Compounds, compositions, and methods for the treatment of disease
Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Z is either S or O;
B 1 is a natural purinyl nucleobase and B 2 is a natural pyrimidinyl nucleobase or B 2 is a natural purinyl nucleobase and B 1 is a natural pyrimidinyl nucleobase;
each of X 1 and X 2 is independently O or S;
each of Y 1 and Y 2 is independently O, S, or NR 5 ;
L 1 is absent, C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl and L 2 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with R 6 ; or L 1 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl, and L 2 is absent, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with R 6 ;
each of R 1 and R 2 is independently hydrogen, halo, —CN, C 1 -C 20 alkyl, or OR 7 ;
each of R 3 and R 4 is independently hydrogen, C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, OC(O)OC 1 -C 20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 8 ;
R 5 is hydrogen or C 1 -C 20 alkyl;
R 6 is halo, —CN, C 1 -C 20 alkyl, OR 7 , oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 ;
R 7 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 ;
each R 8 is independently C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, C(O)—C 1 -C 20 alkyl, OC(O)—C 1 -C 20 alkyl, C(O)O—C 1 -C 20 alkyl, OC(O)O—C 1 -C 20 alkyl, C(O)N(R 5 )—C 1 -C 20 alkyl, N(R 5 )C(O)—C 1 -C 20 alkyl, OC(O)N(R 5 )—C 1 -C 20 alkyl, O-aryl, O-heteroaryl, C(O)-aryl, C(O)-heteroaryl, OC(O)-aryl, C(O)O-aryl, OC(O)-heteroaryl, C(O)O-heteroaryl, C(O)N(R 5 )-aryl, C(O)N(R 5 )-heteroaryl, N(R 5 )C(O)-aryl, N(R 5 ) 2 C(O)-aryl, N(R 5 )C(O)-heteroaryl, or S(O) 2 N(R 5 )-aryl, wherein each alkyl, heteroalkyl, aryl, and heteroaryl is optionally substituted by one or more R 9 ; and
each R 9 is independently C 1 -C 20 alkyl, O—C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, halo, —CN, OH, oxo, aryl, heteroaryl, O-aryl, or O-heteroaryl.
2. The compound of claim 1 , wherein Z is O.
3. The compound of claim 1 , wherein B 1 is a natural purinyl nucleobase and B 2 is a natural pyrimidinyl nucleobase.
4. The compound of claim 1 , wherein B 1 is adenosinyl, and B 2 is uracilyl.
5. The compound of claim 1 , wherein B 2 is a natural purinyl nucleobase and B 1 is a natural pyrimidinyl nucleobase.
6. The compound of claim 1 , wherein B 2 is adenosinyl, and B 1 is uracilyl.
7. The compound of claim 1 , wherein each of R 1 and R 2 is independently hydrogen, halo, or OR 7 .
8. The compound of claim 1 , wherein each of X 1 and X 2 is O.
9. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently O or S.
10. The compound of claim 1 , wherein one of Y 1 or Y 2 is O and the other of Y 1 or Y 2 is S.
11. The compound of claim 1 , wherein each of L 1 and L 2 is independently C 1 -C 6 alkyl.
12. The compound of claim 1 , wherein each of R 3 and R 4 is independently hydrogen, aryl, or heteroaryl, wherein aryl and heteroaryl is optionally substituted with 1-5 R 8 .
13. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 R 8 and R 4 is hydrogen.
14. The compound of claim 1 , wherein each of R 3 and R 4 is independently phenyl substituted with 1 R 8 .
15. The compound of claim 1 , wherein each of Y 1 and Y 2 is O and each of R 3 and R 4 is independently hydrogen.
16. The compound of claim 1 , wherein R 8 is OC(O)-aryl or C(O)-aryl optionally substituted by 1-5 R 9 .
17. The compound of claim 16 , wherein R 9 is O—C 1 -C 12 alkyl.
18. A compound selected from the group consisting of:
Com-
pou-
nd
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
30
31
32
33
34
35
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37
38
39
40
41
42
43
44
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46
47
48
49
50
51
52
53
54
55
56
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58
59
60
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62
63
64
65
66
67
68
69
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71
72
73
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77
78
79
80
81
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83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
wherein X + is a pharmaceutically acceptable cation; or
a pharmaceutically acceptable salt thereof.
19. A method of ameliorating, alleviating, or improving at least one symptom of cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
20. A method of ameliorating, alleviating, or improving at least one symptom of a microbial infection or a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .