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:
B 1 is a purinyl nucleobase and B 2 is a pyrimidinyl nucleobase; or B 2 is a purinyl nucleobase and B 1 is a 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 N(R 5 );
each of Z 1 is independently O or S;
Z 2 is —O—, —N(R 5 )—, —S—, —C(O)—, —C(O)N(R 5 )—, —OC(O)N(R 5 )—, —N(R 5 )C(O)O—, -aryl-, -heteroaryl-, —S(O)—, —S(O) 2 —, —S(O)N(R 5 )—, —S(O) 2 N(R 5 )—or —N(R 5 )S(O)—;
Z 3 is hydrogen, heterocyclyl, heterocyclyl-C 1 -C 20 -alkylene-Q 1 , —OH, —N(R 5 ) 2 , SR 5 , —CHO, —C(O)N(R 5 ) 2 , —OC(O)N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , aryl, heteroaryl, —S(O)R 5 , —S(O) 2 R 5 , —S(O)N(R 5 ) 2 , —S(O) 2 N(R 5 ) 2 , —N(R 5 )S(O)R 5 , —OSi(C 1 -C 4 alkyl) 3 , or —C(O)C 2 -C 6 alkenyl;
L 1 is absent, -C 1 -C 6 - alkylene, or -C 1 -C 6 - heteroalkylene;
L 2 is absent, -C 1 -C 6 - alkylene or -C 1 -C 6 -heteroalkylene, wherein each alkylene and hetero alkylene is optionally substituted with one or more R 6 ;
L 3 is oligopeptide —C(O)—, oligopeptide-aryl-C 1 -C 6 -alkylene-, oligopeptide-aryl-C 1 -C 6 -heteroalkylene, oligopeptide-aryl-C 1 -C 6 -alkylene-C(O)—, oligopeptide-C 1 -C 6 -alkylene-C(O)—, oligopeptide-C 1 -C 6 -heteroalkylene-C(O)—, -C 1 -C 40 - alkylene, -C 1 -C 40 - heteroalkylene, -C 1 -C 40 - alkenylene, or -C 1 -C 40 - alkynylene, wherein the oligopeptide is attached to Z 3 and is optionally substituted by one or more R 14 ;
Q is C(O), C(S), or CH 2 ;
each of R 1 and R 2 is independently hydrogen, halo, —CN, -C 1 -C 20 alkyl, or OR 7 ;
each 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)—C 1 -C 20 alkyl, alkyl, —OC(O)O—C 1 -C 20 alkyl, —C(O)NR 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, or —N(R 5 )C(O)-heteroaryl, —S(O) 2 N(R 5 )-aryl, wherein each alkyl, heteroalkyl, aryl, and heteroaryl is optionally substituted by one or more R 9 ;
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;
and
each R 14 is independently, -C 1 -C 20 alkyl, -C 1 -C 20 heteroalkyl, —OC(O)OC 1 -C 20 alkyl, C(O)N(R 4 ) 2 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1 , wherein each Z 1 is O.
3. The compound of claim 1 , wherein B 1 is a purinyl nucleobase, and B 2 is a pyrimidinyl nucleobase.
4. The compound of claim 1 , wherein B 1 is adeninyl or guaninyl, and B 2 is cytosinyl, thyminyl, or uracilyl.
5. The compound of claim 1 , wherein each of R 1 and R 2 is independently hydrogen, halo, OR 7 , or CN.
6. The compound of claim 1 , wherein each of X 1 and X 2 is O.
7. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently O or S.
8. The compound of claim 1 , wherein one of Y 1 and Y 2 is O and the other of Y 1 and Y 2 is S.
9. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently S.
10. The compound of claim 1 , wherein each of L 1 and L 2 is independently C 1 -C 6 alkylene.
11. The compound of claim 1 , wherein each of R 3 and R 4 is independently hydrogen, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted with 1-5 R 8 .
12. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 R 8 and R 4 is hydrogen.
13. The compound of claim 1 , wherein each of R 3 and R 4 is independently phenyl substituted with 1 R 8 .
14. The compound of claim 1 , wherein each of Y 1 and Y 2 is O and each of R 3 and R 4 is hydrogen.
15. The compound of claim 1 , wherein each of Y 1 and Y 2 is S and each of R 3 and R 4 is independently substituted with 1 R 8 .
16. The compound of claim 15 , wherein Y 1 is S and R 3 is substituted with 1 R 8 .
17. The compound of claim 1 , wherein R 8 is —OC(O)-aryl, and the aryl is optionally substituted by 1-5 R 9 .
18. The compound of claim 17 , wherein R 9 is —O-C 1 -C 12 alkyl.
19. The compound of claim 1 , wherein Z 2 is —N(R 5 )—; and R 5 is hydrogen.
20. The compound of claim 1 , wherein L 3 is C 1 -C 20 - alkylene, -C 1 -C 20 -heteroalkylene, oligopeptide-C(O)—, oligopeptide-aryl-C 1 -C 6 -alkylene-, oligopeptide-aryl-C 1 -C 6 -heteroalkylene, oligopeptide-aryl-C 1 -C 6 -alkylene-C(O)—, oligopeptide-C 1 -C 6 -alkylene-C(O)—, or oligopeptide-C 1 -C 6 -heteroalkylene-C(O)—.
21. The compound of claim 20 , wherein the oligopeptide consists of 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, or 10 amino acid residues.
22. The compound of claim 20 , wherein L 3 is
23. The compound of claim 1 , wherein Z 3 is
and Q 1 is CH 2 .
24. The compound of claim 1 , wherein the compound is selected from the following table:
Number
Compound
7
8
10
11
13
14
16
17
19
21
or a pharmaceutically acceptable salt thereof.
25. A method of alleviating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
26. A method of inducing the expression of a pattern recognition receptor (PRR) for immune-modulation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
27. A method of inducing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
28. A method of alleviating a microbial infection or a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.