Patent US10722591

Cleavable conjugates of TLR7/8 agonist compounds, methods for preparation, and uses thereof
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US10722591

1. A compound of formula (I): (21) (10)

F—[W-L³-L²-L¹-D]_x (I)

D is a TLR7/8 agonist moiety;

L¹is a self-eliminating linker;

L²is a cleavable linker;

L³is a conjugation linker;

W is O, S, or N¹⁰;

R¹⁰is H or C₁-C₈alkyl;

x is an integer from 1 to 500;

F is a conjugation moiety; and

the TLR7/8 agonist moiety is a 1H-imidazo[4,5-c]quinoline derivative.

2. The compound of claim 1, wherein D is of the formula (D-1): (0) (7)

R^1Ais C₁-C₈alkyl, C₁-C₈hydroxyalkyl, or C₃-C₈cycloalkyl;

R²is NHR^2a, where R^2ais H or C₁-C₈alkyl;

each R³⁵is independently halogen or C₁-C₈alkyl;

R^4aand R^4bare independently H or C₁-C₈alkyl;

each R⁵is independently halogen or C₁-C₈alkyl;

p and q are independently 0, 1, 2, 3, or 4; and

the wave line represents the point of attachment of D in formula (I).

3. The compound of claim 1, wherein D is of the formula (D-2): (12) (7)

n is an integer from 4 to 21;

X is —NH— or —NH(C═O)—;

R¹is C₃-C₆alkyl, (CH₂)_pOR^1a, (CH₂)_pNHR^1b, or —(CH₂)_pR^1c; where R^1aand R^1bare independently C₁-C₃alkyl; R^1cis C₃-C₄cycloalkyl; and p is 1 or 2;

each R³is independently halogen, C₁-C₈alkyl, —(C₁-C₇alkylene)-NH₂, or —CH₂-phenylene-CH₂NH₂;

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

R^4aand R^4bare independently H or C₁-C₈alkyl; and

the wave line represents the point of attachment of D in formula (I).

5. The compound of claim 3, wherein X is —NH—. (0)

6. The compound of claim 3, wherein n is an integer from 4 to 15. (0)

7. The compound of claim 3, wherein n is 4, 5, 6, or 7. (0)

8. The compound of claim 3, wherein X is —NH(C═O)—. (0)

9. The compound of claim 3, wherein n is 11, 12, 13, or 14. (0)

10. The compound of claim 3, wherein R¹is C₃-C₆alkyl. (1) (0)

12. The compound of claim 3, wherein R¹is —(CH₂)_pOR^1a. (0)

13. The compound of claim 3, wherein R¹is —(CH₂)_pNHR^1b. (0)

14. The compound of claim 3, wherein R¹is —(CH₂)_pR^1c. (0)

15. The compound of claim 3, wherein q is 0. (0)

16. The compound of claim 3, wherein q is 1 and R³is C₁-C₈alkyl. (0)

17. The compound of claim 3, wherein R^4aand R^4bare each H. (0)

4. The compound of claim 1, wherein D is of the formula (D-2a) or (D-2b): (12) (7)

n is an integer from 4 to 21;

R¹is C₃-C₆alkyl, —(CH₂)_pOR^1a, —(CH₂)_pNHR^1b, or —(CH₂)_pR^1c; where R^1aand R^1bare independently C₁-C₃alkyl; R^1cis C₃-C₄cycloalkyl; and p is 1 or 2;

R²⁰is NHR^20a; where R^20ais H, OH, NH₂, or methyl;

each R³is independently halogen, C₁-C₈alkyl, —(C₁-C₇alkylene)-NH₂, or —CH₂-phenylene-CH₂NH₂;

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

R^4aand R^4bare independently H or C₁-C₈alkyl; and

the wave line represents the point of attachment of D in formula (I).

89. The compound of claim 4, wherein D is of the formula (D-2a). (0)

90. The compound of claim 4, wherein n is an integer from 4 to 15. (0)

91. The compound of claim 4, wherein n is 4, 5, 6, or 7. (0)

92. The compound of claim 4, wherein D is of the formula (D-2b). (0)

93. The compound of claim 4, wherein n is 11, 12, 13, or 14. (0)

94. The compound of claim 4, wherein R¹is C₃-C₆alkyl. (1) (0)

96. The compound of claim 4, wherein R¹is —(CH₂)_pOR^1a. (0)

97. The compound of claim 4, wherein R¹is —(CH₂)_pNHR^1b. (0)

98. The compound of claim 4, wherein R¹is —(CH₂)_pR^1c. (0)

99. The compound of claim 4, wherein q is 0. (0)

100. The compound of claim 4, wherein q is 1 and R³is C₁-C₈alkyl. (0)

101. The compound of claim 4, wherein R^4aand R^4bare each H. (0)

18. The compound of claim 1, wherein D is of the formula (D-3): (6) (7)

R⁰is C₄-C₂₁hydrocarbyl optionally substituted by 1 to 4 halogen atoms;

X is —NH— or —NH(C═O)—;

R¹is C₃-C₆alkyl, —(CH₂)_pOR^1a, —(CH₂)_pNHR^1b, or —(CH₂)_pR^1c; where R^1aand R^1bare independently C₁-C₃alkyl; R^1cis C₃-C₄cycloalkyl; and p is 1 or 2;

each R³is independently halogen, C₁-C₈alkyl, —(C₁-C₇alkylene)-NH₂, or —CH₂-phenylene-CH₂NH₂;

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

R^4aand R^4bare independently H or C₁-C₈alkyl; and

the wave line represents the point of attachment of D in formula (I).

20. The compound of claim 18, wherein X is —NH(C═O)—. (0)

21. The compound of claim 18, wherein X is —NH—. (0)

22. The compound of claim 18, wherein R⁰is C₄-C₁₄hydrocarbyl optionally substituted by 1 to 2 halogen atoms. (0)

23. The compound of claim 18, wherein R⁰is branched C₄-C₁₄alkyl, —(CH₂)_z(C(CH₃)₂)R^A, or —(CH₂)_mR^A; m is 0, 1, 2, or 3; z is 1 or 2; and R^Ais C₃-C₈cycloalkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄alkylene, and halogen. (2) (0)

25. The compound of claim 23, wherein R⁰is —(CH₂)_mR^A. (7) (0)

26. The compound of claim 25, wherein m is 2. (0)

27. The compound of claim 25, wherein m is 1. (0)

30. The compound of claim 25, wherein R^Ais cyclopropyl, cyclobutyl, or cyclopentyl. (0)

31. The compound of claim 25, wherein R^Ais C₃-C₆cycloalkyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl, methylene, and halogen. (0)

32. The compound of claim 25, wherein R^Ais C₃-C₈cycloalkyl. (0)

33. The compound of claim 25, wherein R^Ais cyclopropyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene. (0)

34. The compound of claim 25, wherein m is 0 and R^Ais cyclohexyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene. (0)

28. The compound of claim 23, wherein R⁰is —(CH₂)_z(C(CH₃)₂)R^A. (1) (0)

24. The compound of claim 18, wherein R⁰is branched C₄-C₁₄alkyl. (0)

35. The compound of claim 18, wherein R⁰is selected from the group consisting of: (0)

19. The compound of claim 1, wherein D is of the formula (D-3a) or (D-3b): (7) (7)

R⁰is C₄-C₂₁hydrocarbyl optionally substituted by 1 to 4 halogen atoms;

R¹is C₃-C₆alkyl, —(CH₂)_pOR^1a, —(CH₂)_pNHR^1b, or —(CH₂)_pR^1c; where R^1aand R^1bare independently C₁-C₃alkyl; R^1cis C₃-C₄cycloalkyl; and p is 1 or 2;

R²⁰is NHR^20a, where R^20ais H, OH, NH₂, or methyl;

each R³is independently halogen, C₁-C₈alkyl, —(C₁-C₇alkylene)-NH₂, or —CH₂-phenylene-CH₂NH₂;

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

R^4aand R^4bare independently H or C₁-C₈alkyl; and

the wave line represents the point of attachment of D in formula (I).

87. The compound of claim 19, wherein D is: (0)

88. The compound of claim 19, wherein R⁰is selected from the group consisting of: (0)

102. The compound of claim 19, wherein D is of the formula (D-3b). (0)

103. The compound of claim 19, wherein D is of the formula (D-3 a). (0)

104. The compound of claim 19, wherein R⁰is C₄-C₁₄hydrocarbyl optionally substituted by 1 to 2 halogen atoms. (0)

105. The compound of claim 19, wherein R⁰is branched C₄-C₁₄alkyl, —(CH₂)₂(C(CH₃)₂)R^A, or —(CH₂)_mR^A; m is 0, 1, 2, or 3; z is 1 or 2; and R^Ais C₃-C₈cycloalkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄alkylene, and halogen. (2) (0)

107. The compound of claim 105, wherein R⁰is —(CH₂)_mR^A. (7) (0)

108. The compound of claim 107, wherein m is 2. (0)

109. The compound of claim 107, wherein m is 1. (0)

112. The compound of claim 107, wherein R^Ais cyclopropyl, cyclobutyl, or cyclopentyl. (0)

113. The compound of claim 107, wherein R^Ais C₃-C₆cycloalkyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl, methylene, and halogen. (0)

114. The compound of claim 107, wherein R^Ais C₃-C₆cycloalkyl. (0)

115. The compound of claim 107, wherein R^Ais cyclopropyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene. (0)

116. The compound of claim 107, wherein m is 0 and R^Ais cyclohexyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene. (0)

110. The compound of claim 105, wherein R⁰is —(CH₂)₂(C(CH₃)₂)R^A. (1) (0)

106. The compound of claim 19, wherein R⁰is branched C₄-C₁₄alkyl. (0)

36. The compound of claim 1, wherein D is: (0)

37. The compound of claim 1, wherein L¹is of the formula (L-1): (4) (1)

wherein Y¹is S, O, or NH; Ar¹is an optionally substituted arylene; and R¹¹and R¹²are independently H or optionally substituted C₁-C₈alkyl.

38. The compound of claim 37, wherein Ar¹is optionally substituted 1,4-phenylene or optionally substituted 1,2-phenylene. (0)

39. The compound of claim 37, wherein R¹¹and R¹²are each H. (0)

40. The compound of claim 37, wherein Y¹is NH. (1) (0)

42. The compound of claim 37, wherein Y¹is S. (1) (0)

44. The compound of claim 1, wherein L¹-D is: (0)

45. The compound of claim 1, wherein L¹-D is: (0)

46. The compound of claim 1, wherein L¹-D is (0)

47. The compound of claim 1, wherein L²is of the formula (L-2): (1) (1)

49. The compound of claim 1, wherein L²is a peptide linker. (1) (0)

50. The compound of claim 49, wherein L²is a peptide linker cleavable by one or more endosomal or lysosomal peptidase(s) or protease(s), or one or more pericellular peptidase(s) or protease(s), that are expressed by cells in the tumor microenvironment. (1) (0)

51. The compound of claim 50, wherein L²is a peptide linker cleavable by an endosomal cathepsin or a pericellular protease. (1) (0)

52. The compound of claim 51, wherein the endosomal cathepsin or pericellular protease is selected from the group consisting of Cathepsin B, urokinase-type plasminogen activator (uPA), membrane-type serine protease 1 (matriptase), matriptase-2, and legumain. (2) (0)

53. The compound of claim 52, wherein the peptide linker cleavable by Cathepsin B comprises the amino acid sequence AA₁-AA₂-AA₃-AA₄, wherein: (1) (4)

AA₁is absent, alanine, β-alanine, isoleucine, leucine, valine, or glycine;

AA₂is absent, alanine, β-alanine, isoleucine, leucine, or valine;

AA₃is alanine, β-alanine, isoleucine, leucine, or valine; and

AA₄is arginine, serine, alanine, β-alanine leucine, ornithine, or citrulline.

54. The compound of claim 53, wherein L²is (0)

55. The compound of claim 52, wherein L²is peptide linker cleavable by urokinase-type plasminogen activator (uPA), membrane-type serine protease 1 (matriptase), matriptase-2, and/or legumain. (1) (0)

57. The compound of claim 1, wherein L³is -L³a-Y³-L^3b-, wherein Y³, L^3a, and L^abare independently optional spacer fragments. (13) (0)

58. The compound of claim 57, wherein Y³is: (0)

59. The compound of claim 57, wherein Y³is: (0)

60. The compound of claim 57, wherein Y³is: (0)

61. The compound of claim 57, wherein Y³is: (0)

62. The compound of claim 57, wherein L^3ais absent. (0)

63. The compound of claim 57, wherein L^3ais: (0)

64. The compound of claim 57, wherein L^3ais: (0)

65. The compound of claim 57, wherein L^3ais: (0)

66. The compound of claim 57, wherein L^3bis an acyl spacer fragment of the formula: (1) (0)

68. The compound of claim 57, wherein L³is (0)

69. The compound of claim 57, wherein L³is (0)

70. The compound of claim 57, wherein L³is: (0)

71. The compound of claim 57, wherein L³is: (0)

72. The compound of claim 1, wherein the -L³-L²-L¹-D moiety is: (0)

73. The compound of claim 1, wherein the -L³-L²-L¹-D moiety is: (0)

74. The compound of claim 1, wherein the -L³-L²-L¹-D moiety is: (0)

75. The compound of claim 1, wherein the -L³-L²-L¹-D moiety is: (0)

76. The compound of claim 1, wherein F is a tumor targeting agent. (3) (0)

81. The compound of claim 1, wherein F is an agent that promotes local retention of the compound of formula (I). (2) (0)

117. A pharmaceutical composition comprising (i) the compound according to claim 1; and (ii) a pharmaceutically acceptable excipient. (0)

121. A method for preparing the compound of claim 1, comprising: (0) (3)

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Patent US10722591

Cleavable conjugates of TLR7/8 agonist compounds, methods for preparation, and uses thereof

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