H), 4.27(t, J ═ 5.9Hz, 2H), 4.08(s, 2H), 3.94(s, 6H), 3.66(s, 3H), 3.40-3.36(m, 2H), 3.28(s, 6H), 2.98(s, 3H), 2.90-2.67(m, 3.19H), 2.19-3.86 (m, 1H), 1.74H, 1H), 1.6H, 1H, and 1H. LCMS (ESI) m/z: [ M + H ] ]+＝782.50。

EXAMPLE 24 preparation of N- (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] amino ] ethoxy) ethoxy ] propionamidocarboxylic acid (Compound D13 carboxylic acid)

Compound D13 was prepared in a similar manner to example 20. ObtainObtaining N- (8- [4- [ (dimethylamino) methyl group)]-3, 5-dimethoxyphenyl]-6-methyl-5-oxo-2, 6-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] -piperidine derivative]Amino group]Ethoxy) ethoxy]Propionamidocarboxylic acid (7mg, 6.9%).1H NMR (300MHz, methanol-d 4) δ 8.86(d, J ═ 0.9Hz, 1H), 8.70(d, J ═ 0.9Hz, 1H), 8.56(brs, 0.9H, FA), 7.40(s, 1H), 7.28(d, J ═ 8.4Hz, 1H), 6.82(s, 2H), 6.63(d, J ═ 2.2Hz, 1H), 6.54(dd, J ═ 8.4, 2.2Hz, 1H), 5.05-4.97(m, 1H), 4.33(s, 2H), 3.98(s, 6H), 3.93(t, J ═ 5.6Hz, 2H), 3.75-3.70(m, 6H), 3.58(s, 3H), 3.18(t, J ═ 5.85H), 2.79 (t, 2H), 2H, 1H, 2H). LCMS (ESI) m/z: [ M + H ]]+＝784.55。

EXAMPLE 25 preparation of N- (5- (4- ((dimethylamino) methyl) -3, 5-dimethoxyphenyl) -7-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-3-yl) -3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) propionamidocarboxylic acid (Compound D14 carboxylic acid)

Compound D13 was prepared in a similar manner to example 20. N- (5- [4- [ (dimethylamino) methyl) is obtained as a yellow solid]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) -3- [2- (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl)]Amino group]Ethoxy) ethoxy]Propionamidocarboxylic acid (6mg, 6.62%).1H NMR (300MHz, methanol-d 4) δ 9.19(s, 1H), 8.55(brs, 1.8H, FA), 8.51(s, 1H), 7.65(s, 1H), 7.33(d, J ═ 8.3Hz, 1H), 6.83(s, 2H), 6.67(d, J ═ 2.1Hz, 1H), 6.56(dd, J ═ 8.4, 2.2Hz, 1H), 5.05-4.98(m, 1H), 4.36(s, 2H), 4.00(s, 6H), 3.87(t, J ═ 5.5Hz, 2H), 3.72-3.63(m, 6H), 3.59(s, 3H), 3.13(t, J ═ 5.4, 2H), 2.90(s, 6H), 2.83-2H, 2.13 (t, 2H), 2.5.4, 2H), 2.5.5H, 2H), 2.5.5.5H, 1H, 2H, and the like. LCMS (ESI) m/z: [ M + H ]]+＝784.5。

EXAMPLE 26 preparation of 4- ([5- [9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-4-yl ] -5-oxopentyl ] oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D15 carboxylic acid)

Step 1: preparation of 9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) -1-oxa-4, 9-diazaspiro [5.5] undecane-4-carboxylic acid tert-butyl ester (i26-2)

To 2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl]Benzaldehyde (100mg, 0.283mmol, 1.00 eq.) and 1-oxa-4, 9-diazaspiro [5.5]]A solution of tert-butyl undecane-4-carboxylate (87.1mg, 0.340mmol, 1.20 equiv.) in MeOH (2.00mL) was added NaBH3CN (35.6mg, 0.566mmol, 2.00 equiv.), and the resulting solution was addedStirred for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with DCM/MeOH (20: 1). This gives 9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl) as a yellow solid]Phenyl radical]Methyl) -1-oxa-4, 9-diazaspiro [5.5]Tert-butyl undecane-4-carboxylate (110mg, 65.5%). LCMS (ESI) m/z: [ M + H ]]+＝594。

Step 2: preparation of 4- (3, 5-dimethoxy-4- [ 1-oxa-4, 9-diazaspiro [5.5] undecan-9-ylmethyl ] phenyl) -2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (i 26-3).

To 9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl)]Phenyl radical]Methyl) -1-oxa-4, 9-diazaspiro [5.5]A solution of tert-butyl undecane-4-carboxylate (100.0mg, 0.168mmol, 1.00 equiv.) in DCM (2.00mL) was added TFA (2.00mL) and the resulting solution was dissolved in Stirred for 2 hours. The resulting mixture was concentrated in vacuo to give 4- (3, 5-dimethoxy-4- [ 1-oxa-4, 9-diazaspiro [5.5] as a yellow solid]Undecyl-9-ylmethyl]Phenyl) -2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (90mg, crude) which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝494。

And step 3: preparation of 4- ([5- [9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-4-yl ] -5-oxopentyl ] oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D15 carboxylic acid)

To 5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl group]Oxy radical]A solution of pentanoic acid (15.2mg, 0.041mmol, 1.00 equiv.) and HATU (30.8mg, 0.081mmol, 2.00 equiv.) in solvent DMF (2.00mL) was added 4- (3, 5-dimethoxy-4- [ 1-oxa-4, 9-diazaspiro [5.5] s]Undecyl-9-ylmethyl]Phenyl) -2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (20.0mg, 0.041mmol, 1.00 equiv.) and DIEA (15.7mg, 0.122mmol, 3.00 equiv.), and the resulting solution was dissolved inStirred for 2 hours. The resulting mixture was concentrated. The crude product was purified by preparative HPLC (conditions: XSelectCSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 20% B to 55% B in 8 minutes; 254 nm; rt: 7.12 min) to give 4- ([5- [9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl) as a yellow solid]Phenyl radical]Methyl) -1-oxa-4, 9-diazaspiro [5.5]Undec-4-yl]-5-oxopentyl radical]Oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (20mg, 52.8%).1H NMR (300MHz, methanol-d 4) δ 8.56(br s, 0.5H, FA), 8.51(s, 1H), 7.83-7.74(m, 1H), 7.50-7.42(m, 2H), 7.24(d, J ═ 3.8Hz, 1H), 7.11(s, 1H), 6.83(d, J ═ 9.2Hz, 2H), 5.12(dd, J ═ 12.2, 5.3Hz, 1H), 4.33-4.22(m, 3H), 3.93(d, J ═ 8.5Hz, 7H), 3.83-3.69(m, 3H), 3.67-3.60(m, 5H), 3.51(s, 2H), 3.22-3.10(m, 2H), 2.97(s, 3H), 2.63-3.86 (m, 2H), 3.67-3.83 (m, 2H), 1H). LCMS (ESI) m/z: [ M + H ]]+＝850.60。

EXAMPLE 27 preparation of 4- (4- (9- (2, 6-dimethoxy-4- (2-methyl-7- (methylamino) -1-oxo-1, 2-dihydro-2, 6-naphthyridin-4-yl) benzyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-4-yl) -4-oxobutoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D16 carboxylic acid)

Compound D16 was prepared in a similar manner to example 26. 4- [4- [9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl) is obtained as a pale brown solid]Phenyl radical]Methyl) -1-oxa-4, 9-diazaspiro [5.5]Undec-4-yl]-4-oxobutoxy group]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (16mg, 20.0%).1H NMR (400MHz, methanol-d 4) δ 8.57(brs, 0.6H, FA), 8.54(d, J ═ 4.5Hz, 1H), 7.80(t, J ═ 7.9Hz, 1H), 7.48(dd, J ═ 7.2, 5.0Hz, 2H), 7.25(d, J ═ 1.0Hz, 1H), 7.13(d, J ═ 4.6Hz, 1H), 6.83(d, J ═ 10.9Hz, 2H), 5.13(dd, J ═ 12.5, 5.5Hz, 1H), 4.31(t, J ═ 5.7Hz, 2H), 4.26-4.16(m, 2H), 3.92(d, J ═ 12.1Hz, 6H), 3.75-3.65 (m, 3.65), 3.65 (d, J ═ 12.1Hz, 6H), 3.75 (m, 3.65), 3.65 (d, J ═ 3.0 Hz, 2H), 3.5 (d, 1H), 2H), 3.5H), and cs，3H)，3.60-3.48(m，3H)，3.24-3.02(m，4H)，2.97(s，3H)，2.81-2.65(m，5H)，2.24-2.12(m，3H)，2.10-1.84(m，3H)，1.79-1.65(m，1H)。LCMS(ESI)m/z：[M+H]+＝836.45。

EXAMPLE 28 preparation of 4- (4- (4- (2, 6-dimethoxy-4- (2-methyl-7- (methylamino) -1-oxo-1, 2-dihydro-2, 6-naphthyridin-4-yl) benzyl) piperazin-1-yl) -4-oxobutoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D17 carboxylic acid)

Compound D17 was prepared in a similar manner to example 26. 4- [4- [4- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl) is obtained as a yellow solid ]Phenyl radical]Methyl) piperazin-1-yl]-4-oxobutoxy group]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (11.0mg, 12.8%).1H NMR(400MHz，DMSO-d6)δ11.14(s，1H)，9.63(s，1H)，8.56(brs，0.9H，FA)，7.87-7.77(m，1H)，7.55(d，J＝8.5Hz，1H)，7.47(d，J＝7.2Hz，1H)，7.20(s，1H)，7.13(s，1H)，6.98(d，J＝4.8Hz，1H)，6.86(s，2H)，5.09(dd，J＝12.7，5.4Hz，1H)，4.43(d，J＝12.5Hz，1H)，4.27(dd，J＝13.9，7.8Hz，4H)，4.07(d，J＝13.6Hz，1H)，3.90(s，6H)，3.58-3.48(m，4H)，3.47-3.38(m，3H)，3.26-2.98(m，3H)，2.96-2.88(m，1H)，2.87-2.83(m，3H)，2.65-2.55(m，3H)，2.09-1.95(m，3H)。LCMS(ESI)m/z：[M+H]+＝766.50。

EXAMPLE 29 preparation of 4- (4- (9- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) -1-oxa-4, 9-diazaspiro [5.5] undecane-4-yl) -4-oxobutoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D18 carboxylic acid)

Compound D18 was prepared in a similar manner to example 26. 4- [4- [9- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) is obtained as a white solid]-2, 6-dimethoxyphenyl]Methyl) -1-oxa-4, 9-diazaspiro [5.5]Undec-4-yl]-4-oxobutoxy group]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (12.7 mg). LCMS (ESI) m/z: [ M + H ]]+＝850.55。1H NMR (400MHz, methanol-d 4) δ 9.15(s, 1H), 8.47(brs, 1.2H, FA), 7.80(t, J ═ 7.9Hz, 1H), 7.48(d, J ═ 9.9Hz, 3H), 6.89(d, J ═ 7.2Hz, 2H), 6.49(d, J ═ 3.7Hz, 1H), 5.13(dd, J ═ 12.6, 5.5Hz, 1H), 4.40(s, 2H), 4.31(s, 2H), 3.95(d, J ═ 12.5Hz, 6H), 3.80-3.65(m, 4H), 3.60(d, J ═ 3.1Hz, 3H), 3.57-3.48(m, 2H), 3.34(s, 4H), 3.84 (s, 6H), 3.84 (m, 2H), 1H), 3.84 (m, 2H), 3.5H, 1H, 5(m, 2H).

EXAMPLE 30 preparation of 5- ((5- (9- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-4-yl) -5-oxopentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D19 carboxylic acid)

Compound D19 was prepared in a similar manner to example 26. 5- ([5- [9- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) is obtained as a white solid]-2, 6-dimethoxyphenyl]Methyl) -1-oxa-4, 9-diazaspiro [5.5]Undec-4-yl]-5-oxopentyl radical]Oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (8.1mg, 11.1%). LCMS (ESI) m/z: [ M + H ]]+＝864.55。1H NMR (400MHz, methanol-d 4) δ 9.14(d, J ═ 1.8Hz, 1H), 8.56(brs, 0.5H, FA), 7.80(t, J ═ 9.0Hz, 1H), 7.4(d, J ═ 2.6Hz, 1H), 7.40(dd, J ═ 4.2, 2.2Hz, 1H), 7.35-7.28(m, 1H), 6.85(d, J ═ 6.7Hz, 2H), 6.49(s, 1H), 5.15-5.06(m, 1H), 4.31-4.11(m, 4H), 3.94(d, J ═ 4.9Hz,6H)，3.81-3.71(m，2H)，3.64-3.56(m，5H)，3.55-3.45(m，2H)，3.25-3.00(m，10H)，2.94-2.82(m，1H)，2.81-2.66(m，2H)，2.62-2.45(m，2H)，2.18-1.99(m，3H)，1.96-1.71(m，6H)。

EXAMPLE 31 preparation of 5- (4- (2- (1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) ethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D20 carboxylic acid)

To 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl group](iii) mixture of (30.0mg, 0.082mmol, 1.00 equiv.) of (2, 6-dimethoxybenzaldehyde in DMF (1.00mL) 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperidin-4-yl) ethyl]Piperazin-1-yl]Isoindole-1, 3-dione (37.0mg, 0.082mmol, 1.00 equiv.). The resulting mixture was stirred for 1 hour and NaBH (OAc) was added3(34.6mg, 0.163mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. Without any additional work-up, the mixture was passed through preparative HPLC (conditions: Phenomenex Gemini C6-phenyl, 21.2X 250mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 11% B to 17% B within 17 min; 254 nm; R: 1%T: 14.2 min) to yield 5- (4- (2- (1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) ethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione as a yellow solid; formic acid ester acid (9.0mg, 13.8%).1H NMR (300MHz, DMSO-d6) δ 11.09(s, 1H), 9.45(brs, 0.6H, FA salt), 9.05(s, 1H), 8.14(s, 0.7H, FA), 7.75(d, J ═ 8.5Hz, 1H), 7.61(s, 1H), 7.46(s, 1H), 7.34(d, J ═ 8.9Hz, 1H), 6.90(s, 2H), 6.52(d, J ═ 6.4Hz, 1H), 5.09(dd, J ═ 12.7, 5.4Hz, 1H), 4.21(s, 3H), 3.91(s, 7H), 3.50(s, 4H), 3.47-3.37(m, 4H), 3.20-3.05(m, 9H), 3.04 -2.86(m，4H)，2.74-2.54(m，3H)，2.09-1.98(m，1H)，1.97-1.75(m，3H)，1.70-1.48(m，4H)。LCMS(ESI)m/z：[M+H]+＝805.55。

EXAMPLE 32 preparation of 5- [4- (2- [2- [ ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) (methyl) amino ] ethoxy ] ethyl) piperazin-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (Compound D21)

Step 1: preparation of N- [2- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] ethoxy) ethyl ] -N-methylcarbamic acid tert-butyl ester (i32-2)

To a mixture of 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindole-1, 3-dione (50.00mg, 0.146mmol, 1.00 eq.) and N-methyl-N- [2- (2-oxoethoxy) ethyl]A solution of tert-butyl carbamate (47.60mg, 0.219mmol, 1.50 equiv.) in DMF (2.00mL) was added NaBH3CN (18.36mg, 0.292mmol, 2.00 equiv.), and dissolving the resulting solution inStirred for 3 hours. The resulting mixture was concentrated. Applying the residue to the substrate with CH2Cl2On a column of silica gel in MeOH (20: 1). This gives N- [2- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) as a yellow solid]Piperazin-1-yl]Ethoxy) ethyl]-N-methyl-carbamic acid tert-butyl ester (45mg, 56.68%). LCMS (ESI) m/z: [ M + H ]]+＝544.50。

Step 2: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- [2- [2- (methylamino) ethoxy ] ethyl ] piperazin-1-yl) isoindole-1, 3-dione (i32-3)

Reacting N- [2- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl)]Piperazin-1-yl]Ethoxy) ethyl]-N-methyl-carbamic acid tert-butyl ester (45.00mg, 0.083mmol, 1.00 equiv.) in TFA (1.00mL) and CH2Cl2(1.00mL) of the solution inStirred for 1 hour. The resulting mixture was concentrated and the crude material was used without further purification. Obtaining 2- (2, 6-dioxopiperidin-3-yl) -5- (4- [2- [2- (methylamino) ethoxy ] as a yellow solid]Ethyl radical]Piperazin-1-yl) isoindole-1, 3-dione. LCMS (ESI) m/z: [ M + H ]]+＝444.50。

And step 3: preparation of 5- [4- (2- [2- [ ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) (methyl) amino ] ethoxy ] ethyl) piperazin-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (Compound D2])

To 2- (2, 6-dioxopiperidin-3-yl) -5- (4- [2- [2- (methylamino) ethoxy]Ethyl radical]Piperazin-1-yl) isoindole-1, 3-dione (50.00mg, 0.113mmol, 1.00 equiv.) and 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl](iii) -2, 6-dimethoxybenzaldehyde (49.70mg, 0.135mmol, 1.20 equiv.) in DMF (2.00mL) NaBH was added 3CN (14.17mg, 0.225mmol, 2.00 equiv.), and the resulting solution was addedStirred for 3 hours. The resulting mixture was concentrated. The crude product was passed through preparative HPLC (conditions: XSelect CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 8 min)20% B to 55% B in clock; 254 nm; rT: 7.12 min). This gave 5- [4- (2- [2- [ ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid]-2, 6-dimethoxyphenyl]Methyl) (methyl) amino]Ethoxy radical]Ethyl) piperazin-1-yl]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (10mg, 18.60%).1H NMR(400MHz，DMSO-d6)δ11.07(s，1H)，9.04(s，1H)，8.14(brs，0.2H，FA)，7.67(d，J＝8.5Hz，1H)，7.58(s，1H)，7.32(d，J＝2.3Hz，1H)，7.23(dd，J＝8.7，2.3Hz，1H)，6.85(s，2H)，6.46(s，1H)，5.07(dd，J＝12.9，5.4Hz，1H)，4.39-4.01(m，2H)，3.88(s，7H)，3.76(s，3H)，3.62(t，J＝5.7Hz，3H)，3.48(s，5H)，3.37-3.26(m，4H)，3.06(s，6H)，2.94-2.84(m，1H)，2.63-2.56(m，8H)，2.07-1.98(m，1H)。LCMS(ESI)m/z：[M+H]+＝795.45。

EXAMPLE 33 preparation of 5- [10- (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) -4, 7-dioxa-1, 10-diaza-undec-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D22 carboxylic acid)

Compound D22 was prepared in a similar manner to example 21.1H NMR (400MHz, methanol-d 4) δ 9.06(s, 1H), 8.55(brs, 1.7H, FA), 7.45(d, J ═ 8.4Hz, 1H), 7.40(s, 1H), 6.89(d, J ═ 2.2Hz, 1H), 6.83(s, 2H), 6.74(dd, J ═ 8.4, 2.2Hz, 1H), 6.51(d, J ═ 0.7Hz, 1H), 5.03(dd, J ═ 12.7, 5.5Hz, 1H), 4.56(s, 2H), 3.95(s, 6H), 3.72-3.62(m, 8H), 3.58-3.52(m, 5H), 3.29(t, J ═ 5.3, 2H), 3.81, 13.81-3.81H, 2H), 13.79 (m, 2H), 1.79 (t, 2H). LCMS (ESI) m/z: [ M + H ] ]+＝770.45。

EXAMPLE 34 preparation of 5- ([5- [9- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-4-yl ] -5-oxopentyl ] oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D23 carboxylic acid)

Compound D22 was prepared in a similar manner to example 26.1H NMR (400MHz, methanol-d 4) δ 8.58(brs, 1.1H, formic acid), 8.51(s, 1H), 7.80(t, J ═ 8.9Hz, 1H), 7.43-7.39(m, 1H), 7.35-7.29(m, 1H), 7.24(d, J ═ 5.0Hz, 1H), 7.10(d, J ═ 3.2Hz, 1H), 6.83(d, J ═ 8.3Hz, 2H), 5.10(dt, J ═ 11.0, 5.5Hz, 1H), 4.22(t, J ═ 6.2Hz, 3H), 4.10(s, 1H), 3.93(d, J ═ 6.8Hz, 6H), 3.81-3.75(m, 1H), 3.75-3.75 (m, 3.75-3.70H), 3.10 (s, 1H), 3.93(d, J ═ 6.8Hz, 6H), 3.3.3.3.75 (m, 3.3.3.3.3.3H), 3.3.3.3.3.3H, 3.3.3.3.3H, 3.3.3.65 (m-3.3.3.3.3H), 3.3.3.3.3.3H, 3.3.3.3.3.3.3H, 3H, 3.3.3H, 3H, 3.3.3H, 3.3H, 3H, 3.3.3H, 3H, 3.3.3.3H, 3.3H, 3H, 3.3H, 3H, 3.3H, 3.3.3.3H, 3H, 3.3.3H, 3.3H, 3H, 3.3H, 3H, 3.3H, 3H, 1H) 2.07-1.97(m, 2H), 1.96-1.69(m, 6H). LCMS (ESI) m/z: [ M + H ]]+＝850.45。

Example 35-preparation of 4- [ [2- (2- [2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] ethoxy) ethyl ] amino ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (Compound D24)

Compound D24 was prepared in a similar manner to example 21.1H NMR (400MHz, methanol-d 4) δ 8.44(d, J ═ 0.9Hz, 1H), 7.52-7.42(m, 1H), 7.23(d, J ═ 0.9Hz, 1H), 7.07(s, 1H), 6.97(dd, J ═ 18.7, 7.8Hz, 2H), 6.83(s, 2H), 5.02-4.96(m, 1H), 4.28-4.11(m, 2H), 3.96(s, 6H), 3.80-3.75(m, 4H), 3.74-3.70(m, 4H), 3.61(s, 3H), 3.55(t, J ═ 5.3Hz, 2H), 3.47(t, J ═ 5.1, 2H), 2.81-2.63(m, 9.04H), 2.04(m, 1H). LCMS (ESI) m/z: [ M + H ]]+＝756.33。

Example preparation of 36-4- ((5- ((8- (4- ((dimethylamino) methyl) -2, 5-dimethoxyphenyl) -6-methyl-5-oxo-5, 6-dihydro-2, 6-naphthyridin-3-yl) amino) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound D25)

Compound D25 was prepared in a similar manner to example 17.1H NMR (300MHz, methanol-d 4) δ 7.94(s, 1H), 7.76(dd, J ═ 8.6, 7.2Hz, 1H), 7.54(s, 1H), 7.46-7.40(m, 2H), 7.24(s, 1H), 7.15(s, 1H), 7.08(s, 1H), 5.11(d, J ═ 10.8Hz, 1H), 4.42(s, 2H), 4.28(t, J ═ 5.8Hz, 2H), 3.95(s, 3H), 3.77(s, 3H), 3.61(s, 3H), 3.46(t, J ═ 6.5Hz, 2H), 2.94(s, 6H), 2.92-2.83(m, 1H), 2.80-2.76(m, 1H), 2.68(m, 1H), 2.01-2.75 (m, 1H), 1.87 (m, 1H), 2.87 (m, 1H). LCMS (ESI) m/z: [ M + H ] ]+＝711.85。

Example 37 preparation of 2- [ (8- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -6-methyl-5-oxo-2, 6-naphthyridin-3-yl) amino ] -N- (5- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl ] oxy ] pentyl) acetamide (Compound D26)

Compound D26 was prepared in a similar manner to example 22.1H NMR (300MHz, methanol-d 4) δ 8.53(br s, 1.3H, FA), 8.50(s, 1H), 7.78(dd, J ═ 8.6, 7.2Hz, 1H), 7.48-7.43(m, 2H), 7.37(s, 1H), 7.15(s, 1H), 6.88(s, 2H), 5.10(dd, J ═ 12.3, 5.4Hz, 1H), 4.81(s, 2H), 4.27(t, J ═ 5.9Hz, 2H), 4.08(s, 2H), 3.94(s, 6H), 3.65(s, 3H), 3.27(s, 6H), 2.95-2.64(m, 4H), 2.19-2.07(m, 1H), 1.96-1.96 (m, 1H), 1.79-5 (m, 58H). LCMS (ESI) m/z: [ M + H ]]+＝768.40。

EXAMPLE 38 preparation of 4- ((5- (9- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-4-yl) -5-oxopentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione carboxylic acid (Compound D27 carboxylic acid)

Compound D27 was prepared in a similar manner to example 23. 1H NMR (300MHz, methanol-d 4) δ 9.15(s, 1H), 8.55(brs, 1.0H, formic acid), 7.79(t, J ═ 7.9Hz, 1H), 7.46(d, J ═ 8.4Hz, 3H), 6.87(d, J ═ 7.2Hz, 2H), 6.49(s, 1H), 5.12(dd, J ═ 12.1, 5.4Hz, 1H), 4.36-4.23(m, 4H), 3.95(d, J ═ 6.4Hz, 6H), 3.82-3.72(m, 2H), 3.66-3.60(m, 2H), 3.59(s, 3H), 3.52(s, 2H), 3.30-3.16(m, 4H), 3.12(s, 6H), 2.91-2H (m, 2H), 3.59 (m, 3.00-2H), 3.76 (m, 2H), 3.00-2H). LCMS (ESI) m/z: [ M + H ]]+＝864.40。

EXAMPLE 39 preparation of 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) -N- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] ethyl) azetidine-3-sulfonamide (Compound D28)

Mixing N- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl)]Piperazin-1-yl]Ethyl) azetidine-3-sulfonamide (60.00mg, 0.119mmol, 1.00 equiv.) and 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl]A solution of-2, 6-dimethoxybenzaldehyde (52.43mg, 0.143mmol, 1.20 equiv.) in DMF (1.50mL) was stirred at room temperature for 20 min. Then NaBH is added 3CN (14.95mg, 0.238mmol, 2.00 equiv.) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The crude product was passed through preparative HPLC (conditions: column, Phenomenex Gemini C6-phenyl, 21.2X 250mm, 5 μm; mobile phase; HPLC; conditions: column, columnWater (0.05% FA) and ACN (5% phase B to 23% in 20 min); detector, UV) purification. This gives 1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a green solid]-2, 6-dimethoxyphenyl]Methyl) -N- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl)]Piperazin-1-yl]Ethyl) azetidine-3-sulfonamide (13.4mg, 13.16%).1H NMR(400MHz，DMSO-d6)δ11.08(s，1H)，9.02(s，1H)，8.26(s，0.3H，FA)，7.66(d，J＝8.5Hz，1H)，7.55(s，1H)，7.33(d，J＝2.3Hz，1H)，7.23(dd，J＝8.7，2.3Hz，1H)，7.07(t，J＝5.9Hz，1H)，6.75(s，2H)，6.47(s，1H)，5.07(dd，J＝12.9，5.4Hz，1H)，4.01(q，J＝7.2Hz，1H)，3.81(s，6H)，3.62(s，2H)，3.49-3.45(m，5H)，3.44-3.39(m，7H)，3.06(s，8H)，2.94-2.82(m，1H)，2.59(d，J＝16.8Hz，3H)，2.55(s，2H)，2.42(t，J＝6.7Hz，2H)，2.07-1.97(m，1H)。LCMS(ESI)m/z：[M+H]+＝856.34。

EXAMPLE 40 preparation of 4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) piperazin-1-yl ] -2-oxoethoxy ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (Compound D29)

Compound D27 was prepared in a similar manner to example 23.1H NMR (300MHz, methanol-d 4) δ 8.55(d, J ═ 0.9Hz, 1H), 7.79(dd, J ═ 8.5, 7.3Hz, 1H), 7.52(d, J ═ 7.2Hz, 1H), 7.40(d, J ═ 8.5Hz, 1H), 7.24(d, J ═ 0.9Hz, 1H), 7.10(s, 1H), 6.81(s, 2H), 5.16-5.07(m, 3H), 4.06(s, 2H), 3.91(s, 6H), 3.83-3.69(m, 4H), 3.65(s, 3H), 3.00-2.85(m, 7H), 2.83-2.68(m, 3H), 2.21-2.07(m, 1H). LCMS (ESI) m/z: [ M + H ] ]+＝738.45。

EXAMPLE 41 preparation of 5- (4- [2- [1- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) piperidin-4-yl ] ethyl ] piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D30 carboxylic acid)

Step 1: preparation of 4-bromo-2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (i41-2)

To a stirred solution of 4-bromo-7-chloro-2-methyl-2, 6-naphthyridin-1-one (200.00mg, 0.731mmol, 1.00 equiv.) and methylamine hydrochloride (493.73mg, 7.312mmol, 10.00 equiv.) in DMSO (15.00mL) was added K2CO3(2021.21mg, 14.625mmol, 20.00 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 16 hours. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (4 × 15 mL). The resulting mixture was washed with brine (15 mL). The resulting mixture was concentrated under reduced pressure to give 4-bromo-2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (100mg, 51.01%) as a yellow solid.

Step 2: preparation of 2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] benzaldehyde (i85-3)

To a stirred solution of 4-bromo-2-methyl-7- (methylamino) -2, 6-naphthyridin-1-one (100.00mg, 0.373mmol, 1.00 equiv.) and 4-formyl-3, 5-dimethoxyphenylboronic acid (93.99mg, 0.448mmol, 1.20 equiv.) in 1, 4-dioxane/H2O (4: 1) (5.00mL) was added cesium carbonate (243.80mg, 0.746mmol, 2.00 equiv.) and pd (dppf) Cl 2(27.29mg, 0.037mmol, 0.10 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 16 hours. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM: MeOH (40: 1 to 10: 1) to give 2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl as a yellow solid]Benzaldehyde (30mg, 22.76%).

And step 3: preparation of 5- (4- [2- [1- ([2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl ] phenyl ] methyl) piperidin-4-yl ] ethyl ] piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid (Compound D30 carboxylic acid)

2, 6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl]Benzaldehyde (25.00mg, 0.071mmol, 1.00 equiv.) and 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperidin-4-yl) ethyl]Piperazin-1-yl]A solution of isoindole-1, 3-dione (32.09mg, 0.071mmol, 1.00 equiv.) in DMF (1.00mL)The mixture was stirred under nitrogen for 1 hour. Adding NaBH (OAc) to the mixture3(29.99mg, 0.141mmol, 2 equiv.). Mixing the obtained mixture in Followed by stirring for an additional 1 hour. The crude product was passed through preparative HPLC (conditions: SunFire C18 OBD Prep column,5 μm, 19mm X250 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 9B to 16B in 13 minutes; 254 nm; rT: 11.47 min) to give 5- (4- [2- [1- ([2 ] as a yellow solid6-dimethoxy-4- [ 2-methyl-7- (methylamino) -1-oxo-2, 6-naphthyridin-4-yl]Phenyl radical]Methyl) piperidin-4-yl]Ethyl radical]Piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (11.7mg, 20.91%).1H NMR(400MHz，DMSO-d6)δ11.08(s，1H)，8.54(s，1H)，8.15(s，0.9H，FA)，7.68(d，J＝8.4Hz，1H)，7.34(d，J＝2.4Hz，1H)，7.28-7.23(m，1H)，7.18(s，1H)，7.13(s，1H)，6.93(d，J＝5.1Hz，1H)，6.78(s，2H)，5.07(dd，J＝12.8，5.4Hz，1H)，3.85(s，9H)，3.53(s，4H)，3.44-3.42(m，5H)，3.12-3.08(m，2H)，2.91-2.87(m，1H)，2.85(d，J＝4.9Hz，3H)，2.64-2.53(m，3H)，2.37-2.32(m，3H)，2.04-1.99(m，1H)，1.77-1.70(m，2H)，1.47-1.37(m，3H)，1.32-1.23(m，3H)。LCMS(ESI)m/z：[M+H]+＝791.50。

EXAMPLE 42 preparation of 4- [10- (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) -4, 7-dioxa-1, 10-diaza-undec-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (Compound D31)

Step 1: preparation of tert-butyl N- [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino ] ethoxy ] ethyl ] carbamate (i42-2)

To 6-chloro-4- [4- [ (dimethylamino) methyl group at room temperature]-3, 5-dimethoxyphenyl]-2-methyl-2, 7-naphthyridin-1-one (335.0mg, 0.864mmol, 1.00 equiv.) and N- [2- [2- (2-aminoethoxy) ethoxy ] ethoxy ]Ethyl radical]A stirred solution of tert-butyl carbamate (643.4mg, 2.591mmol, 3.00 equiv.) in DMSO (2mL) was added K2CO3(238.7mg, 1.727mmol, 2.00 equiv.). Mixing the obtained mixture inStirring was continued overnight. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Cl2(2x3mL) washing. The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase A: water/0.05% TFA, mobile phase B: ACN; flow rate: 50 mL/min; gradient: 0% B to 40% B over 15 min; detector, 254nm) to give N- [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl ] carbonyl ] as a yellow oil]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino]Ethoxy radical]Ethoxy) ethyl]Tert-butyl carbamate (380mg, 73.36%). LCMS (ESI) m/z: [ M + H ]]+＝600。

Step 2: preparation of tert-butyl N- [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) (methyl) amino ] ethoxy ] ethyl ] carbamate (i42-3)

To N- [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl group at room temperature]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) amino ]Ethoxy radical]Ethoxy) ethyl]Tert-butyl carbamate (190.0mg, 0.317mmol, 1.00 eq.) and K2CO3(87.6mg, 0.634mmol, 2 equiv.) of the stirred solution/mixture in acetone (3mL) was added dimethyl sulfate (44.0mg, 0.348mmol, 1.10 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. By CH2Cl2Isopropanol (3 × 5mL) extracts the aqueous layer. The combined organic layers were washed with brine (1 × 10mL) and over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl) carbonyl ] amide as a yellow oil]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) (methyl) amino]Ethoxy radical]Ethoxy) ethyl]Carbamic acid tert-butyl esterButyl ester (95.00mg, 48.86%). The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝614。

And step 3: 3, 3, 3-trifluoropropionic acid; preparation of 6- ([2- [2- (2-aminoethoxy) ethoxy ] ethyl ] (methyl) amino) -4- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -2-methyl-2, 7-naphthyridin-1-one (i42-4)

To N- [2- (2- [2- [ (5- [4- [ (dimethylamino) methyl group at room temperature]-3, 5-dimethoxyphenyl ]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) (methyl) amino]Ethoxy radical]Ethoxy) ethyl]A stirred solution of tert-butyl carbamate (75.00mg, 0.122mmol, 1.00 equiv.) in dichloromethane (3mL) was added TFA (1mL) dropwise. The resulting mixture was concentrated in vacuo to give 3, 3, 3-trifluoropropionic acid as a yellow oil; 6- ([2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical](methyl) amino) -4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl]-2-methyl-2, 7-naphthyridin-1-one (103mg, crude). The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝514。

And 4, step 4: preparation of 4- [10- (5- [4- [ (dimethylamino) methyl ] -3, 5-dimethoxyphenyl ] -7-methyl-8-oxo-2, 7-naphthyridin-3-yl) -4, 7-dioxa-1, 10-diazaundec-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (Compound D31)

To 6- ([2- [2- (2-aminoethoxy) ethoxy) at room temperature]Ethyl radical](methyl) amino) -4- [4- [ (dimethylamino) methyl group]-3, 5-dimethoxyphenyl](iii) -2-methyl-2, 7-naphthyridin-1-one (68.00mg, 0.132mmol, 1.00 equiv.) to a stirred solution in DMF (1mL) was added 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindole-1, 3-dione (34.6mg, 0.125 mmo) l, 0.95 equiv.) and DIEA (85.6mg, 0.662mmol, 5.00 equiv.). Mixing the obtained mixture inStirring was continued overnight. The crude product was purified by preparative HPLC (conditions: XSelect CSH F-Phenyl OBD column 19 x 150mm 5 um; mobile phase A: water (0.1% FA; mobile phase B: ACN; flow rate: 25 mL/min; gradient: 9B to 19B; 254 nm; R within 12 min; gradient: 1 min)t: 12.63 min) to give 4- [10- (5- [4- [ (dimethylamino) methyl ] as a yellow solid]-3, 5-dimethoxyphenyl]-7-methyl-8-oxo-2, 7-naphthyridin-3-yl) -4, 7-dioxa-1, 10-diazaundec-1-yl]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (3.2mg, 3.14%).1H NMR (400MHz, methanol-d 4) δ 8.96(s, 1H), 7.54-7.46(m, 2H), 6.99(dd, J ═ 15.8, 7.7Hz, 2H), 6.84(s, 2H), 6.74(s, 1H), 4.96-4.94(m, 1H), 4.57(s, 2H), 3.97(s, 6H), 3.77-3.69(m, 8H), 3.59-3.53(m, 5H), 3.41(t, J ═ 5.2Hz, 2H), 3.17-3.11(m, 9H), 2.83-2.53(m, 3H), 2.04-1.95(m, 1H). LCMS (ESI) m/z: [ M + H ]]+＝770.50。

Example 43 preparation of Compounds D32-D184

In analogy to the procedure described in the above examples, compound D32 was prepared using the appropriate starting materials-D184

Example 44 preparation of Compounds D185-D316

In analogy to the procedure described in the above examples, compounds D185-D316 were prepared using the appropriate starting materials

EXAMPLE 45 preparation of 4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde

Step 1: preparation of 6-chloro-4-methylpyridine-3-carboxamide

To 6-chloro-4-methylpyridine-3-carboxylic acid (20.00g, 116.564mmol, 1.00 eq.) and NH4A stirred mixture of Cl (62.35g, 1.17mol, 10.00 eq) in DCM (400mL) was added DIEA (22.60g, 174.846mmol, 3.00 eq). After stirring for 5 min, HATU (66.48g, 174.846mmol, 1.50 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE/EtOAc from 1/1 to 3/2 to give 6-chloro-4-methylpyridine-3-carboxamide as a yellow solid (18.30g, 61.3%). LCMS (ESI) m/z: [ M + H ]]+＝171。

Step 2: preparation of 6-chloro-N- [ (1E) - (dimethylamino) methylene ] -4-methylpyridine-3-carboxamide

In thatTo a stirred mixture of 6-chloro-4-methylpyridine-3-carboxamide (18.30g, 107.268mmol, 1.00 equiv.) and 2-methyltetrahydrofuran (100mL) under nitrogen was added DMF-DMA (19.17g, 160.903mmol, 1.50 equiv.) and stirred for an additional 1 h. The mixture was then cooled and concentrated to give 6-chloro-N- [ (1E) - (dimethylamino) methylene as a yellow crude solid ]-4-methylpyridine-3-carboxamide (26.3g, 91.3%) which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝226。

And step 3: preparation of 6-chloro-2H-2, 7-naphthyridin-1-one

To 6-chloro-N- [ (1E) - (dimethylamino) methylene]A stirred mixture of-4-methylpyridine-3-carboxamide (26.30g) in THF (170.00mL) was added t-BuOK (174.00mL, 1mol/L in THF), and the resulting solution was dissolved inStirred under nitrogen for 30 minutes. The mixture was then cooled and concentrated under reduced pressure, and the crude solid was taken up in saturated NaHCO3The solution (100mL) was washed and collected to give 6-chloro-2H-2, 7-naphthyridin-1-one (14.1g, 67.0%) as a pink solid, which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝181。

And 4, step 4: preparation of 6-chloro-2-methyl-2, 7-naphthyridin-1-one

In thatTo a stirred mixture of 6-chloro-2H-2, 7-naphthyridin-1-one (14.10g, 78.077mmol, 1.00 equiv.) in anhydrous THF (280.00mL) was added NaH (9.37g, 234.232mmol, 3.00 equiv., 60%) in portions. After 10 minutes, inMeI (33.25g, 234.232mmol, 3.00 equiv.) was added to the above mixture and the mixture was stirred atStirred for 10 minutes. The mixture was then stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The crude solid was slurried with water (100mL), and the solid was filtered and collected to give 6-chloro-2-methyl-2, 7-naphthyridin-1-one (14.6g, 94.1%) as a yellow solid, which was used without further purification. LCMS (ESI) m/z: [ M + H ] ]+＝195。

And 5: preparation of 4-bromo-6-chloro-2-methyl-2, 7-naphthyridin-1-one

To a stirred mixture of 6-chloro-2-methyl-2, 7-naphthyridin-1-one (8.00g, 41.106mmol, 1.00 equiv.) in DMF (160.00mL) was added NBS (8.78g, 49.327mmol, 1.20 equiv.) and the resulting mixture was stirredStirred for 2 hours. The reaction mixture was cooled and diluted with DCM (150mL) and washed with water (3 × 100mL), the organic layer was dried and concentrated. The residue was then slurried with EtOAc (20mL), the slurry filtered, and the filter cake washed with EtOAc (20mL) to give 4-bromo-6-chloro-2-methyl-2, 7-naphthyridin-1-one (6.32g, 55.7%) as a white solid, which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝273。

Step 6: preparation of 4-bromo-6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one

4-bromo-6-chloro-2-methyl-2, 7-naphthyridin-1-one (6.00g, 21.937mmol, 1.00 equiv.), dimethylamine hydrochloride (5.37g, 65.811mmol, 3.00 equiv.) and K2CO3(15.16g, 109.685mmol, 5.00 equiv.) of a stirred mixture in DMSO (60.00mL)Heated under nitrogen atmosphere. After 3 hours, the resulting mixture was cooled and diluted with water (100mL) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated NaCl solution (3 × 50mL) over anhydrous Na 2SO4Drying and concentration under reduced pressure gave 4-bromo-6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (5.91g, 93.6%) as a yellow solid, which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝282。

And 7: preparation of (4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde

To 4-bromo-6- (dimethylamino) -2-methyl-2, 7-naphthyridin-1-one (5.70g, 20.203mmol, 1.00 equiv.) and 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (8.26g, 28.284mmol, 1.40 equiv.) in dioxane (100.00mL) and H2Stirring mixture in O (10.00mL) Pd (dppf) Cl was added2.CH2Cl2(1.65g, 2.020mmol, 0.10 equiv.) and Cs2CO3(13.16g, 40.405mmol, 2.00 equiv.) and the mixture was then stirred at room temperatureThe mixture was stirred under nitrogen for 4 hours. The resulting mixture was cooled and concentrated under reduced pressure, the residue was slurried with water (100mL) and filtered, and the filter cake was collected. And the solid was further slurried with MeOH (100mL) and filtered, the solid was collected to give the product as a brown solid 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl]-2, 6-dimethoxybenzaldehyde (6.10g, 77.6%). LCMS (ESI) m/z: [ M + H ] ]+＝368。

Example 46-3- (6- (1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione carboxylic acid; and preparation of 3- (5- (1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione carboxylic acid

Step 1: preparation of 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione.

To a stirred solution of 5-bromo-2-benzofuran-1, 3-dione (10.00g, 44.050mmol, 1.00 equiv.), NaOAc (7.23mg, 88.134mmol, 2.00 equiv.), and 3-aminopiperidine-2, 6-dione (11.29g, 88.113mmol, 2.00 equiv.) in AcOH (80.00mL) at room temperature was added. Mixing the obtained mixture inStirred for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (10: 1) to give 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione as a dark brown solid (13.6g, 91.6%). LCMS (ESI) m/z: [ M + H ]]+＝337。

Step 2: preparation of 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (3.00g, 8.899mmol, 1.00 equiv.), 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxopentan-borane-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.30g, 10.672mmol, 1.20 equiv.), K at room temperature under a nitrogen atmosphere3PO4(5.67g, 26.712mmol, 3.00 equiv.) in dioxane (20.00mL) and H2Stirred solution in O (4.00mL) Pd (PPh) was added3)2Cl2(0.62g, 0.883mmol, 0.10 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (8/1) to give 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl as a colorless oil]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.8g, 20.5%). LCMS (ESI) m/z: [ M + H ]]+＝440。

And step 3: preparation of 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperidine-1-carboxylic acid tert-butyl ester

To 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl in a 100mL round-bottomed flask under nitrogen atmosphere]A stirred solution of tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate (0.80g) in THF (20.00mL) was added 10% Pd/C (500.0 mg). The mixture was hydrogenated at room temperature under hydrogen atmosphere using a hydrogen balloon for 12 hours, and filtered through a celite pad And concentrated under reduced pressure. This gives 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] as a white solid]Tert-butyl piperidine-1-carboxylate (0.73g, crude) was used in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝442。

And 4, step 4: 4- (2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxoisoindolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester; preparation of 4- (2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxoisoindolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl at room temperature]A stirred solution of piperidine-1-carboxylic acid tert-butyl ester (0.73g, 16.55mmol, 1.00 equiv.) and Zn (1.08g, 1.65mmol, 10.00 equiv.) in AcOH (10.00 mL). Mixing the obtained mixture inStirred for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (2: 1) to give tert-butyl 4- (2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxoisoindolin-5-yl) piperidine-1-carboxylate as a colorless solid; tert-butyl 4- (2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxoisoindolin-5-yl) piperidine-1-carboxylate (0.546g, 74.8%, mixture of two regioisomers). LCMS (ESI) m/z: [ M + H ] ]+＝444。

And 5: 3- (1-oxo-6- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; preparation of 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione.

To 4- (2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxoisoindoline at room temperature-5-yl) piperidine-1-carboxylic acid tert-butyl ester; a stirred solution of tert-butyl 4- (2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxoisoindolin-5-yl) piperidine-1-carboxylate (mixture of two regioisomers, 573.00mg, 1.00 eq) and TFA (3.00mL) in DCM (9.00mL) was added TES (450.7mg, 3.876mmol, 3.00 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and used without further purification to give 3- (1-oxo-6- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione as an off-white oil; 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (200mg of 36.6% mixture of the two regioisomers). LCMS (ESI) m/z: [ M + H ]]+＝328。

Step 6: 3- (6- (1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione carboxylic acid; and preparation of 3- (5- (1- (4- (6- (dimethylamino) -2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione carboxylic acid

To 3- [ 1-oxo-6- (piperidin-4-yl) -3H-isoindol-2-yl group at room temperature]Piperidine-2, 6-dione (165.0mg, 0.504mmol, 1.00 equiv.) and 3- (1-oxo-6- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (mixture of two regioisomers, 222.2mg, 0.605mmol, 1.20 equiv.) in DMF (4.00mL) was added NaBH (OAc)3(427.3mg, 2.016mmol, 4.00 eq.). The resulting mixture was stirred at room temperature for 16 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.05% FA), gradient 0% to 50% over 30 min; detector, UV 254 nm. The crude product was purified by preparative HPLC using the following conditions: column, Sunfire Prep C18 OBD column, 10 μm, 19 × 250 mm; mobile phase, water (0.05% FA) and CH3CN (15% to 22% CH in 15 min)3CN); detector, UV 254 nm. This gives 3- [6- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl ]Piperidine-2, 6-dione; formic acid (52.5mg, 26.3%) and 3- [5- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; formic acid (68.4mg, 34.2%).

For 3- [6- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; formic acid:1H NMR(400MHz，DMSO-d6)δ10.97(s，1H)，9.04(s，1H)，8.20(s，1H，FA)，7.58(d，J＝14.5Hz，2H)，7.52(s，2H)，6.79(s，2H)，6.50(s，1H)，5.10(dd，J＝13.4，5.1Hz，1H)，4.41(d，J＝17.1Hz，1H)，4.28(d，J＝17.0Hz，1H)，3.84(s，6H)，3.68(s，2H)，3.49(s，3H)，3.08-3.05(m，8H)，2.91-2.89(m，1H)，2.66-2.56(m，2H)，2.40-2.35(m，1H)，2.30(t，J＝11.3Hz，2H)，2.03-1.95(m，1H)，1.88-1.57(m，4H)。LCMS(ESI)m/z：[M+H]+＝679.32。

for 3- [5- [1- ([4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; formic acid:1H NMR(400MHz，DMSO-d6)δ10.98(s，1H)，9.05(s，1H)，8.15(s，1H，FA)，7.69(d，J＝7.8Hz，1H)，7.60(s，1H)，7.48(s，1H)，7.40(d，J＝7.9Hz，1H)，6.87(s，2H)，6.51(s，1H)，5.11(dd，J＝13.3，5.1Hz，1H)，4.44(d，J＝17.3Hz，1H)，4.31(d，J＝17.3Hz，1H)，4.05(s，2H)，3.90(s，6H)，3.49(s，3H)，3.31(d，J＝11.7Hz，2H)，3.09(s，6H)，2.99-2.71(m，4H)，2.65-2.56(m，1H)，2.47-2.33(m，1H)，2.04-1.96(m，1H)，1.92(m，4H)。LCMS(ESI)m/z：[M+H]+＝679.32。

EXAMPLE 47 preparation of 3- [6- [ (7- [ [1- (2- [4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] ethyl) piperidin-4-yl ] methyl ] -7-azaspiro [3.5] nonan-2-yl) oxy ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione bis (trifluoroacetic acid)

Step 1: preparation of 2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] oxy ] -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester

To a mixture of 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindole-1, 3-dione (1.37g, 4.996mmol, 1.00 equiv.) and 2-hydroxy-7-azaspiro [3.5]]A solution of tert-butyl nonane-7-carboxylate (1.81g, 7.494mmol, 1.5 eq) in THF (30.00mL) was added PPh3(1.97g, 7.494mmol, 1.5 equiv.). In thatDIAD (1.52g, 7.494mmol, 1.5 equiv.) was added dropwise to the above mixture over 10 min. The resulting mixture was stirred at room temperature for an additional 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous FA, 0% to 100% gradient over 45 min; detector, UV 254 nm. This gives 2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] as a white solid]Oxy radical]-7-azaspiro [3.5]Nonane-7-carboxylic acid tert-butyl ester (1.964g, 79.0%). LCMS (ESI) m/z: [ M + H ]]+＝498。

Step 2: 5- [ 7-azaspiro [3.5] nonan-2-yloxy ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione; preparation of formic acid

To 2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl group]Oxy radical]-7-azaspiro [3.5]A solution of tert-butyl nonane-7-carboxylate (1.96g, 3.939mmol) in DCM (10.00mL) was added TFA (10.00 mL). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo to give crude 5- [ 7-azaspiro [3.5] ]Nonan-2-yloxy]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione; formic acid, which was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝398。

And step 3: preparation of 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] oxy ] -7-azaspiro [3.5] nonan-7-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester

To 5- [ 7-azaspiro [3.5] at room temperature]Nonan-2-yloxy]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (2.65g, 6.668mmol, 1.00 equiv.) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (1.42g, 6.668mmol, 1 equiv.) in DMF (30.00mL) NaBH (OAc)3(4.24g, 20.003mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by addition of water (100mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 150mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) as a pale yellow solid]Oxy radical]-7-azaspiro [3.5]Nonan-7-yl) methyl]Piperidine-1-carboxylic acid tert-butyl ester (3.11g, 78.4%); LCMS (ESI) m/z: [ M + H ] ]+＝595。

And 4, step 4: preparation of 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxo-1H-isoindol-5-yl ] oxy ] -7-azaspiro [3.5] nonan-7-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester and 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl ] oxy ] -7-azaspiro [3.5] nonan-7-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester

To 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) at room temperature]Oxy radical]-7-azaspiro [3.5]Nonan-7-yl) methyl]A solution of piperidine-1-carboxylic acid tert-butyl ester (3.00g, 5.044mmol, 1.00 equiv.) in AcOH (60.00mL) was added Zn (3.30g, 50.445mmol, 10 equiv.). Mixing the obtained mixture inStirred for 3 hours. The resulting mixture was filtered and the filter cake was washed with MeCN (3x100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous FA, 0% to 100% gradient over 35 min; detector, UV 254 nm. This gave 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxo-1H-isoindol-5-yl) as a pale yellow solid]Oxy radical]-7-azaspiro [3.5]Nonan-7-yl) methyl ]Piperidine-1-carboxylic acid tert-butyl ester and 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl)]Oxy radical]-7-azaspiro [3.5]Nonan-7-yl) methyl]Mixture of tert-butyl piperidine-1-carboxylate (mixture, 1.6g, 53.2%). LCMS (ESI) m/z: [ M + H ]]+＝597。

And 5: preparation of 3- (1-oxo-6- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5] nonan-2-yl ] oxy ] -3H-isoindol-2-yl) piperidine-2, 6-dione and 3- (1-oxo-5- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5] nonan-2-yl ] oxy ] -3H-isoindol-2-yl) piperidine-2, 6-dione.

To 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxo-1H-isoindol-5-yl) at room temperature]Oxy radical]-7-azaspiro [3.5]Nonan-7-yl) methyl]Piperidine-1-carboxylic acid tert-butyl ester (2.40g, 4.022mmol, 1.00 equiv.) and 4- [ (2- [ [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl)]Oxy radical]-7-azaspiro [3.5]Nonan-7-yl) methyl]Piperidine-1-carboxylic acid tert-butyl ester) in DCM (50.00mL) was added TFA (5.00mL, 67.315mmol, 16.74 equiv.) and Et3SiH (4.68g, 40.220mmol, 10 equiv.). The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous TFA, gradient 0% to 10% over 45 min; detector, UV 254 nm. This gave 3- (1-oxo-6- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5] as a pale yellow solid ]Nonan-2-yl]Oxy radical]-3H-isoindol-2-yl) piperidine-2, 6-dione (600mg, 31.0%) and 3- (1-oxo-5- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5 ]]Nonan-2-yl]Oxy radical]-3H-isoindol-2-yl) piperidine-2, 6-dione (1.2g, 62.1%). LCMS (ESI) m/z: [ M + H ]]+＝481。

Step 6: 2- [4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] acetaldehyde

To a stirred mixture of 4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde (150.0mg, 0.408mmol, 1.00 equiv.) and (methoxymethyl) triphenylphosphonium chloride (559.8mg, 1.633mmol, 4 equiv.) in THF (5.0mL) was added t-BuOK (183.2mg, 1.633mmol, 4 equiv.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. To the above mixture was added HCl (6M, 0.5mL, 0.30mmol) dropwise. The resulting mixture was stirred at room temperature for another 30 minutes. The resulting mixture was concentrated under vacuum. The residue was purified by passing through a reverse phase column under the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient from 10% to 80% over 15 min; detector, UV 254 nm. This gave 2- [4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] acetaldehyde (160mg, 95.1%) as a white solid. LCMS (ESI) m/z: [ M + H ] + -382.

And 7: 3- [6- [ (7- [ [1- (2- [4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] ethyl) piperidin-4-yl ] methyl ] -7-azaspiro [3.5] nonan-2-yl) oxy ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione bis (trifluoroacetic acid).

To 2- [4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl group]-2, 6-dimethoxyphenyl]Acetaldehyde (150.0mg, 0.393mmol, 1.00 equiv.) and 3- (1-oxo-6- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5]]Nonan-2-yl]Oxy radical](iii) -3H-isoindol-2-yl) piperidine-2, 6-dione (189.0mg, 0.393mmol, 1 eq.) in a stirred solution of DMF (2.0mL) NaBH (OAc)3(250.0mg, 1.180mmol, 3 equiv.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The crude reaction mixture was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19X 250mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 8B to 25B; 254/220 nm; RT 1: 12.28min) to give 3- [6- [ [1- (2- [4- [6- (dimethylamino) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid ]-2, 6-dimethoxyphenyl]Ethyl) piperidin-4-yl]Methyl radical]-7-azaspiro [3.5]Nonan-2-yl) oxy]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; bis (trifluoroacetic acid) (101.2mg, 30.4%).1H NMR (400MHz, DMSO-d6) δ 11.00(s, 1H), 9.49(d, J ═ 109.5Hz, 2H, TFA salt), 9.04(s, 1H), 7.57-7.48(m, 2H), 7.18-7.09(m, 2H), 6.81(d, J ═ 2.8Hz, 2H), 6.48(s, 1H), 5.11(dd, J ═ 13.1, 5.2Hz, 1H), 4.89(p, J ═ 6.8Hz, 1H), 4.38(d, J ═ 17.0Hz, 1H), 4.28-4.22(m, 2H), 3.85(s, 6H), 3.68(d, J ═ 11.3Hz, 2H)，3.48(s，3H)，3.40(d，J＝11.9Hz，1H)，3.33-3.18(m，1H)，3.08(s，6H)，3.06-2.84(m，9H)，2.65-2.56(m，2H)，2.46-2.36(m，2H)，2.14-1.93(m，6H)，1.92-1.79(m，5H)，1.46(q，J＝12.2Hz，2H)。LCMS(ESI)m/z：[M+H]+＝846.25。

EXAMPLE 48 preparation of 4- (6-cyclopropyl-2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde

Step 1: preparation of 6-cyclopropyl-2-methyl-2, 7-naphthyridin-1-one.

To a stirred solution of 6-chloro-2-methyl-2, 7-naphthyridin-1-one (500.00mg, 2.569mmol, 1.00 equiv.) and cyclopropylboronic acid (441.37mg, 5.138mmol, 2 equiv.) in toluene (20.00mL) and water (1.00mL) was added tricyclohexylphosphine (144.09mg, 0.514mmol, 0.20 equiv.), Pd (AcO) at room temperature under a nitrogen atmosphere2(57.68mg, 0.257mmol, 0.10 equiv.) and K3PO4(1636.01mg, 7.707mmol, 3.00 equiv.). Mixing the obtained mixture in Stirred for 1 hour. The mixture was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (50: 1) afforded 6-cyclopropyl-2-methyl-2, 7-naphthyridin-1-one (340mg, 59.48%) as a brown solid. LCMS (ESI) m/z: [ M + H ]]+＝201。

Step 2: preparation of 4-bromo-6-cyclopropyl-2-methyl-2, 7-naphthyridin-1-one

At room temperatureTo a stirred solution of 6-cyclopropyl-2-methyl-2, 7-naphthyridin-1-one (100.00mg, 0.499mmol, 1.00 equiv) in DMF (4.00mL) under nitrogen was added NBS (106.66mg, 0.599mmol, 1.20 equiv). Mixing the obtained mixture inStirred for 2 hours. The resulting mixture was diluted with water (12mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4-bromo-6-cyclopropyl-2-methyl-2, 7-naphthyridin-1-one (400mg, 75.96%) as a brown solid. It was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝279。

And step 3: preparation of 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde

To a stirred solution of 4-bromo-6-cyclopropyl-2-methyl-2, 7-naphthyridin-1-one (420.00mg, 1.505mmol, 1.00 equiv.) and 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (527.48mg, 1.806mmol, 1.2 equiv.) in dioxane (10.00mL) and water (2.00mL) under a nitrogen atmosphere at room temperature was added Pd (dppf) Cl 2(110.09mg, 0.150mmol, 0.10 equiv.) and K2CO3(415.90mg, 3.009mmol, 2.00 equiv.). Mixing the obtained mixture inStirring was continued overnight. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2/MeOH 50: 1) to give 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (440mg, 72.22%) as a yellow solid. LCMS (ESI) m/z: [ M + H ]]+＝365。

EXAMPLE 49 preparation of 5- [4- [2- (4- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] piperazin-1-yl) ethyl ] piperidin-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Step 1: preparation of benzyl 4- (2- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethyl) piperazine-1-carboxylate.

To a solution of tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (4.02g, 17.709mmol, 1.00 equiv.) and benzyl piperazine-1-carboxylate (3.90g, 17.727mmol, 1.00 equiv.) in MeOH (40mL) was added NaBH3CN (2.26g, 35.313mmol, 2 equiv.), and the resulting solution was addedStirred for 1 hour. The resulting mixture was diluted with water (50mL) and extracted with EA (30 mL. times.3). The combined organic layers were passed over anhydrous Na2SO4Dried, filtered and evaporated to give the crude product. The crude product was purified by flash silica chromatography eluting with a gradient of 0% to 45% THF in petroleum ether. The pure fractions were evaporated to dryness to give benzyl 4- (2- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethyl) piperazine-1-carboxylate (2.76g, 35.71%) as a colorless oil. LCMS (ESI) m/z: [ M + H ] ]+＝432。

Step 2: preparation of benzyl 4- (2- (piperidin-4-yl) ethyl) piperazine-1-carboxylate

To a solution of benzyl 4- (2- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethyl) piperazine-1-carboxylate (2.76g, 6.403mmol, 1.00 equiv.) in DCM (8.00mL) was added a solution of HCl in 1, 4-dioxane (8.00mL, 4mol/L) and the resulting mixture was dissolved in DCM (8.00mL, 4mol/L)Stirred for 1 hour. The resulting mixture was filtered and the filter cake was washed with DCM (5 mL). The collected solid was dried under reduced pressure to give 4- (2- (piperidin-4-yl) ethyl) piperazine-1-carboxylate (2.08g, 98.11%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝331。

And step 3: preparation of benzyl 4- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) ethyl) piperazine-1-carboxylate

To a solution of 4- (2- (piperidin-4-yl) ethyl) piperazine-1-carboxylate (1.50g, 4.532mmol, 1.00 eq.) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (1.25g, 4.532mmol, 1 eq.) in DMSO (15.00mL) was added DIEA (3.51g, 27.192mmol, 6 eq.) and the resulting solution wasStirred for 2 hours. The reaction mixture was diluted with EA (500 mL).

The resulting mixture was washed with water (300mL x 3) and saturated brine (300mL x 1). Subjecting the organic layer to Na 2SO4Dried, filtered and evaporated to give the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to give benzyl 4- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) ethyl) piperazine-1-carboxylate as a yellow solid (1.44g, 54.13%). LCMS (ESI) m/z: [ M + H ]]+＝588。

And 4, step 4: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (piperazin-1-yl) ethyl) piperidin-1-yl) isoindoline-1, 3-dione

To a solution of 4- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) ethyl) piperazine-1-carboxylate (1.04g, 1.772mmol, 1.00 eq) in DCM (30.00mL) was added BBr3Solution in DCM (20mL, 1M), and the resulting mixture was dissolved inStirred for 1 hour. The reaction mixture was poured into ice water (100mL), extracted with DCM (30mL × 3) and the aqueous layer was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography eluting a gradient of 0% to 50% MeCN in water (containing 0.1% HCl). The pure fractions were evaporated to dryness to give 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (piperazin-1-yl) ethyl) piperidin-1-yl) isoindoline-1, 3-dione as a yellow solid (794mg, 98.75%). LCMS (ESI) m/z: [ M + H ] ]+＝454。

And 5: preparation of 5- [4- [2- (4- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] piperazin-1-yl) ethyl ] piperidin-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

To 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (200.00mg, 0.549mmol, 1.00 eq.) and 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperazin-1-yl) ethyl ] -2, 6-dimethoxybenzaldehyde at room temperature under nitrogen]Piperidin-1-yl radical]A stirred mixture of isoindole-1, 3-dione (373.39mg, 0.823mmol, 1.50 equiv.) in DMF (3.00mL) was added NaBH (OAc)3(68.98mg, 1.098mmol, 2.00 equiv.). Mixing the obtained mixture inStirred for 2 hours. The mixture solution was purified by preparative HPLC using the following conditions (column: XSelect CSH F-Phenyl OBD column, 19X 250, 5 μm; mobile phase A: water (0.1% FA), mobile phase B:ACN; flow rate: 25 mL/min; gradient: 6B to 27B in 16 minutes; 254/220 nm; RT 1: 15.34min) to yield 5- [4- [2- (4- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] as a yellow solid]Methyl radical]Piperazin-1-yl) ethyl]Piperidin-1-yl radical]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (165mg, 28.16%). 1H NMR(400MHz，DMSO-d6)δ11.09(s，1H)，9.30(s，1H)，7.80(s，1H)，7.67(d，J＝8.5Hz，1H)，7.44(s，1H)，7.34(s，1H)，7.26(d，J＝8.8Hz，1H)，6.88(s，2H)，5.07(dd，J＝12.9，5.5Hz，1H)，4.35(s，2H)，4.08(d，J＝12.7Hz，2H)，3.90(s，7H)，3.58(s，7H)，3.27-3.21(m，5H)，3.01-2.82(m，3H)，2.64-2.53(m，2H)，2.22(t，J＝6.5Hz，1H)，2.02(d，J＝12.0Hz，1H)，1.77(d，J＝12.6Hz，2H)，1.63(s，3H)，1.22(d，J＝11.6Hz，2H)，1.02(d，J＝8.0Hz，4H)。LCMS(ESI)m/z：[M+H]+＝802.15。

EXAMPLE 50 preparation of 3- [6- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] azetidin-3-yl) oxy ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

Step 1: preparation of tert-butyl 3- [ (4-methylphenylsulfonyl) oxy ] azetidine-1-carboxylate (5).

In thatTo a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.50g, 14.433mmol, 1.00 equiv.) and TsCl (4.13g, 21.650mmol, 1.50 equiv.) in DCM were added DMAP (264.49mg, 2.165mmol, 0.15 equiv.) and TEA (4.38g, 43.300mmol, 3.00 equiv.) portionwise under an air atmosphere. Mixing the obtained mixtureThe mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (1: 1) to give 3- [ (4-methylphenylsulfonyl) oxy group as a brown oil]Azetidine-1-carboxylic acid tert-butyl ester (4.4g, 93.11%). LCMS (ESI) m/z: [ M + H ]]+＝328。

Step 2: preparation of tert-butyl 3- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] oxy ] azetidine-1-carboxylate

In thatThen under an air atmosphere to produce 3- [ (4-methylbenzenesulfonyl) oxy group]A solution of azetidine-1-carboxylic acid tert-butyl ester (4.40g, 13.439mmol, 1.00 equiv.) and KI (0.22g, 1.344mmol, 0.10 equiv.) in DMF was added KHCO in portions 3(4.04g, 40.318mmol, 3.00 equiv.). The resulting mixture was washed with 3 × 150mL EtOAc. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous, 0% to 100% gradient over 40 min; detector, UV 254 nm. This gives 3- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] as an off-white solid]Oxy radical]Azetidine-1-carboxylic acid tert-butyl ester (1.73g, 29.98%). LCMS (ESI) m/z: [ M + H ]]+＝430。

And step 3: preparation of tert-butyl 3- [ [2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxo-1H-isoindol-5-yl ] oxy ] azetidine-1-carboxylate and tert-butyl 3- [ [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl ] oxy ] azetidine-1-carboxylate

Reacting 3- [ [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoIndol-5-yl]Oxy radical]A solution of azetidine-1-carboxylic acid tert-butyl ester (1.73g, 4.029mmol, 1.00 equiv.) and Zn (2.64g, 40.286mmol, 10.00 equiv.) in AcOHThe mixture was stirred for 2 hours under an air atmosphere. The resulting mixture was washed with 3 × 100mL of ethyl acetate. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification to give 3- [ [2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxo-1H-isoindol-5-yl ] as an off-white solid ]Oxy radical]Azetidine-1-carboxylic acid tert-butyl ester and 3- [ [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl]Oxy radical]Azetidine-1-carboxylic acid tert-butyl ester (2.73g, 78.53%). LCMS (ESI) m/z: [ M + H ]]+＝432。

And 4, step 4: preparation of 3- [6- (azetidin-3-yloxy) -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

To 3- [ [2- (2, 6-dioxopiperidin-3-yl) -1-hydroxy-3-oxo-1H-isoindol-5-yl ] at room temperature in an air atmosphere]Oxy radical]Azetidine-1-carboxylic acid tert-butyl ester and 3- [ [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl]Oxy radical]A solution of azetidine-1-carboxylic acid tert-butyl ester (2.73g, 3.164mmol, 1.00 equiv.) and TFA (1.50mL, 20.195mmol, 6.38 equiv.) in DCM was added in portions with Et3SiH (3.68g, 31.638mmol, 10.00 equiv.). The resulting mixture was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC using the following conditions (column: Xcelect CSH F-Phenyl OBD column, 19 x 250mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: can; flow rate: 30 mL/min; gradient: 5B to 21B within 10 min; 254/220 nm; RT 1: 7.20/8.67min) to give 3- [6- (azetidin-3-yloxy) -1-oxo-3H-isoindol-2-yl) as an off-white solid ]Piperidine-2, 6-dione (165mg, 8.27%). LCMS (ESI) m/z: [ M + H ]]+＝316。

And 5: preparation of 3- [6- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] azetidin-3-yl) oxy ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

To a stirred solution of 3- [6- (azetidin-3-yloxy) -1-oxo-3H-isoindol-2-ylpiperidine-2, 6-dione (75.00mg, 0.238mmol, 1.00 equiv.) and 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (86.67mg, 0.238mmol, 1.00 equiv.) in DMF at room temperature under an air atmosphere was added dropwise NaBH (OAc)3(100.82mg, 0.476mmol, 2.00 equiv.) for 2 hours. The crude product (mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19X 250mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 15B to 23B; 254/220 nm; RT 1: 10.38 min) to give 3- [6- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl) as an off-white solid]Methyl radical]Azetidin-3-yl) oxy ]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione (18.9mg, 11.69%).1H NMR (400MHz, methanol-d 4) δ 9.39(d, J ═ 0.8Hz, 1H), 7.80(d, J ═ 4.5Hz, 1H), 7.60(t, J ═ 7.2Hz, 1H), 7.42(d, J ═ 5.4Hz, 1H), 7.32-7.24(m, 1H), 7.22(d, J ═ 3.2Hz, 1H), 6.89(s, 2H), 5.35-5.19(m, 1H), 5.16(dd, J ═ 13.3, 5.2Hz, 1H), 4.84-4.69(m, 2H), 4.65(s, 2H), 4.48(d, J ═ 10.6Hz, 2H), 4.42(s, 2H), 3.98(d, J ═ 6.6 Hz, 2H), 4.7.17, 7.6H, 2H), 3.7.7.7.5.7 (dd, 2H), 5.6H, 2H), 3.9.6 (dd, 2H), 3.3.3, 2H), 3.9.5.5.5.5.5H, 2H, 3, 2H, 3, 3.9, 2H), 1.23-1.12(m, 2H), 1.09(d, J ═ 4.4Hz, 2H). LCMS (ESI) m/z: [ M + H ]]+＝664。

EXAMPLE 51.5 preparation of- ((7- ((1- (4- (6-cyclopropyl-2-methyl-1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzyl) piperidin-4-yl) methyl) -7-azaspiro [3.5] nonan-2-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione

To 2- (2, 6-dioxopiperidin-3-yl) -5- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5]]Nonan-2-yl]Oxy radical]A stirred solution of isoindole-1, 3-dione (100.00mg, 0.202mmol, 1.00 equiv.) and 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (73.68mg, 0.202mmol, 1 equiv.) in MeOH (3.00mL) was added NaBH 3CN (25.41mg, 0.404mmol, 2 equiv.). Mixing the obtained mixture inStirred for 4 hours. Without any additional work-up, the mixture was passed through preparative HPLC (column: Kinetex EVO C18 column, 21.2X 150, 5 μm; mobile phase A: water (10mM NH)4HCO3) And the mobile phase B: ACN; flow rate: 25 mL/min; gradient: 25B to 50B in 12 minutes; 254/220 nm; RT 1: 11.92 min) to give 5- ([7- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl) as a white solid]Methyl radical]Piperidin-4-yl) methyl]-7-azaspiro [3.5]Nonan-2-yl]Oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (35mg, 20.53%).1H NMR(300MHz，DMSO-d6)δ11.13(s，1H)，9.29(s，1H)，8.19(s，2H)，7.87-7.74(m，2H)，7.44(s，1H)，7.35-7.21(m，2H)，6.74(s，2H)，5.12(dd，J＝12.8，5.4Hz，1H)，4.99(t，J＝6.9Hz，1H)，3.82(s，6H)，3.60(s，2H)，3.59-3.57(m，3H)2.93-2.84(m，4H)，2.63(s，1H)，2.62-2.60(s，1H)，2.55(s，3H)，2.23(d，J＝6.9Hz，3H)，2.20-2.15(s，1H)，2.10(dd，J＝15.2，4.6Hz，4H)，1.80(dd，J＝12.0，6.3Hz，2H)，1.69-1.60(m，4H)，1.60-1.50(m，2H)1.47(s，1H)，1.07(d，J＝11.5Hz，2H)，1.03-0.96(m，4H)。LCMS(ESI)m/z：[M+H]+＝843.55。

EXAMPLE 52 preparation of 3- [6- ([7- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] piperidin-4-yl) methyl ] -7-azaspiro [3.5] nonan-2-yl ] oxy) -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

To 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde) and 3- (1-oxo-6- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5] at room temperature]Nonan-2-yl]Oxy radical]-3H-isoindol-2-yl) piperidine-2, 6-dione) in DMF (10mL) was added NaBH (OAc) portionwise 3. The resulting mixture was stirred at room temperature for 12 hours. The crude product was purified by preparative HPLC to give 3- [6- ([7- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl) -2 as an off-white solid]Methyl radical]Piperidin-4-yl) methyl]-7-azaspiro [3.5]Nonan-2-yl]Oxy) -1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione (14.6mg, 8.0%).1H NMR (300MHz, methanol-d 4) δ 9.40(s, 1H), 7.76(s, 1H), 7.51(d, J ═ 8.4Hz, 1H), 7.42(d, J ═ 6.3Hz, 1H), 7.25-7.14(m, 2H), 6.89(s, 2H), 5.16(dd, J ═ 13.3, 5.1Hz, 1H), 4.92-4.83(m, 1H), 4.58-4.35(m, 4H), 3.99(s, 6H), 3.69(s, 3H), 3.67-3.44(m, 4H), 3.28-2.63(m, 9H), 2.61-2.46(m, 2H), 2.36-1.86(m, 11H), 1.68(q, J ═ 1.13, 1H), 1.23H (m, 4H). LCMS (ESI) m/z: [ M + H ]]+＝830.01。

Example preparation of 53-5- [7- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] azetidin-3-yl) methyl ] -2, 7-diazaspiro [3.5] nonan-2-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Step 1: preparation of 2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester

To a mixture of 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindole-1, 3-dione (5.00g, 18.101mmol, 1.00 equiv.) and 2, 7-diazaspiro [3.5]]A stirred solution of tert-butyl nonane-7-carboxylate (4.10g, 0.018mmol, 1 eq) in DMSO (50mL) was added DIEA (9.36g, 72.422mmol, 4.00 eq) and the resulting solution was dissolved in DMSOThe mixture was stirred under nitrogen for 4 hours. The resulting mixture was diluted with EtOAc (500mL) and the resulting mixture was washed with 3 × 300mL of water and 300mL of saturated brine. Subjecting the organic layer to Na2SO4Drying, filtering and evaporating to obtain 2- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] as a yellow solid]-2, 7-diazaspiro [3.5]Nonane-7-carboxylic acid tert-butyl ester (9g, crude). The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝483

Step 2: preparation of 5- [2, 7-diazaspiro [3.5] nonan-2-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

To 2- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl]-2, 7-diazaspiro [3.5]A solution of tert-butyl nonane-7-carboxylate (9.00g, 18.651mmol, 1.00 eq.) in DCM (90.00mL) was added TFA (30.00mL) and the resulting solution was dissolved inStirred for 1 hour. The resulting mixture was evaporated to dryness to give 5- [2, 7-diazaspiro [3.5] as a yellow solid]Nonan-2-yl]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (11.4g, crude), which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝383。

And step 3: preparation of tert-butyl 3- ([2- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] -2, 7-diazaspiro [3.5] nonan-7-yl ] methyl) azetidine-1-carboxylate

To 5- [2, 7-diazaspiro [3.5]]Nonan-2-yl](iii) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (3.00g, 7.845mmol, 1.00 equiv.) and a stirred solution of 3-formylazetidine-1-carboxylic acid tert-butyl ester (1.45g, 7.845mmol, 1.00 equiv.) in DMF (30.00mL) NaBH (OAc)3(3.33g, 15.690mmol, 2 equiv.) and the resulting solution was addedStirred for 12 hours. The reaction mixture was diluted with EA (500 mL). The resulting mixture was washed with 3 × 300mL water and 300mL saturated brine. Subjecting the organic layer to Na2SO4Drying, filtering and evaporating to obtain 3- ([2- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) as a yellow solid]-2, 7-diazaspiro [3.5]Nonan-7-yl]Methyl) azetidine-1-carboxylic acid tert-butyl ester (3.13g, 72.33%) which was used without further purification. LCMS (ESI) m/z: [ M + H ] ]+＝552

And 4, step 4: preparation of 5- [7- (azetidin-3-ylmethyl) -2, 7-diazaspiro [3.5] nonan-2-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

To 3- ([2- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl)]-2, 7-diazaspiro[3.5]Nonan-7-yl]Methyl) azetidine-1-carboxylic acid tert-butyl ester (3.13g, 5.674mmol, 1.00 equiv.) in DCM (30.00mL) was added TFA (10.00mL) and the resulting solution was stirred inStirred for 1 hour. The resulting mixture was evaporated to dryness to give 5- [7- (azetidin-3-ylmethyl) -2, 7-diazaspiro [3.5] as a yellow solid]Nonan-2-yl]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (4.1g, crude), which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝452

And 5: preparation of 5- [7- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] azetidin-3-yl) methyl ] -2, 7-diazaspiro [3.5] nonan-2-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

To 5- [7- (azetidin-3-ylmethyl) -2, 7-diazaspiro [3.5]]Nonan-2-yl]A stirred solution of (E) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (110.00mg, 0.244mmol, 1.00 equiv.) and 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (88.77mg, 0.244mmol, 1.00 equiv.) in MeOH (2.00mL, 24.699mmol, 1115.22 equiv.) is added NaBH 3CN (30.62mg, 0.487mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture solution was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 5B to 27B; 254/220 nm; RT 1: 12.38 min) to give 5- [7- [ (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl) as a yellow solid]Methyl radical]Azetidin-3-yl) methyl]-2, 7-diazaspiro [3.5]Nonan-2-yl]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (63.9mg, 3)1.71％)。LCMS(ESI)m/z：[M+H]+＝800。1H NMR (400MHz, methanol-d 4) δ 9.39(s, 1H), 7.79(d, J ═ 6.3Hz, 1H), 7.68(d, J ═ 8.4, 1.2Hz, 1H), 7.41(d, J ═ 2.9Hz, 1H), 6.88(s, 3H), 6.76-6.67(m, 1H), 5.13-5.02(m, 1H), 4.55(d, 2H), 4.40(t, J ═ 9.3Hz, 2H), 4.29-4.11(m, 2H), 4.05-3.76(m, 10H), 3.69(s, 3H), 3.61-3.43(m, 5H), 3.22-2.98(m, 2H), 2.94-2.80(m, 1H), 2.65(m, 2.79-2H), 1.93-1H, 14H, 1H), 14.9.9, 1H, 14H, 1H, and 1H.

EXAMPLE 54 preparation of 5- [4- [2- (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] piperidin-4-yl) ethyl ] piperazin-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Step 1: 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindole-1, 3-dione (3.00g, 10.861mmol, 1.00 equiv.) and piperazine-1-carboxylic acid tert-butyl ester (2.02g, 10.861mmol, 1.00 equiv.) in NMP (30.00mL) was added DIPEA (4.21g, 32.574mmol, 3.00 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 2 hours. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 5% to 90% over 30 min; detector, UV 254 nm. This gives 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-1 as a yellow solidIsoindol-5-yl radical]Piperazine-1-carboxylic acid tert-butyl ester (1.6g, 33.29%). LCMS (ESI) m/z: [ M + H ]]+＝443。

Step 2: 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindole-1, 3-dione

To a stirred solution of tert-butyl 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperazine-1-carboxylate (2.10g, 4.746mmol, 1.00 eq) in DCM (32.00mL) was added TFA (8.00 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindol-1, 3-dione as a yellow solid (2.6g, 160%). It was used without further purification. LCMS (ESI) m/z: [ M + H ] + -343.

And step 3: 4- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] ethyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindole-1, 3-dione (2.00g, 5.842mmol, 1.00 eq) in DMF (25.00mL) under nitrogen atmosphere was added tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (1.33g, 5.842mmol, 1.00 eq). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 16 hours. In thatAdd NaBH (OAc) to the mixture3(2.48g, 11.684mmol, 2.00 equiv.). Mixing the obtained mixture inFollowed by stirring for an additional 2 hours. The resulting mixture was diluted with water (70 mL). The aqueous layer was extracted with EtOAc (4 × 30 mL). The organic layer was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with DCM: MeOH (50: 1 to 10: 1) to give 4- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) as a yellow oil]Piperazin-1-yl]Ethyl) piperidine-1-carboxylic acid tert-butyl ester (3g, 92.75%). LCMS (ESI) m/z: [ M + H ]]+＝555。

And 4, step 4: 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperidin-4-yl) ethyl ] piperazin-1-yl ] isoindole-1, 3-dione

To a stirred solution of tert-butyl 4- (2- [4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] ethyl) piperidine-1-carboxylate (3.00g, 5.418mmol, 1.00 equiv.) in DCM (20.00mL) was added TFA (5.00mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to give 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperidin-4-yl) ethyl ] piperazin-1-yl ] isoindol-1, 3-dione as a yellow oil (3.5g, 126.33%). It was used without further purification. LCMS (ESI) m/z: [ M + H ] + ═ 454.

And 5: 5- [4- [2- (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] piperidin-4-yl) ethyl ] piperazin-1-yl ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

To 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (150.00mg, 0.412mmol, 1.00 equiv.) and 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperidin-4-yl) ethyl ] ethyl at room temperature under an air atmosphere]Piperazin-1-yl]Isoindole-1, 3-dione (186.69mg, 0.412mmol, 1.00 equiv.) inA stirred solution in DMF (3.00mL) was added NaBH (OAc) dropwise3(261.73mg, 1.235mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture solution was purified by preparative HPLC using the following conditions (column: XSelect CSH F-Phenyl OBD column, 19X 250, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 12B to 12B; 254/220 nm; RT 1: 11.13 min) to give 5- [4- [2- (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] as a pale yellow solid]Methyl radical]Piperidin-4-yl) ethyl]Piperazin-1-yl ]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (62mg, 18.78%). LCMS (ESI) m/z: [ M + H ]]+＝802.30。1H NMR(400MHz，DMSO-d6)δ9.30(s，1H)，7.83(d，J＝1.7Hz，1H)，7.77(dd，J＝8.4，4.8Hz，1H)，7.51-7.40(m，2H)，7.40-7.32(m，1H)，6.85(s，2H)，5.13-5.03(m，1H)，4.24(s，4H)，3.88(s，6H)，3.57(s，5H)，3.44(d，J＝11.9Hz，2H)，3.20(q，J＝10.4，9.5Hz，6H)，3.02(t，J＝12.2Hz，2H)，2.94-2.80(m，1H)，2.65-2.56(m，1H)，2.54(d，J＝4.9Hz，1H)，2.30-2.19(m，1H)，2.08-1.99(m，1H)，1.91-1.70(m，3H)，1.67-1.41(m，4H)，1.11-0.98(m，4H)。

EXAMPLE 55 preparation of 3- (6- [4- [2- (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl ] methyl ] piperidin-4-yl) ethyl ] piperazin-1-yl ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione carboxylic acid

To 3- (1-oxo-6- [4- [2- (piperidin-4-yl) ethyl group]Piperazin-1-yl](iii) -3H-isoindol-2-yl) piperidine-2, 6-dione (160.00mg, 0.364mmol, 1.00 equiv.) and a stirred solution of 4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde (132.64mg, 0.364mmol, 1.00 equiv.) in DMF (2.00mL) NaBH (AcO)3(154.29mg, 0.728mmol, 2.00 equivalents) and titanium isopropoxide (10.35mg, 0.036mmol, 0.10 equivalents). Mixing the obtained mixtureStirred at room temperature for 28 hours. The mixture solution was purified by preparative HPLC using the following conditions: column: xselect CSH F-Phenyl OBD column, 19 x 250, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 8B to 19B in 10 minutes; 220/254 nm; RT 1: 8.28 minutes. This gave 3- (6- [4- [2- (1- [ [4- (6-cyclopropyl-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) -2, 6-dimethoxyphenyl) -2-methyl-4-oxo-2, 7-naphthyridin-4-yl ] -phenyl as a white solid ]Methyl radical]Piperidin-4-yl) ethyl]Piperazin-1-yl]-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione; formic acid (16.6mg, 5.78%). LCMS (ESI) m/z: [ M + H ]]+＝788。1H NMR(400MHz，DMSO-d6)δ10.98(s，1H)，9.28(s，1H)，8.18(s，4H，FA)，7.80(s，1H)，7.45-7.39(m，2H)，7.26(dd，J＝8.4，2.4Hz，1H)，7.16(d，J＝2.4Hz，1H)，6.74(s，2H)，5.10(dd，J＝13.3，5.1Hz，1H)，4.39-4.16(m，2H)，3.82(s，6H)，3.60(s，3H)，3.56(s，4H)，3.18(s，5H)，2.90(d，J＝11.6Hz，3H)，2.73-2.56(m，3H)，2.35-2.32(m，2H)，2.30-2.22(m，1H)，2.18-2.08(m，2H)，2.05-1.90(m，1H)，1.64(d，J＝12.3Hz，2H)，1.39(d，J＝7.7Hz，2H)，1.26-1.19(m，1H)，1.19-1.09(m，2H)，0.99(dd，J＝10.0，3.7Hz，4H)。

EXAMPLE 56 preparation of 4- (6-cyclopropyl-2- (methyl-d 3) -1-oxo-1, 2-dihydro-2, 7-naphthyridin-4-yl) -2, 6-dimethoxybenzaldehyde

Step 1: preparation of 6-chloro-2- (2H3) methyl-2, 7-naphthyridin-1-one

A solution of 6-chloro-2H-2, 7-naphthyridin-1-one (500.00mg, 2.769mmol, 1.00 eq.) in THF (5.00mL) was dissolved in waterAdding NaH (132.89mg, 5.537 mmo)l, 2.00 eq) for 5 minutes, followed byAddition of CD in portions3I (802.69mg, 5.537mmol, 2.00 equiv.). In thatAfter stirring for 1 hour, the reaction mixture was poured into ice water (50mL), the precipitated solid was collected by filtration and washed with water (3 × 50mL), then the solid was dried under vacuum to give 6-chloro-2- (2H3) methyl-2, 7-naphthyridin-1-one (500mg, 91.37%) as a pale yellow solid, which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝198。

Step 2: preparation of 6-cyclopropyl-2- (2H3) methyl-2, 7-naphthyridin-1-one

Mixing 6-chloro-2- (2H3) methyl-2, 7-naphthyridin-1-one (400.00mg, 2.024mmol, 1.00 equiv.), cyclopropylboronic acid (260.78mg, 3.036mmol, 1.50 equiv.), K 3PO4(1288.81mg, 6.072mmol, 3.00 equiv.), PCy3(113.51mg, 0.405mmol, 0.20 eq.) and Pd (AcO)2(45.44mg, 0.202mmol, 0.10 equiv.) in toluene (20.00mL) and H2Mixture in O (1.00mL)The mixture was stirred under nitrogen for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (10: 1) afforded 6-cyclopropyl-2- (2H3) methyl-2, 7-naphthyridin-1-one (350mg, 85.08%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝204

And step 3: preparation of 4-bromo-6-cyclopropyl-2- (2H3) methyl-2, 7-naphthyridin-1-one

A mixture of 6-cyclopropyl-2- (2H3) methyl-2, 7-naphthyridin-1-one (300.00mg, 1.476mmol, 1.00 equiv.) and NBS (315.23mg, 1.771mmol, 1.20 equiv.) in ACN (3.00mL) was addedStirred for 2 hours. The resulting mixture was diluted with 1x50mL water. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 50mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to give 4-bromo-6-cyclopropyl-2- (2H3) methyl-2, 7-naphthyridin-1-one (350mg, 84.04%) as a yellow solid, which was used without further purification. LCMS (ESI) m/z: [ M + H ] ]+＝282。

And 4, step 4: preparation of 4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde

4-bromo-6-cyclopropyl-2- (2H3) methyl-2, 7-naphthyridin-1-one (350.00mg, 1.240mmol, 1.00 equiv.), 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (434.86mg, 1.489mmol, 1.20 equiv.), Cs2CO3(808.33mg, 2.481mmol, 2.00 equiv.) and Pd (dppf) Cl2(90.76mg, 0.124mmol, 0.10 equiv.) in dioxane (3.00mL) and H2Mixture in O (1.00mL)The mixture was stirred under nitrogen for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluting with MeOH (10: 1) to give 4- [ 6-cyclopropyl-2 (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl as an orange solid]-2, 6-dimethoxybenzaldehyde (200mg, 43.88)％)。LCMS(ESI)m/z：[M+H]+＝368。

Example preparation of 5- (7- [ [1- ([4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidin-3-yl ] methyl ] -2, 7-diazaspiro 13.5] nonan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid

4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl ]-2, 6-dimethoxybenzaldehyde (120.00mg, 0.327mmol, 1.00 equiv.), 2- (2, 6-dioxopiperidin-3-yl) -5- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5]]Nonan-2-yl]Oxy radical]Isoindole-1, 3-dione (161.54mg, 0.327mmol, 1.00 eq.) and NaBH (AcO)3A mixture of (138.44mg, 0.653mmol, 2.00 equiv.) in DMF (3.00mL) was stirred at room temperature for 2 h. The mixture was purified by preparative HPLC without any additional work-up under the conditions (column: XSelect CSH Prep C18 OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 10B to 18B within 15 minutes; 254/220 nm; RT 1: 12.37; RT 2:; injection volume: mL; run number) to give 5- (7- [ [1- ([4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid]-2, 6-dimethoxyphenyl]Methyl) azetidin-3-yl]Methyl radical]-2, 7-diazaspiro [3.5]Nonan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione; formic acid (12.2 mg).1H NMR(400MHz，DMSO-d6)δ11.08(s，1H)，9.29(s，1H)，8.20(s，1H，FA)，7.78(s，1H)，7.64(d，J＝8.2Hz，1H)，7.40(s，1H)，6.76(d，J＝4.0Hz，3H)，6.64(dd，J＝8.4，2.1Hz，1H)，5.05(dd，J＝12.9，5.4Hz，1H)，3.84(s，6H)，3.79(s，2H)，3.74(s，4H)，3.55(s，3H)，3.13(s，3H)，2.97-2.79(m，1H)，2.71-2.56(m，2H)，2.46(d，J＝7.0Hz，2H)，2.36-2.21(m，4H)，2.05-1.95(m，1H)，1.78-1.69(m，4H)，1.00(dd，J＝6.6，4.3Hz，4H)。LCMS(ESI)m/z：[M+H]+＝803。

Example preparation of 58-5- [ (7- [ [1- ([4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] methyl ] -7-azaspiro [3.5] nonan-2-yl) oxy ] -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl]-2, 6-dimethoxybenzaldehyde (60.00mg, 0.163mmol, 1.00 equiv.), 2- (2, 6-dioxopiperidin-3-yl) -5- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5 ]]Nonan-2-yl]Oxy radical]Isoindole-1, 3-dione (80.77mg, 0.163mmol, 1.00 eq.) and NaBH (AcO)3A mixture of (69.22mg, 0.327mmol, 2.00 equiv.) in DCM (2.00mL) was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19 x 250mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 16B to 21B; 254/220 nm; RT 1: 10.97 min) to give 5- [ (7- [ [1- ([4- [ 6-cyclopropyl-2- (2H3) methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]Methyl radical]-7-azaspiro [3.5]Nonan-2-yl) oxy]-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (11.1 mg).1H NMR (300MHz, methanol-d 4) δ 9.38(s, 1H), 8.56(s, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.66(s, 1H), 7.38(d, J ═ 0.9Hz, 1H), 7.31-7.20(m, 2H), 6.86(s, 2H), 5.13(dd, J ═ 12.4, 5.4Hz, 1H), 4.32(s, 2H), 3.97(s, 6H), 3.50(d, J ═ 12.2Hz, 2H), 3.03(s, 2H), 2.91-2.70(m, 3H), 2.51(d, J ═ 8.6Hz, 6H), 2.33(d, J ═ 6.7, 2H), 2.21-2.08(m, 2H), 1.83 (m, 1H), 1.07 (m, 1H), 1.3.3.3.3.3H, 1H, and 1H. LCMS (ESI) m/z: [ M + H ] ]+＝846。

EXAMPLE 59 preparation of 5- (4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-6- (oxetan-3-yl) -1-oxo-2, 7-naphthyridin-4-yl ] phenyl ] methyl) piperazin-1-yl ] ethyl ] piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione carboxylic acid

Step 1: preparation of 2-methyl-6- (oxetan-3-yl) -2, 7-naphthyridin-1-one

To a solution of 6-chloro-2-methyl-2, 7-naphthyridin-1-one (300.0mg, 1.541mmol, 1.00 equiv.) and 3-bromooxetane (422.3mg, 3.083mmol, 2.00 equiv.) in DMF (3.00mL) was added Zn (302.5mg, 4.624mmol, 3.00 equiv.) and NaI (57.8mg, 0.385mmol, 0.25 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 12 hours. The resulting mixture was concentrated. The crude mixture was directly purified by passing through a reverse phase column (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient: 8% B to 80% B over 20 min; 254/220nm) to give 2-methyl-6- (oxetan-3-yl) -2, 7-naphthyridin-1-one (150mg, 45.0%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝217。

Step 2: preparation of 4-bromo-2-methyl-6- (oxetan-3-yl) -2, 7-naphthyridin-1-one

To a solution of 2-methyl-6- (oxetan-3-yl) -2, 7-naphthyridin-1-one (100.0mg, 0.462mmol, 1.00 equiv) in DMF (3.00mL) was added NBS (90.5mg, 0.509mmol, 1.10 equiv). Mixing the obtained mixture in Stirring at the lower part for 2 hoursThen (c) is performed. The resulting mixture was concentrated. The crude mixture was directly purified by passing through a reverse phase column using the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient: 8% B to 80% B over 20 min; 254/220nm) to give 4-bromo-2-methyl-6- (oxetan-3-yl) -2, 7-naphthyridin-1-one (105mg, 76.9%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝295。

And step 3: preparation of 2, 6-dimethoxy-4- [ 2-methyl-6- (oxetan-3-yl) -1-oxo-2, 7-naphthyridin-4-yl ] benzaldehyde

To 4-bromo-2-methyl-6- (oxetan-3-yl) -2, 7-naphthyridin-1-one (100.0mg, 0.339mmol, 1.00 equiv.) and 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (148.5mg, 0.508mmol, 1.50 equiv.) in dioxane (3.00mL) and H under a nitrogen atmosphere2Solution in O (1.00mL) with addition of Cs2CO3(331.2mg, 1.016mmol, 3.00 eq.) and Pd (dppf) Cl2(24.8mg, 0.034mmol, 0.10 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 3 hours. The resulting mixture was concentrated. The crude mixture was directly purified by passing through a reverse phase column under the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient: 8% B to 80% B in 20 minutes; 254/220nm) to obtain. This gave (130mg, crude) 2, 6-dimethoxy-4- [ 2-methyl-6- (oxetan-3-yl) -1-oxo-2, 7-naphthyridin-4-yl as a yellow solid ]Benzaldehyde (110mg, 85.3%). LCMS (ESI) m/z: [ M + H ]]+＝381。

And 4, step 4: 5- (4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-6- (oxetan-3-yl) -1-oxo-2, 7-naphthyridin-4-yl ] phenyl ] methyl) piperazin-1-yl ] ethyl ] piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione; preparation of formic acid

To 2, 6-dimethoxy-4- [ 2-methyl-6- (oxetan-3-yl) -1-oxo-2, 7-naphthyridin-4-yl group at room temperature]Benzaldehyde (50.0mg, 0.131mmol, 1.00 equiv.) and 2- (2, 6-dioxopiperidin-3-yl) -5- [4- [2- (piperazin-1-yl) ethyl]Piperidin-1-yl radical]A stirred mixture of isoindole-1, 3-dione (65.6mg, 0.145mmol, 1.10 equiv.) in DMF (2.00mL) was added NaBH (OAc)3(55.72mg, 0.263mmol, 2.00 equiv.). The mixture was stirred for 3 hours. The crude reaction mixture was then directly purified by preparative HPLC (column: XSelect CSH F-Phenyl OBD column, 19 x 250mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 15% B to 24% B in 14 min; 254/220 nm; Rt: 12.97 min). This gives 5- (4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-6- (oxetan-3-yl) -1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid ]Phenyl radical]Methyl) piperazin-1-yl]Ethyl radical]Piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione; formic acid (40mg, 37.2%).1H NMR(400MHz，DMSO-d6)δ11.08(s，1H)，9.50(s，1H)，8.15(s，1H，FA)，7.87(s，1H)，7.65(d，J＝8.5Hz，1H)，7.46(s，1H)，7.30(d，J＝2.2Hz，1H)，7.23(dd，J＝8.8，2.3Hz，1H)，6.74(s，2H)，5.07(dd，J＝13.0，5.3Hz，1H)，4.89(dd，J＝8.4，5.5Hz，2H)，4.79(dd，J＝6.7，5.5Hz，2H)，4.59-4.47(m，1H)，4.04(d，J＝13.0Hz，2H)，3.81(s，6H)，3.58(d，J＝8.8Hz，6H)，3.00-2.82(m，3H)，2.73-2.57(m，4H)，2.55-2.41(m，4H)，2.40-2.23(m，3H)，2.05-1.97(m，1H)，1.78-1.71(m，2H)，1.66-1.51(m，1H)，1.42-1.34(m，2H)，1.24-1.11(m，2H)。LCMS(ESI)m/z：[M+H]+＝818.60。

EXAMPLE 60 preparation of 3- [5- (4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-1-oxo-6- (trifluoromethyl) -2, 7-naphthyridin-4-yl ] phenyl ] methyl) piperazin-1-yl ] ethyl ] piperidin-1-yl) -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

Step 1: preparation of 4-methyl-6- (trifluoromethyl) pyridine-3-carbonitrile

To a mixture of 5-bromo-4-methyl-2- (trifluoromethyl) pyridine (500.00mg, 2.083mmol, 1.00 eq.) and Zn (CN)2(146.79mg, 1.250mmol, 0.6 equiv.) in DMF (5.00mL) was added Pd2(dba)3(38.15mg, 0.042mmol, 0.02 equiv.) and DPPF (46.03mg, 0.083mmol, 0.04 equiv.), and the resulting solution was dissolved inStirred for 3 hours. Without any additional work-up, the mixture was purified by flash C18-flash chromatography with an elution gradient of 0% to 80% in water (containing 0.1% NH)4HCO3) MeCN in (1). The pure fractions were evaporated to dryness to give 4-methyl-6- (trifluoromethyl) pyridine-3-carbonitrile as a yellow oil (220mg, 56.74%). LCMS (ESI) m/z: [ M + H ]]+＝187。

Step 2: preparation of 4-methyl-6- (trifluoromethyl) pyridine-3-carboxamide

To 4-methyl-6- (trifluoromethyl) pyridine-3-carbonitrile (200.00mg, 1.074mmol, 1.00 equiv.) and NH 3.H2A stirred solution of O (1.00mL) in EtOH (1.00mL) was added H2O2(0.20mL) and the resulting solution was added toStirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give 4-methyl-6- (trifluoromethyl) pyridine-3-carboxamide (372mg, crude product) as a white solidUsed without further purification. LCMS (ESI) m/z: [ M + H ]]+＝205。

And step 3: preparation of N- [ (1Z) - (dimethylamino) methylene ] -4-methyl-6- (trifluoromethyl) pyridine-3-carboxamide

To a stirred solution of 4-methyl-6- (trifluoromethyl) pyridine-3-carboxamide (350.00mg, 1.714mmol, 1.00 equiv.) and DMF-DMA (306.44mg) in 2-methyltetrahydrofuran (5.00mL) was addedStirred for 2 hours. The mixture was then concentrated under reduced pressure to give N- [ (1z) - (dimethylamino) methylene group as a yellow solid]-4-methyl-6- (trifluoromethyl) pyridine-3-carboxamide (360mg crude) which was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝260。

And 4, step 4: preparation of 6- (trifluoromethyl) -2H-2, 7-naphthyridin-1-one

To N- [ (1Z) - (dimethylamino) methylene group]A stirred solution of (E) -4-methyl-6- (trifluoromethyl) pyridine-3-carboxamide (350.00mg, 1.350mmol, 1.00 equiv.) and t-BuOK (227.25mg, 2.025mmol, 1.50 equiv.) in THF (4.00mL) was dissolved in water Stirred for 2 hours. The resulting mixture was cooled and concentrated under reduced pressure, and the residue was taken up in saturated NaHCO3The solution (100mL) was washed. The solid was then dried under vacuum to give 6- (trifluoromethyl) -2H-2, 7-naphthyridin-1-one (295mg, crude) as an off-white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝215。

And 5: preparation of 2-methyl-6- (trifluoromethyl) -2, 7-naphthyridin-1-one

In thatTo a stirred mixture of 6- (trifluoromethyl) -2H-2, 7-naphthyridin-1-one (275.00mg, 1.284mmol, 1.00 equiv.) in anhydrous DMF (3.00mL) was added NaH (36.98mg, 1.541mmol, 1.20 equiv., 60%) in portions. After 10 minutes, inMeI (546.82mg, 3.852mmol, 3.00 equiv.) was added to the above mixture, and the mixture was stirred inStirred for 10 minutes. The mixture was then stirred at room temperature under nitrogen atmosphere for 12 hours. The crude solid was slurried with water (100mL), and the solid was filtered and collected to give 2-methyl-6- (trifluoromethyl) -2, 7-naphthyridin-1-one (242mg, 82.59%) as a yellow solid, which was used directly without further purification. LCMS (ESI) m/z: [ M + H ]]+＝229。

Step 6: preparation of 4-bromo-2-methyl-6- (trifluoromethyl) -2, 7-naphthyridin-1-one

To a stirred mixture of 2-methyl-6- (trifluoromethyl) -2, 7-naphthyridin-1-one (220.00mg, 0.964mmol, 1.00 equiv.) in anhydrous DMF (5.00mL) was added NBS (188.77mg, 1.061mmol, 1.10 equiv.) and the mixture was stirredStirred for 2 hours. Without any additional work-up, the residue was purified by preparative TLC (PE/EtOAc 1: 1) to give a white solid4-bromo-2-methyl-6- (trifluoromethyl) -2, 7-naphthyridin-1-one (192mg, 64.85%) of the body. LCMS (ESI) m/z: [ M + H ]]+＝307。

And 7: preparation of 2, 6-dimethoxy-4- [ 2-methyl-1-oxo-6- (trifluoromethyl) -2, 7-naphthyridin-4-yl ] benzaldehyde

To a solution of 4-bromo-2-methyl-6- (trifluoromethyl) -2, 7-naphthyridin-1-one (142.00mg, 0.462mmol, 1.00 equiv.) and 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (189.13mg, 0.647mmol, 1.4 equiv.) in dioxane (3.00mL) was added pd (dppf) Cl2(33.84mg, 0.046mmol, 0.10 equiv.) and Cs2CO3(301.34mg, 0.925mmol, 2 equiv.) and the resulting solution was addedStirred for 3 hours. Without any additional work-up, the residue is passed over with CH2Cl2Purification by column chromatography on silica gel eluting with MeOH (10: 1) to give 2, 6-dimethoxy-4- [ 2-methyl-1-oxo-6- (trifluoromethyl) -2, 7-naphthyridin-4-yl as a brown solid ]Benzaldehyde (275mg, crude), which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝393。

And 8: preparation of 3- [5- (4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-1-oxo-6- (trifluoromethyl) -2, 7-naphthyridin-4-yl ] phenyl ] methyl) piperazin-1-yl ] ethyl ] piperidin-1-yl) -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

To 2, 6-dimethoxy-4- [ 2-methyl-1-oxo-6- (trifluoromethyl) -2, 7-naphthyridin-4-yl]Benzaldehyde (78.00mg, 0.199mmol, 1.00 equiv.) and 3- (1-oxo-5- [4- [2- (piperazin-1-yl) ethyl]Piperidin-1-yl radical]-3H-isoindole(iii) -2-Yl) piperidine-2, 6-dione (131.08mg, 0.298mmol, 1.50 equiv.) in DMF (2.00mL) NaBH (OAc)3(84.27mg, 0.398mmol, 2 equiv.) and the resulting solution was dissolved inStirred for 12 hours. The mixture was purified by preparative HPLC (column: SunAire Prep C18 OBD column, 19X 150mm 5 μm 10 nm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 10B to 32B; 254/220 nm; RT 1: 8.95 min) without any additional work-up to give 3- [5- (4- [2- [4- ([2, 6-dimethoxy-4- [ 2-methyl-1-oxo-6- (trifluoromethyl) -2, 7-naphthyridin-4-yl) as a pale brown solid ]Phenyl radical]Methyl) piperazin-1-yl]Ethyl radical]Piperidin-1-yl) -1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione (25mg, 15.41%).1H NMR(400MHz，DMSO-d6)δ10.96(s，1H)，9.59(s，1H)，8.08(s，1H)，7.93(s，1H)，7.52(d，J＝8.5Hz，1H)，7.06(d，J＝8.2Hz，2H)，6.94(d，J＝18.1Hz，2H)，5.05(dd，J＝13.4，5.1Hz，1H)，4.38-4.15(m，3H)，3.87(s，8H)，3.67(s，3H)，3.63(s，3H)，3.11-3.25(m，4H)，2.87(dt，J＝36.3，12.4Hz，6H)，2.59(d，J＝18.0Hz，2H)，2.36-2.29(m，1H)，2.00-1.91(m，1H)，1.75(d，J＝12.5Hz，2H)，1.57(s，3H)，1.25(d，J＝11.0Hz，2H)。LCMS(ESI)m/z：[M+H]+＝816.15。

EXAMPLE 61 preparation of 3- [5- [7- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione carboxylic acid

Step 1: preparation of 6- (azetidin-1-yl) -4-bromo-2-methyl-2, 7-naphthyridin-1-one

To a solution of 4-bromo-6-chloro-2-methyl-2, 7-naphthyridin-1-one (5.00g, 18.281mmol, 1.00 equiv.) and azetidine hydrochloride (3.2g, 54.843mmol, 3 equiv.) in DMSO (50.00mL) was added K2CO3(12.6g, 91.404mmol, 5 equiv.). The obtained solution is mixed inStirred for 2 hours. The resulting mixture was cooled and diluted with water (100mL) then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated NaCl solution (3 × 50mL) over anhydrous Na2SO4Drying and concentration under reduced pressure gave 6- (azetidin-1-yl) -4-bromo-2-methyl-2, 7-naphthyridin-1-one (3.7g, 68.8%) as a grey solid which was used without further purification. LCMS (ESI) m/z: [ M + H ]]+＝294。

Step 2: preparation of 4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde

To 6- (azetidin-1-yl) -4-bromo-2-methyl-2, 7-naphthyridin-1-one (1.42g, 4.827mmol, 1.00 equiv.) and 4-formyl-3, 5-dimethoxyphenylboronic acid (1.52g, 7.241mmol, 1.5 equiv.) in dioxane (16.00mL) and H2Solution in O (4.00mL) was added Pd (dppf) Cl2(353.2mg, 0.483mmol, 0.1 equiv.) and Cs2CO3(3.15g, 9.655mmol, 2 equiv.) and dissolving the resulting solution inStirred for 2 hours. The resulting mixture was cooled and concentrated under reduced pressure. The residue was slurried with water (30mL) and filtered, collecting the filter cake. And the solid was further slurried with MeOH (30mL) and filtered. The solid was collected to give the product as a grey and solid 4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthalenePyridin-4-yl]-2, 6-dimethoxybenzaldehyde (1.42g, 77.5%). LCMS (ESI) m/z: [ M + H ]]+＝380。

EXAMPLE 62 preparation of 3- [5- [7- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione carboxylic acid

Step 1: preparation of 2- [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl ] -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester

To 2- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl]-2, 7-diazaspiro [3.5]A stirred solution of tert-butyl nonane-7-carboxylate (500.0mg, 1.036mmol, 1.00 equiv.) in AcOH (4.00mL) was added Zn (677.7mg, 10.362mmol, 10.00 equiv.). Mixing the obtained mixture inStirred for 2 hours. The reaction mixture was filtered and the filtrate was evaporated to give the crude product. The crude product was purified by reverse phase column eluting with a gradient of 0% to 30% MeCN in water (containing 0.1% formic acid). The pure fractions were evaporated to dryness to give 2- [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl as a yellow solid]-2, 7-diazaspiro [3.5]Nonane-7-carboxylic acid tert-butyl ester (277.3mg, 55.2%). LCMS (ESI) m/z: [ M + H ]]+＝485。

Step 2: preparation of 3- (5- [2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

To 2- [2- (2, 6-dioxopiperidin-3-yl) -3-hydroxy-1-oxo-3H-isoindol-5-yl]-2, 7-diazaspiro [3.5]A stirred solution of nonane-7-carboxylic acid tert-butyl ester (250.0mg, 0.516mmol, 1.00 eq) in DCM (2.00mL) was added TFA (0.50mL) and Et3SiH (0.20 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This gives 3- (5- [2, 7-diazaspiro [3.5] as a yellow gum ]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione (267.5mg, crude). The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝369。

And step 3: 3- [5- [7- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione; preparation of formic acid

To 3- (5- [2, 7-diazaspiro [3.5] at room temperature]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione (400.0mg, 1.086mmol, 1.00 equiv.) and 4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl]A stirred solution of (494.3mg, 1.303mmol, 1.20 equiv.) 2, 6-dimethoxybenzaldehyde in DMF (3.00mL) was added NaBH (OAc)3(920.4mg, 4.343mmol, 4.00 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The crude reaction solution was directly purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 14B to 22B within 15 min; 254/220 nm; RT 1: 11.72 min) to give 3- [6- [7- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid ]-2, 6-dimethoxyphenyl]Methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-bisA ketone; formic acid (99.2mg, 12.5%).1H NMR(400MHz，DMSO-d6)δ10.94(s，1H)，9.02(s，1H)，8.15(s，1H，FA)，7.61(s，1H)，7.48(d，J＝8.2Hz，1H)，6.75(s，2H)，6.53-6.44(m，2H)，6.21(s，1H)，5.04(dd，J＝13.3，5.2Hz，1H)，4.30(d，J＝17.0Hz，1H)，4.17(d，J＝16.9Hz，1H)，4.01(t，J＝7.4Hz，4H)，3.83(s，6H)，3.61(d，J＝13.2Hz，6H)，3.48(s，3H)，2.96-2.84(m，1H)，2.63-2.54(m，3H)，2.51-2.45(m，2H)，2.35(q，J＝6.6Hz，3H)，1.95(d，J＝12.9Hz，1H)，1.75(s，4H)。LCMS(ESI)m/z：[M+H]+＝732.45。

EXAMPLE 63 preparation of 3- [5- (7- [ [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidin-3-yl ] methyl ] -2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione bis (carboxylic acid)

Step 1: preparation of methyl 5-bromo-2- (bromomethyl) benzoate

A solution of methyl 5-bromo-2-methylbenzoate (1.0g, 4.365mmol, 1.00 equiv.), BPO (223.7mg, 0.873mmol, 0.20 equiv.), and NBS (777.0mg, 4.365mmol, 1.00 equiv.) in solvent CCl4(10.00mL) was dissolved inStirred for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column eluted with petroleum ether/EtOAc (20: 1) to give methyl 5-bromo-2- (bromomethyl) benzoate (1.1g, 81.8%) as a pale yellow liquid.

Step 2: preparation of 3- (6-bromo-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

DIEA (1.26g, 9.741mmol, 3.00 equiv.) was added to a solution of methyl 5-bromo-2- (bromomethyl) benzoate (1.0g, 3.247mmol, 1.00 equiv.), 3-aminopiperidine-2, 6-dione (499.26mg, 3.896mmol, 1.20 equiv.) in solvent DMF (10.00mL) at room temperature, and the resulting solution was dissolved in DMF Stirred for 12 hours. The resulting mixture was concentrated. The residue was dissolved in water (100mL) and washed with 30% i-PrOH/CH2Cl2(100 mL. times.3) extraction. The combined organic layers were washed with brine (100mL) and dried over anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave 3- (6-bromo-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione as a grey solid (500mg, 47.7%). LCMS (ESI) m/z: [ M + H ]]+＝323。

And step 3: preparation of 4- [6- [7- (tert-butoxycarbonyl) -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl ] -4-carbamoylbutyric acid

To 3- (6-bromo-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione (500.0mg, 1.547mmol, 1.00 eq.) 2, 7-diazaspiro [3.5] under nitrogen]Nonane-7-carboxylic acid tert-butyl ester (350.2mg, 1.547mmol, 1.00 equiv.), Cs2CO3(1.51g, 4.642mmol, 3.00 equiv.) and Ruphos Palladacycle Gen 3(129.4mg, 0.155mmol, 0.10 equiv.) solvent dioxane (5.00mL) was added and the resulting mixture was added to a flaskThe mixture was stirred under nitrogen for 6 hours. The resulting mixture was concentrated. The crude product is passed through a reverse phase column under the conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL-min; gradient: 8% B to 80% B in 20 minutes; 254/220nm) to give 4- [6- [7- (tert-butoxycarbonyl) -2, 7-diazaspiro [3.5] as a yellow solid ]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl]-4-carbamoyl butyric acid (150mg, 19.9%). LCMS (ESI) m/z: [ M + H ]]+＝487。

And 4, step 4: preparation of 2- [2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1H-isoindol-5-yl ] -2, 7-2-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester

To 4- [6- [7- (tert-butoxycarbonyl) -2, 7-diazaspiro [3.5]]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl]-4-carbamoyl butyric acid (200.0mg, 0.411mmol, 1.00 equiv.) in solvent CH3CN (5.00mL) was added CDI (133.3mg, 0.822mmol, 2.00 equiv). The obtained solution is mixed inStirred for 6 hours. The resulting mixture was concentrated. The crude product was directly purified by passing through a reverse phase column under the conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient: 8% B to 80% B in 20 minutes; 254/220nm) to give 2- [2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1H-isoindol-5-yl as a yellow solid]-2, 7-diazaspiro [3.5]Nonane-7-carboxylic acid tert-butyl ester (170mg, 88.3%). LCMS (ESI) m/z: [ M + H ]]+＝469。

And 5: preparation of 3- (6- [2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

To 2- [2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1H-isoindol-5-yl at room temperature ]-2, 7-diazaspiro [3.5]Dissolution of nonane-7-carboxylic acid tert-butyl ester (100.0mg, 0.213mmol, 1.00 equiv.) in DCM (3.00mL)TFA (1.00mL) was added. The resulting mixture was stirred at room temperature for 1 hour. It was then concentrated in vacuo to give the crude product, which was used directly in the next step. LCMS (ESI) m/z: [ M + H ]]+＝369。

Step 6: preparation of 3- ([2- [2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1H-isoindol-5-yl ] -2, 7-diazaspiro [3.5] nonan-7-yl ] methyl) azetidine-1-carboxylic acid tert-butyl ester

To 3- (6- [2, 7-diazaspiro [3.5]]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione (100.0mg, 0.271mmol, 1.00 equiv.), 3-formylazetidine-1-carboxylic acid tert-butyl ester (50.3mg, 0.271mmol, 1.00 equiv.) in solvent DMF (3.00mL) NaBH (OAc)3(172.6mg, 0.814mmol, 3.00 equiv.). The obtained solution is mixed inStirred for 3 hours. The mixture was concentrated. The crude product was directly purified by passing through a reverse phase column under the conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient: 8% B to 80% B in 20 min; 254/220nm) to give 3- ([2- [2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1H-isoindol-5-yl) as a yellow solid ]-2, 7-diazaspiro [3.5]Nonan-7-yl]Methyl) azetidine-1-carboxylic acid tert-butyl ester (60mg, 41.1%). LCMS (ESI) m/z: [ M + H ]]+＝538。

And 7: preparation of 3- [6- [7- (azetidin-3-ylmethyl) -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

To 3- ([2- [2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1H-isoindol-5-yl) at room temperature]2, 7-diazaspiro [ alpha ], [ beta ] -a3.5]Nonan-7-yl]Methyl) azetidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.186mmol, 1.00 equiv.) in DCM (3.00mL) was added TFA (1.00 mL). The resulting mixture was stirred at room temperature for 1 hour. It was then concentrated in vacuo to give the crude product, which was used directly in the next step. LCMS (ESI) m/z: [ M + H ]]+＝438。

And 8: 3- [5- (7- [ [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) azetidin-3-yl ] methyl ] -2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione bis (carboxylic acid)

To 3- [5- [7- (azetidin-3-ylmethyl) -2, 7-diazaspiro [3.5] at room temperature]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl ]Piperidine-2, 6-dione (35.0mg, 0.080mmol, 1.00 equiv.) and 4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl](iii) A stirred solution of-2, 6-dimethoxybenzaldehyde (30.4mg, 0.080mmol, 1.00 eq) in DMF (4.00mL) was added NaBH (OAc)3(50.9mg, 0.240mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 19 x 250mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 5B to 17B; 254/220 nm; RT 1: 8.9-9.53 min) to give 3- [6- (7- [ [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a pale yellow solid]-2, 6-dimethoxyphenyl]Methyl) azetidin-3-yl]Methyl radical]-2, 7-diazaspiro [3.5]Nonan-2-yl) -1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; bis (formic acid) (5.1mg, 7.6%).1H NMR(400MHz，DMSO-d6)δ10.97(s，1H)，9.02(s，1H)，8.18(s，2H，FA)，7.61(s，1H)，7.38(d，J＝8.2Hz，1H)，6.79(s，2H)，6.68(d，J＝7.5Hz，2H)，6.18(s，1H)，5.08(dd，J＝13.2，5.1Hz，1H)，4.31(d，J＝16.6Hz，1H)，4.18(d，J＝16.7Hz，1H)，4.11-3.97(m，6H)，3.86(s，6H)，3.82-3.69(m，4H)，3.58(s，3H)，3.49(s，3H)，2.96-2.85(m，2H)，2.78-2.71(m，1H)，2.64-2.60(m，1H)，2.59-2.55(m，1H)，2.43-2.26(m，7H)，2.06-1.95(m，2H)，1.78-1.67(m，4H)。LCMS(ESI)m/z：[M+H]+＝800.96。

Example 64-3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione carboxylic acid; and preparation of 3- [6- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione carboxylic acid

Step 1: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (piperidin-4-yl) isoindole-1, 3-dione

To 4- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl at room temperature]A stirred solution of piperidine-1-carboxylic acid tert-butyl ester (1.00g, 2.265mmol, 1.00 eq.) in DCM (8mL) was added TFA (2.00 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This gave 2- (2, 6-dioxopiperidin-3-yl) -5- (piperidin-4-yl) isoindole-1, 3-dione as a white solid (1.23g, crude) which was used directly in the next step without further purification. LCMS (ESI) m/z: [ M + H ]]+＝342。

Step 2: preparation of 3- [ 3-hydroxy-1-oxo-5- (piperidin-4-yl) -3H-isoindol-2-yl ] piperidine-2, 6-dione and 3- [ 1-hydroxy-3-oxo-5- (piperidin-4-yl) -1H-isoindol-2-yl ] piperidine-2, 6-dione

To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (piperidin-4-yl) isoindole-1, 3-dione (300.0mg, 0.879mmol, 1.00 equiv.) in AcOH (5.00mL) was added Zn (574.9mg, 8.788mmol, 10 equiv.) and the resulting solution was dissolved inStirred for 2 hours. The mixture was diluted with EtOAc (30mL) and washed with water (30mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was chromatographed by flash C18 (elution gradient 0% to 11% in medium H) 2ACN of O) to give 3- [ 3-hydroxy-1-oxo-5- (piperidin-4-yl) -3H-isoindol-2-yl as a white solid]Piperidine-2, 6-dione and 3- [ 1-hydroxy-3-oxo-5- (piperidin-4-yl) -1H-isoindol-2-yl]Piperidine-2, 6-dione (280mg, mixture of two regioisomers, 92.8%). LCMS (ESI) m/z: [ M + H ]]+＝344。

And step 3: 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] -3-hydroxy-1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione and 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] -1-hydroxy-3-oxo Preparation of 1H-isoindol-2-yl piperidine-2, 6-dione

To 3- [ 3-hydroxy-1-oxo-5- (piperidin-4-yl) -3H-isoindol-2-yl]Piperidine-2, 6-dione and 3- [ 1-hydroxy-3-oxo-5- (piperidin-4-yl) -1H-isoindol-2-yl]Piperidine-2, 6-dione (mixture of two regioisomers, 260.0mg, 0.757mmol, 1.00 equiv.), 4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl]-2, 6-dimethoxybenzaldehyde (28)7.3mg, 0.757mmol, 1 equiv) of DMF (3mL) NaBH (OAc) 3(321.0mg, 1.514mmol, 2 equiv.) and dissolving the resulting solution inStirred for 4 hours. The mixture was diluted with EtOAc (20mL) and washed with water (20 mL. times.3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was passed through preparative TLC (CH)2Cl2MeOH 10: 1) to give 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione and 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-hydroxy-3-oxo-1H-isoindol-2-yl]Piperidine-2, 6-dione (208mg, mixture of two regioisomers, 38.9%). LCMS (ESI) m/z: [ M + H ]]+＝707。

And 4, step 4: 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione carboxylic acid; and preparation of 3- [6- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione carboxylic acid

To 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione and 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-hydroxy-3-oxo-1H-isoindol-2-yl]Piperidine-2, 6-dione (two regions)Mixture of isomers, 200.0mg, 0.141mmol, 1.00 equiv.) in DCM (3.00mL) was added TFA (2.00mL, 26.926mmol, 95.16 equiv.) and triethylsilane (1.00mL, 6.192mmol, 21.88 equiv.), and the resulting solution was stirred inStirred for 1 hour. The crude product was purified by preparative HPLC (column: XSelectCSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 3B to 26B; 254 nm; RT 1: 13.32 min) to give 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a white solid]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione (39.5mg, 39.1%) and 3- [6- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) ]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; formic acid (24.8mg, 22.7%).

For 3- [5- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione:1H NMR(400MHz，DMSO-d6)δ10.99(s，1H)，9.02(s，1H)，8.16(s，1H，FA)，7.68-7.60(m，2H)，7.49(s，1H)，7.39(dd，J＝7.8，1.4Hz，1H)，6.76(s，2H)，6.22(s，1H)，5.10(dd，J＝13.3，5.1Hz，1H)，4.42(d，J＝17.3Hz，1H)，4.28(d，J＝17.3Hz，1H)，4.01(t，J＝7.4Hz，4H)，3.84(s，6H)，3.69(s，2H)，3.49(s，3H)，3.05(d，J＝11.2Hz，2H)，2.92(ddd，J＝17.3，13.6，5.4Hz，1H)，2.66-2.60(m，1H)，2.60-2.55(m，1H)，2.46-2.38(m，1H)，2.37-2.28(m，4H)，2.04-1.95(m，1H)，1.78-1.65(m，4H)。LCMS(ESI)m/z：[M+H]+＝691.35。

for 3- [6- [1- ([4- [6- (azetidin-1-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl)]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione; formic acid:1H NMR(400MHz，DMSO-d6)δ10.99(s，1H)，9.02(s，1H)，8.18(s，FA)，7.62(s，1H)，7.58-7.48(m，3H)，6.75(s，2H)，6.22(s，1H)，5.10(dd，J＝13.3，5.1Hz，1H)，4.41(d，J＝17.1Hz，1H)，4.27(d，J＝17.1Hz，1H)，4.01(t，J＝7.4Hz，4H)，3.84(s，6H)，3.63(s，2H)，3.48(s，3H)，3.00(d，J＝11.0Hz，2H)，2.97-2.85(m，1H)，2.65-2.60(m，1H)，2.60-2.56(m，1H)，2.45-2.37(m，1H)，2.37-2.30(m，1H)，2.24(t，J＝11.3Hz，2H)，2.03-1.96(m，1H)，1.80-1.73(m，2H)，1.73-1.62(m，2H)。LCMS(ESI)m/z：[M+H]+＝691.55。

EXAMPLE 65 preparation of 3- (5- [ [1- ([2, 6-dimethoxy-4- [ 2-methyl-6- (morpholin-4-yl) -1-oxo-2, 7-naphthyridin-4-yl ] phenyl ] methyl) azetidin-3-yl ] oxy ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

Step 1: preparation of 4-bromo-2-methyl-6- (morpholin-4-yl) -2, 7-naphthyridin-1-one

To a stirred solution of 4-bromo-6-chloro-2-methyl-2, 7-naphthyridin-1-one (547.00mg, 2.000mmol, 1.00 equiv.) and morpholine (522.71mg, 6.000mmol, 3.00 equiv.) in DMSO (6.00mL) was added K2CO3(1382.00mg, 10.000mmol, 5.00 equiv.). Mixing the obtained mixture inThe mixture was stirred under nitrogen for 1 hour. The reaction mixture was diluted with EA (100 mL). The resulting mixture was washed with 3x100mL water and 1x100mL saturated brine. Subjecting the organic layer to Na 2SO4Dried, filtered and evaporated to give the crude product. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 10% MeOH in DCM. Evaporating the pure fraction toDry to give 4-bromo-2-methyl-6- (morpholin-4-yl) -2, 7-naphthyridin-1-one (541mg, 83.44%) as a pale yellow solid. LCMS (ESI) m/z: [ M + H ]]+＝324。

Step 2: preparation of 2, 6-dimethoxy-4- [ 2-methyl-6- (morpholin-4-yl) -1-oxo-2, 7-naphthyridin-4-yl ] benzaldehyde

4-bromo-2-methyl-6- (morpholin-4-yl) -2, 7-naphthyridin-1-one (540.00mg, 1.666mmol, 1.00 equiv.) and 4-formyl-3, 5-dimethoxyphenylboronic acid (454.73mg, 2.165mmol, 1.30 equiv.), Cs under nitrogen2CO3(1628.20mg, 4.997mmol, 3.00 equiv.) in H2Solution in O (1.00mL) and dioxane (5.00mL) was added Pd (dppf) Cl2CH2Cl2(136.03mg, 0.167mmol, 0.10 equiv.). In thatAfter stirring under nitrogen for 1 hour, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 10% MeOH in DCM. The pure fractions were evaporated to dryness to give 2, 6-dimethoxy-4- [ 2-methyl-6- (morpholin-4-yl) -1-oxo-2, 7-naphthyridin-4-yl as a yellow solid]Benzaldehyde (356mg, 52.20%). LCMS (ESI) m/z: [ M + H ] ]+＝410。

And step 3: preparation of 3- (5- [ [1- ([2, 6-dimethoxy-4- [ 2-methyl-6- (morpholin-4-yl) -1-oxo-2, 7-naphthyridin-4-yl ] phenyl ] methyl) azetidin-3-yl ] oxy ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

To 3- [5- (azetidin-3-yloxy) -1-oxo-3H-isoindol-2-yl at room temperature under an air atmosphere]Piperidine-2, 6-dione (100.00mg, 0.317mmol, 1.00 equiv.) and 2, 6-dimethoxy-4- [ 2-methyl-6- (morpholin-4-yl) -1-oxo-2, 7-naphthyridin-4-yl]A stirred solution of benzaldehyde (129.85mg, 0.317mmol, 1.00 eq) in DMF was added dropwise to NaBH (OAc)3(134.43mg, 0.634mmol, 2.00 equiv.) for 2 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous, 0% to 100% gradient over 45 min; detector, UV 254 nm. The crude product was purified by preparative HPLC using the following conditions (column: Xcelect CSH F-Phenyl OBD column, 19X 250mm, 5 μm; mobile phase A: water (0.05% FA); mobile phase B: ACN; flow rate: 30 mL/min; gradient: 13B to 33B; 254/220 nm; RT 1: 12.85 min) in 14 min to give 3- (5- [ [1- ([2, 6-dimethoxy-4- [ 2-methyl-6- (morpholin-4-yl) -1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid ]Phenyl radical]Methyl) azetidin-3-yl]Oxy radical]-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione (100mg, 44.15%).1H NMR (400MHz, methanol-d 4) δ 9.18(s, 1H), 7.80(t, J ═ 6.7Hz, 1H), 7.49(s, 1H), 7.09(t, J ═ 7.3Hz, 2H), 6.88(s, 2H), 6.63(d, J ═ 4.9Hz, 1H), 5.40-5.20(m, 1H), 5.15(dd, J ═ 13.3, 5.2Hz, 1H), 4.77(ddd, J ═ 24.3, 12.5, 6.8Hz, 2H), 4.65(d, J ═ 22.0Hz, 2H), 4.48(d, J ═ 6.3Hz, 2H), 4.44-4.28(m, 2H), 3.96(d, J ═ 23.6, 6H), 4.48(d, J ═ 6.3Hz, 2H), 4.44-4.28(m, 2H), 3.96(d, J ═ 23.7.7, 6, 6.7H, 5H), 3H, 5(dd, 3H, 5H, 1H), 4.3H, 3H, 5(dd, 3H, 5H, 2H), 4.3H, 3H), 1H) in that respect LCMS (ESI) m/z: [ M + H ]]+＝709。

EXAMPLE 66 preparation of 3- [5- [ (7- [ [1- ([4- [6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] methyl ] -7-azaspiro [3.5] nonan-2-yl) oxy ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

Step 1: preparation of ethyl 2-methyl-2- (7-methyl-8-oxo-2, 7-naphthyridin-3-yl) propionate

In thatTo a stirred mixture of LDA (825.63mg, 7.707mmol, 1.5 equivalents) in THF (20mL) was added ethyl isobutyrate (895.28mg, 7.707mmol, 1.5 equivalents) dropwise under a nitrogen atmosphere. Mixing the obtained mixture inStirred under nitrogen for 30 minutes. In that6-chloro-2-methyl-2, 7-naphthyridin-1-one (1.00g, 5.138mmol, 1.00 equiv.) in THF (1mL) was added dropwise to the above mixture over 2 minutes. The resulting mixture was stirred at room temperature for an additional 2 hours. Reacting the reactant inNH used at the lower part4Aqueous Cl (5mL) was quenched. Subjecting the obtained mixture to CH2Cl2(100mL) was extracted. The combined organic layers were washed with water (100mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The reaction mixture was purified by reverse phase flash with the following conditions (mobile phase A: water (0.3% FA); mobile phase B: ACN; flow rate: 80 mL/min; gradient: 5% B to 50% B over 30 min) to give ethyl 2-methyl-2- (7-methyl-8-oxo-2, 7-naphthyridin-3-yl) propionate as a yellow solid (320mg, 11.35%). LCMS (ESI) m/z: [ M + H ]]+＝275。

Step 2: preparation of 6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-2, 7-naphthyridin-1-one

In thatLiBH was added portionwise to a stirred mixture of ethyl 2-methyl-2- (7-methyl-8-oxo-2, 7-naphthyridin-3-yl) propionate (240.00mg, 0.875mmol, 1.00 eq) in EtOH (20.00mL) under nitrogen atmosphere 4(209.64mg, 9.624mmol, 11.00 equiv.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction was quenched with water at room temperature. Subjecting the obtained mixture to CH2Cl2(20mL) was extracted. The combined organic layers were washed with water (2 × 20mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (20: 1) afforded 6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-2, 7-naphthyridin-1-one (120mg, 53.14%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝233。

And step 3: preparation of 4-bromo-6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-2, 7-naphthyridin-1-one

To a stirred mixture of 6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-2, 7-naphthyridin-1-one (90.00mg, 0.387mmol, 1.00 eq) in DMF (1.00mL) was added NBS (82.75mg, 0.465mmol, 1.2 eq) at room temperature under a nitrogen atmosphere. Mixing the obtained mixture inThe mixture was stirred under nitrogen for 2 hours. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (17: 1) afforded 4-bromo-6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-2, 7-naphthyridin-1-one (80mg, 66.35%) as a yellow oil. LCMS (ESI) m/z: [ M + H ] ]+＝311。

And 4, step 4: preparation of 4- [6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxybenzaldehyde

To a solution of 4-bromo-6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-2, 7-naphthyridin-1-one (50.00mg, 0.161mmol, 1.00 equiv.) and 2, 6-dimethoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (70.41mg, 0.241mmol, 1.50 equiv.) in dioxane (2.00mL) and water (0.40mL) was added K3PO4(102.32mg, 0.482mmol, 3.00 equiv.) and Pd (PPh)3)2Cl2(11.28mg, 0.016mmol, 0.10 eq.). In thatAfter stirring under nitrogen for 16 hours, the resulting mixture was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluting with MeOH (17: 1) to give 4- [6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a yellow oil]-2, 6-dimethoxybenzaldehyde (38mg, 53.69%). LCMS (ESI) m/z: [ M + H ]]+＝397。

And 5: preparation of 3- [5- [ (7- [ [1- ([4- [6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl ] -2, 6-dimethoxyphenyl ] methyl) piperidin-4-yl ] methyl ] -7-azaspiro [3.5] nonan-2-yl) oxy ] -1-oxo-3H-isoindol-2-yl ] piperidine-2, 6-dione

To 4- [6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl under nitrogen atmosphere at room temperature]-2, 6-dimethoxybenzaldehyde (80.00mg, 0.202mmol, 1.00 equiv.) and 3- (1-oxo-5- [ [7- (piperidin-4-ylmethyl) -7-azaspiro [3.5]]Nonan-2-yl]Oxy radical](iii) -3H-isoindol-2-yl) piperidine-2, 6-dione (96.98mg, 0.202mmol, 1.00 eq.) in a stirred mixture of DMF (1.00mL) NaBH (OAc)3(85.54mg, 0.404mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The crude product was purified by preparative HPLC using the following conditions (column: XSelect CSH F-Phenyl OBD column 19 x 150mm 5 μm; mobile phase A: water (0.05% TFA); mobile phase B: ACN; flow rate: 25 mL/min; gradient: 12B to 24B; 254/220 nm; RT 1: 9.07 min) to give 3- [5- [ (7- [ [1- ([4- [6- (1-hydroxy-2-methylpropan-2-yl) -2-methyl-1-oxo-2, 7-naphthyridin-4-yl) as a yellow solid]-2, 6-dimethoxyphenyl]Methyl) piperidin-4-yl]Methyl radical]-7-azaspiro [3.5]Nonan-2-yl) oxy]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione (73.3mg, 41.60%).1H NMR(400MHz，DMSO-d6)δ9.42(d，J＝0.7Hz，1H)，7.89(d，J＝2.9Hz，1H)，7.70-7.61(m，2H)，7.06(d，J＝2.2Hz，1H)，6.98(dd，J＝8.4，2.3Hz，1H)，6.91(s，2H)，5.05(dd，J＝13.2，5.1Hz，1H)，4.87(q，J＝6.5Hz，1H)，4.43-4.32(m，2H)，4.26(d，J＝13.6Hz，2H)，3.91(s，6H)，3.55(s，3H)，3.45(d，J＝12.0Hz，2H)，3.37(s，4H)，3.23-3.14(m，1H)，3.10-2.83(m，6H)，2.61(d，J＝16.6Hz，2H)，2.45-2.33(m，2H)，2.08(d，J＝11.8Hz，1H)，1.87(d，J＝28.7Hz，9H)，1.55-1.41(m，2H)，1.27(s，6H)。LCMS(ESI)m/z：[M+H]+＝861。

EXAMPLE 67 preparation of 3- (6- [7- [ (1- [ [2, 6-dimethoxy-4- (6-methoxy-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) phenyl ] methyl ] azetidin-3-yl) methyl ] -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

Step 1: preparation of 6-methoxy-2-methyl-2, 7-naphthyridin-1-one

6-chloro-2-methyl-2, 7-naphthyridin-1-one (1.00g, 5.138mmol,1.00 equiv.) and KOH (0.43g, 7.707mmol, 1.50 equiv.) in MeOH (10.00mL)The mixture was stirred under nitrogen for 4 hours. The resulting mixture was diluted with 100mL of water. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluted with MeOH (10: 1) afforded 6-methoxy-2-methyl-2, 7-naphthyridin-1-one (800mg, 81.86%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝191。

Step 2: preparation of 4-bromo-6-methoxy-2-methyl-2, 7-naphthyridin-1-one

A mixture of 6-methoxy-2-methyl-2, 7-naphthyridin-1-one (800.00mg, 4.206mmol, 1.00 equiv.) and NBS (898.33mg, 5.047mmol, 1.20 equiv.) in DMF (10.00mL) was addedThe mixture was stirred under nitrogen for 2 hours. The resulting mixture was diluted with 100mL of water. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue is passed through with CH 2Cl2Purification by column chromatography on silica gel eluted with MeOH (10: 1) afforded 4-bromo-6-methoxy-2-methyl-2, 7-naphthyridin-1-one (600mg, 53.01%) as a white solid. LCMS (ESI) m/z: [ M + H ]]+＝269。

And step 3: preparation of 4- [3- (2, 6-dioxopiperidin-3-yl) -2-methyl-4-oxoquinazolin-6-yl ] piperazine-1-carboxylic acid tert-butyl ester

4-bromo-6-methoxy-2-methyl-2, 7-naphthyridin-1-one (600.00mg, 2.230mmol, 1.00 equiv.), 4-boryl-2, 6-dimethoxybenzaldehyde (396.86mg, 2.230mmol, 1.00 equiv.), Pd (dppf) Cl2(163.15mg, 0.223mmol, 0.10 equiv.) and Cs2CO3(1452.94mg, 4.459mmol, 2.00 equiv.) of a mixture in DMF (10.00mL)The mixture was stirred under nitrogen for 4 hours. The resulting mixture was diluted with 100mL of water and the resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue is passed through with CH2Cl2Purification by column chromatography on silica gel eluting with MeOH (10: 1) afforded 2, 6-dimethoxy-4- (6-methoxy-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) benzaldehyde (100mg, 12.66%) as a yellow solid. LCMS (ESI) m/z: [ M + H ]]+＝355。

And 4, step 4: preparation of 3- (6- [7- [ (1- [ [2, 6-dimethoxy-4- (6-methoxy-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) phenyl ] methyl ] azetidin-3-yl) methyl ] -2, 7-diazaspiro [3.5] nonan-2-yl ] -1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione

2, 6-dimethoxy-4- (6-methoxy-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) benzaldehyde (80.00mg, 0.226mmol, 1.00 equiv.), 3- [6- [7- (azetidin-3-ylmethyl) -2, 7-diazaspiro [3.5 ]]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl]Piperidine-2, 6-dione (98.78mg, 0.226mmol, 1.00 eq.) and NaBH (AcO)3A mixture of (95.69mg, 0.452mmol, 2.00 equiv.) in DMF (2.00mL) was stirred at room temperature for 3 h. Without any additional work-up, the mixture was passed through preparative HPLC using the following conditions(column: XSelect CSH Prep C18 OBD column 5um, 19 x 150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 13B to 20B; 254/220 nm; RT 1: 13.18-14 min.) purification to give 3- (6- [7- [ (1- [ [2, 6-dimethoxy-4- (6-methoxy-2-methyl-1-oxo-2, 7-naphthyridin-4-yl) phenyl) as a yellow solid]Methyl radical]Azetidin-3-yl) methyl]-2, 7-diazaspiro [3.5]Nonan-2-yl]-1-oxo-3H-isoindol-2-yl) piperidine-2, 6-dione (11.8mg, 6.74%).1H NMR (300MHz, methanol-d 4) δ 9.25(s, 1H), 7.57(s, 1H), 7.41(d, J ═ 8.2Hz, 1H), 6.96-6.72(m, 5H), 5.14(dd, J ═ 13.2, 5.1Hz, 1H), 4.55(s, 2H), 4.49-4.30(m, 4H), 4.27-4.07(m, 2H), 3.99(d, J ═ 9.8Hz, 9H), 3.78(s, 4H), 3.64(s, 3H), 3.59-3.48(m, 5H), 3.27-3.01(m, 2H), 3.00-2.69(m, 2H), 2.50(dd, J ═ 13.1, 4.8, 1H), 2.00-2.35H), 2.00-5H (dd, 5H). LCMS (ESI) m/z: [ M + H ] ]+＝776。

Example 68-BRD9 Bromomol Domain TR-FRET competitive binding assay

This example demonstrates the ability of compounds of the present disclosure to biochemically inhibit the BRD9 bromodomain in a competitive binding assay.

The procedure is as follows: His-Flag-BRD9 (P133-K239; Swiss Prot Q9H8M 2; SEQ ID NO: 1 mgsshhhhenlyfq/gdykdddkgsllfqg/PAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMIIKHPMDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSK) was cloned, expressed, purified, and then treated with TEV protease. The cleaved His tag is removed by purification. Via aThe TR-FRET platform (PerkinElmer) assesses the binding of the biotinylated small molecule ligand of BRD9 and measures the inhibitory activity of the compound on this interaction.

As a result: biotinylated ligand and SureLightTMA mixture of allophycocyanin-streptavidin (APC-SA, PerkinElmer AD0201) in 50mM HEPES (pH 7.4), 50mM NaCl, 1mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01% (w/v) bovine serum albumin was added to the white blood serum albuminColor 384 well Perkinelmer Proxiplate Plus plate. DMSO or 3-fold serial dilutions of the compound were then added to the Proxiplate followed by Flag-BRD 9. After 10 min incubation at room temperature, Eu-W1024 anti-FLAG (PerkinElmer, AD0273) was added. Will contain 3.75nM biotinylated ligand, 3nM Flag-BRD9, 7.5nM SureLight TMThe final reaction mixture of allophycocyanin-streptavidin and 0.2nM Eu-W1024 anti-FLAG was incubated at room temperature for 90 min.

The plates were then read on a PerkinElmer Envision plate reader to determine the emission ratio at 665nm and 615 nm. Data were normalized to DMSO control (100%) and no protein control (0%) and then fitted to a four parameter nonlinear curve fit to calculate IC50(. mu.M) as shown in Table 5. As shown by the results in Table 5, many of the compounds of the present disclosure exhibited IC < 1 μ M for BRD9 binding50Values indicating their affinity for targeting BRD 9.

TABLE 5 Bromomol domain TR-FRET binding

"+" indicates an inhibitory effect of 1000nM or greater;

"+ +" indicates an inhibitory effect of ≧ 100 nM;

"+ + + +" indicates an inhibitory effect of ≧ 10 nM;

"+ +++" indicates an inhibitory effect of < 10 nM;

"NT" indicates not tested

Example 69-SYO1 BRD9 NanoLuc degradation assay

This example demonstrates the ability of compounds of the present disclosure to degrade the nanoflucerase-BRD 9 fusion protein in a cell-based degradation assay.

The procedure is as follows: a stable SYO-1 cell line expressing 3xFLAG-NLuc-BRD9 was generated. On day 0, cells were seeded into each well of a 384-well cell culture plate in 30 μ L of medium. The seeding density was 8000 cells/well. On day 1, cells were treated with 30nL DMSO or 30nL of compound diluted in 3-fold serial DMSO (in duplicate, 10 dots total, 1 μ M is the final highest dose). Subsequently, the plates were incubated in a standard tissue culture incubator for 6 hours and allowed to equilibrate for 15 minutes at room temperature. The Nano-luciferase activity was measured by adding 15 μ L of freshly prepared Nano-Glo luciferase assay reagent (Promega N1130), shaking the plate for 10 minutes and reading the bioluminescence using an EnVision reader.

As a result: the% inhibition was calculated using the formula: inhibition%HC-LumSample (I))/(LumHC-LumLC). DMSO-treated cells were used as High Control (HC) and 1 μ M of cells treated with a known BRD9 degradant standard were used as Low Control (LC). Fitting the data to a four parameter nonlinear curve fit to calculate IC50The (. mu.M) values are shown in tables 6A, 6B and 6C. As shown by the results in tables 6A, 6B, and 6C, many of the compounds of the present disclosure exhibited IC for degradation of BRD950Values < 1 μ M, indicating their use as compounds that reduce the level and/or activity of BRD9 and their potential for use in the treatment of BRD 9-related conditions.

TABLE 6A. SYO1 BRD9-NanoLuc degradation

"+" indicates an inhibitory effect of 1000nM or greater;

"+ +" indicates an inhibitory effect of ≧ 100 nM;

"+ + + +" indicates an inhibitory effect of ≧ 10 nM;

"+ +++" indicates an inhibitory effect of < 10 nM;

"NT" indicates not tested

TABLE 6B SYO1 BRD9-NanoLuc degradation

"+" indicates an inhibitory effect of 1000nM or greater;

"+ +" indicates an inhibitory effect of ≧ 100 nM;

"+ + + +" indicates an inhibitory effect of ≧ 10 nM;

"+ +++" indicates an inhibitory effect of < 10 nM;

"NT" indicates not tested

TABLE 6C.SYO1 BRD9-NanoLuc degradation

"+" indicates an inhibitory effect of 1000nM or greater;

"+ +" indicates an inhibitory effect of ≧ 100 nM;

"+ + + +" indicates an inhibitory effect of ≧ 10 nM;

"+ +++" indicates an inhibitory effect of < 10 nM;

"NT" indicates not tested

Other embodiments

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

While the invention has been described in connection with specific embodiments thereof, it will be understood that it 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 as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Other embodiments are within the claims.

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