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 adeninyl;
B 2 is uracilyl;
each of X 1 and X 2 is independently O or S;
Y 1 is S or NR 5 and Y 2 is O, S, or NR 5 ; or Y 2 is S or NR 5 and Y 1 is O, S, or NR 5 ;
each of L 1 and L 2 is independently 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 , 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)O-aryl, 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 ;
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 the compound is a compound of Formulas (I-b), (I-c), (I-d), or (I-e):
or a pharmaceutically acceptable salt thereof, wherein each of B 1 , B 2 , X 1 , X 2 , Y 1 , Y 2 , L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , and subvariables thereof are defined as in claim 1 .
3. The compound of claim 1 , wherein each of R 1 and R 2 is independently hydrogen, halo, or OR 7 .
4. The compound of claim 1 , wherein each of R 1 and R 2 is independently halo.
5. The compound of claim 1 , wherein each of R 1 and R 2 is not hydrogen or OR 7 .
6. The compound of claim 1 , wherein each of X 1 and X 2 is independently 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 or Y 2 is O and the other of Y 1 or Y 2 is S.
9. The compound of claim 1 , wherein each of Y 1 or 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 alkyl.
11. 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 .
12. The compound of claim 1 , wherein R 3 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R 8 , and R 4 is hydrogen.
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 Y 2 is O and R 4 is hydrogen.
16. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently S and each of R 3 and R 4 is independently substituted with 1 R 8 .
17. The compound of claim 1 , wherein Y 1 is S and R 3 is substituted with 1 R 8 .
18. The compound of claim 1 , wherein R 8 is OC(O)-aryl optionally substituted by 1-5 R 9 .
19. The compound of claim 1 , wherein R 9 is O—C 1 -C 12 alkyl.
20. The compound of claim 1 , wherein the compound is selected from:
Structure
or a pharmaceutically acceptable salt thereof; wherein X is a pharmaceutically acceptable cation.
21. A method of treating acute monocytic leukemia, lymphoma, melanoma, colon cancer, or breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
22. The method of claim 21 , wherein the method comprises intratumoral administration of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
23. The method of claim 21 , wherein the method comprises oral administration of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
24. The method of claim 21 , wherein the method comprises parenteral administration of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
25. The method of claim 24 , wherein the parenteral administration comprises intraperitoneal administration.
26. The method of claim 21 , further comprising administration of an additional agent.
27. The method of claim 26 , wherein the additional agent comprises methotrexate, 5-fluorouracil, doxorubicin, vincristine, bleomycin, vinblastine, dacarbazine, toposide, cisplatin, epirubicin, or sorafenib tosylate.
28. A method of inducing the expression of a pattern recognition receptors (PRRs) for immune-modulation in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
29. A method of inducing the expression of a pattern recognition receptors for immunomodulation and inducing a therapeutic response in a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
30. A method of inducing an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
31. The method of claim 30 , wherein the immune response comprises antitumoral immunity.
32. The method of claim 30 , wherein the immune response comprises induction of a PRR.