1,2,4-oxadiazole derivatives as immunomodulators
The present invention relates to 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signaling pathway. The invention also refers to derivatives of the therapeutic agents. The invention also encompasses the use of the said therapeutic agents and derivatives for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them.
1. A compound of formula (I)
wherein,
Q is S or O;
R 1 represents —CH 2 OH or —CH(CH 3 )OH, optionally substituted with alkyl or acyl;
R 2 is hydrogen or —CO-Aaa;
Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is a free terminus, is amidated, or is esterified;
R 3 represents —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , or —CH 2 CH 2 C(O)OH;
----- is an optional bond;
R 4 and R 5 independently are hydrogen or absent;
R 6 is hydrogen, alkyl, or acyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
2. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IA):
or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
R 1 represents —CH 2 OH or —CH(CH 3 )OH, optionally substituted with alkyl or acyl;
R 3 represents —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , or —CH 2 CH 2 C(O)OH; and
Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is a free terminus, is amidated, or is esterified.
3. The compound according to claim 2 , wherein R 1 represents —CH 2 OH or —CH(CH 3 )OH.
4. The compound according to claim 3 , wherein Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus is free.
5. The compound according to claim 2 , wherein Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus is free.
6. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IB):
or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
R 1 represents —CH 2 OH or —CH(CH 3 )OH, optionally substituted with alkyl or acyl; and
R 3 represents —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , or —CH 2 CH 2 C(O)OH.
7. The compound of claim 1 , wherein Q is O.
8. The compound according to claim 7 , wherein R 1 represents —CH 2 OH or —CH(CH 3 )OH.
9. The compound according to claim 8 , wherein Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus is free.
10. The compound of claim 7 , wherein R 6 is H.
11. The compound according to claim 10 , wherein R 1 represents —CH 2 OH or —CH(CH 3 )OH.
12. The compound according to claim 10 , wherein Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus is free.
13. The compound according to claim 7 , wherein Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus is free.
14. The compound according to claim 1 , wherein R 1 represents —CH 2 OH or —CH(CH 3 )OH.
15. The compound according to claim 1 , wherein R 2 is —CO-Aaa.
16. The compound according to claim 1 , wherein R 3 represents —CH 2 C(O)NH 2 or —CH 2 CH 2 C(O)NH 2 .
17. The compound according to claim 1 , wherein R 6 is —C(O)CH 3 , —C(O)CH 2 CH 3 , —C(O)(CH 2 ) 2 CH 3 , —C(O)(CH 2 ) 3 CH 3 , —C(O)(CH 2 ) 4 CH 3 or —C(O)(CH 2 ) 5 CH 3 .
18. The compound of claim 1 , wherein R 6 is H.
19. The compound according to claim 1 , wherein Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus is free.
20. The compound according to claim 19 , wherein R 2 is —CO-Aaa.
21. The compound according to claim 1 , having the following structure:
22. The compound according to claim 1 , having the following structure:
23. The compound according to claim 1 , having the following structure:
24. The compound according to claim 1 , having the following structure:
25. The compound according to claim 1 , having the following structure:
26. The compound according to claim 1 , having the following structure:
27. The compound according to claim 1 , having the following structure:
28. The compound according to claim 1 , having the following structure:
29. The compound according to claim 1 , having the following structure:
30. The compound according to claim 1 , having the following structure:
31. The compound according to claim 1 , having the following structure:
32. The compound according to claim 1 , having the following structure:
33. The compound according to claim 1 , having the following structure:
34. The compound according to claim 1 , having the following structure:
35. The compound according to claim 1 , having the following structure:
36. The compound according to claim 1 , having the following structure:
37. The compound according to claim 1 , having the following structure:
38. The compound according to claim 1 , having the following structure:
39. The compound according to claim 1 , having the following structure:
40. The compound according to claim 1 , having the following structure:
41. The compound according to claim 1 , having the following structure:
42. The compound according to claim 1 , having the following structure:
43. The compound according to claim 1 , having the following structure:
44. The compound according to claim 1 , having the following structure:
45. The compound according to claim 1 , having the following structure:
46. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and at least one compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein,
Q is S or O;
R 1 represents —CH 2 OH or —CH(CH 3 )OH, optionally substituted with alkyl or acyl;
R 2 is hydrogen or —CO-Aaa;
Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is a free terminus, is amidated, or is esterified;
R 3 represents —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , or —CH 2 CH 2 C(O)OH;
----- is an optional bond;
R 4 and R 5 independently are hydrogen or absent; and
R 6 is hydrogen, alkyl, or acyl.
47. The pharmaceutical composition according to claim 46 further comprising at least one of an anticancer agent, a chemotherapy agent, or an antiproliferative compound.