1,2,4-Oxadiazole and thiadiazole compounds as immunomodulators
The present invention relates to 1,2,4-oxadiazole compounds of formula (I) and their use to inhibit the programmed cell death 1 (PD-1) signaling pathway and/or for treatment of disorders by inhibiting an immunosuppressive signal induced by PD-1, PD-L1 or PD-L2.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof; wherein,
X is O or S;
R 1 and R 2 are independently a side chain of an amino acid selected from Ala, Glu, Gln, Ser, Trp, Tyr, Lys, Ile, Asp, Asn, Phe, Thr, Val, Cys, Arg, His, Met, and Leu, hydrogen, cycloalkyl, or (C 1 -C 6 )alkyl; wherein the (C 1 -C 6 )alkyl is optionally substituted by one or more substituents selected from amino, heterocyclylamino, alkylamino, acylamino, carboxylicacid, —CONR 7 R 8 , hydroxy, cycloalkyl, aryl, heteroaryl, guanidino, —SH and —S(alkyl); optionally wherein the aryl is further substituted by one or more substituents; or optionally wherein two or three carbon atoms of the (C 1 -C 6 )alkyl form part of a 3-7 membered heterocyclic ring;
R 3 is —CO-[Aaa1] m ;
R 6 is hydrogen, acyl or alkyl;
R 7 and R 8 independently are hydrogen, (C 1 -C 6 )alkyl, aryl, or heteroaryl;
[Aaa1], independently for each occurrence, represent an amino acid residue having a side chain; wherein a C-terminal carboxyl moiety of the amino acid residue is a free C-terminal carboxyl moiety (—COOH) or a modified C-terminal carboxyl moiety, and an N-terminal amino moiety of the amino acid residue is a free N-terminus (—NH 2 ) or a modified N-terminal amino moiety;
R a is hydrogen, alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl or alkoxyalkyl;
R b is hydrogen, alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl or alkoxyalkyl; or R b and R 2 , together with the atoms to which they are attached, form pyrrolidine or piperidine, each optionally substituted with one or more substituents independently selected from hydroxyl, halo, amino, cyano and alkyl;
m is 1 to 3;
and
provided that when R 2 is a side chain of Asp, Asn, Glu or Gln, R 3 is —CO-Ser or —CO-Thr, R 6 is hydrogen, alkyl or acyl and R a and R b are hydrogen, then R 1 is not a side chain of Ser or Thr.
2. The compound of claim 1 , wherein the compound is of formula (IA):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R b is H.
4. The compound of claim 1 , wherein the side chain of Aaa1 comprises a (C 1 -C 4 )alkyl optionally substituted by one or more substituents, each independently selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, —CONR 7 R 8 , hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, heterocyclyl, heteroaryl, guanidino, —SH, and —S(alkyl); and optionally wherein each cycloalkyl, aryl, heterocyclyl or heteroaryl is further substituted by one or more of hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl.
5. The compound of claim 1 , wherein the side chain of Aaa1 comprises a (C 1 -C 4 )alkyl substituted by one or more substituents each independently selected from amino, acylamino, carboxylic acid, —CONR 7 R 8 , hydroxy, cycloalkyl, aryl, heteroaryl, guanidino, —SH and —S(alkyl); and wherein R 7 and R 8 independently are hydrogen, alkyl, aryl or heterocyclyl.
6. The compound of claim 1 , wherein R a is H.
7. The compound of claim 1 , wherein R 1 is (C 1 -C 6 )alkyl substituted by one or more substituents each independently selected from amino, acylamino, carboxylic acid, —CONR 7 R 8 , hydroxy, cycloalkyl, aryl, heteroaryl, guanidino, —SH, and —S(alkyl); and wherein R 7 and R 8 independently are hydrogen, (C 1 -C 6 )alkyl or aryl.
8. The compound of claim 1 , wherein R 1 is the side chain of an amino acid selected from Ala, Glu, Ser, Trp, Tyr, Lys, Ile, Asn, Phe, Thr, Val, Cys, Arg, His, Met, and Leu.
9. The compound of claim 1 , wherein R 2 is (C 1 -C 6 )alkyl substituted by one or more substituents each independently selected from amino, acylamino, carboxylic acid, —CONR 7 R 8 , hydroxy, cycloalkyl, aryl, heteroaryl, guanidino, —SH and —S(alkyl); and wherein R 7 and R 8 independently are hydrogen or (C 1 -C 6 )alkyl.
10. The compound of claim 1 , wherein R 2 is the side chain of an amino acid selected from Ala, Glu, Ser, Trp, Tyr, Lys, Ile, Asn, Phe, Thr, Val, Cys, Arg, His, Met, and Leu.
11. The compound of claim 1 , wherein R b and R 2 , together with the atoms to which they are attached, form pyrrolidine or piperidine, optionally substituted with one or more substituents, each independently selected from hydroxyl, halo, amino, cyano and alkyl.
12. The compound of claim 1 , wherein R 6 is alkyl.
13. The compound of claim 1 , wherein R 6 is H.
14. The compound of claim 1 , wherein at least one of the amino acid residues is a D amino acid residue.
15. The compound of claim 1 , wherein at least one of the amino acid residues is an L amino acid residue.
16. The compound of claim 1 , represented by a compound of the following table:
Compound 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
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
105
106
107
108
109
110
111
112
113
114
115
117
118
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
18. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 1 .
19. The method of claim 18 , wherein the cancer is selected from lung cancer, breast cancer, colon cancer, renal cancer, bladder cancer, thyroid cancer, prostate cancer, osteosarcoma and Hodgkin's lymphoma.
20. The method of claim 18 , wherein the subject is a mammal.
21. The method of claim 18 , further comprising conjointly administering to the subject a second chemotherapeutic agent.
22. The method of claim 18 , further comprising conjointly administering to the subject one or more non-chemical cancer treatments.
23. A method for inhibiting the PD-1 pathway in a subject, comprising administering to the subject a compound of claim 1 .
24. A method for treating a bacterial infection, a viral infection, a-fungal infection, or an immunological condition, comprising administering to a subject in need thereof a compound of claim 1 .
25. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.