1,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators
The present invention relates to 1,2,4-oxadiazole and thiadiazole compounds of formula (I) and their use to inhibit the programmed cell death 1 (PD1) 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 each independently a side chain of an amino acid, hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or cycloalkyl; wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or cycloalkyl is optionally substituted by one or more substituents, selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic acid ester, thiocarboxylate, thioacid, —CONR 7 R 8 , hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, guanidino, —SH and —S(alkyl); optionally wherein cycloalkyl, aryl, heterocyclyl or heteroaryl is further substituted by one or more substituents and optionally wherein two or three carbon atoms of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl form part of a 3-7-membered carbocyclic or heterocyclic ring;
R 3 is —S(O) p -[Aaa1] m ;
R 6 is hydrogen, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, or acyl;
R 7 and R 8 independently are hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or heterocyclyl; wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or heterocyclyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, aryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl; optionally wherein two or three carbon atoms of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl form part of a 3-7-membered carbocyclic or heterocyclic ring; or
alternatively R 7 and R 8 together with the nitrogen to which they are attached form an optionally substituted 3-7-membered ring containing 0-2 additional heteroatoms independently selected from N, O and S in any stable combination; wherein the optional substituent at each occurrence is selected from hydroxyl, —COOH, —COO-alkyl, amide, halo, amino, nitro and cyano;
[Aaa1] 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 or an alkyl substituted C-terminal carboxyl moiety or the C-terminal moiety is optionally substituted amido, or optionally substituted heteroaryl, and an N-terminal amino moiety of the amino acid residue is a free N-terminus;
R a is hydrogen or alkyl;
R b is hydrogen, 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, 2, or 3; and
p is 1 or 2.
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, 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); optionally wherein cycloalkyl, aryl, heterocyclyl or heteroaryl.
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, 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 8 )alkyl optionally substituted by one or more substituents, selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic acid ester, thiocarboxylate, thioacid, —CONR 7 R 8 , hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, guanidino, —SH, and —S(alkyl); and optionally wherein cycloalkyl, aryl, heterocyclyl or heteroaryl.
8 . The compound of claim 1 , wherein R 1 is (C 1 -C 8 )alkyl substituted by one or more substituents 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 or aryl.
9 . The compound of claim 1 , wherein R 1 is the side chain of an amino acid.
10 . The compound of claim 1 , wherein R 1 is a side chain of an amino acid selected from Ala, Asn, Asp, Tyr, Lys, Ser, Thr, Gln, Ile, Val, Glu, Arg, Leu, Trp, His, Met, Cys, and Phe.
11 . The compound of claim 1 , wherein R 2 is (C 1 -C 8 )alkyl optionally substituted by one or more substituents, selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic acid ester, thiocarboxylate, thioacid, —CONR 7 R 8 , hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, guanidino, —SH, and —S(alkyl); and optionally wherein cycloalkyl, aryl, heterocyclyl or heteroaryl.
12 . The compound of claim 1 , wherein R 2 is (C 1 -C 8 )alkyl substituted by one or more substituents, 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 alkyl.
13 . The compound of claim 1 , wherein R 2 is the side chain of an amino acid.
14 . The compound of claim 1 , wherein R 2 is a side chain of an amino acid selected from Ala, Asn, Ile, Lys, Phe, Glu, Asp, Trp, Val, Ser, Gln, Tyr, Thr, Met, Arg, and Leu.
15 . 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, independently selected from hydroxyl, halo, amino, cyano and alkyl.
16 . The compound of claim 1 , wherein R 6 is H.
17 . The compound of claim 1 , wherein at least one of the amino acid residues is a D amino acid residue.
18 . The compound of claim 1 , wherein at least one of the amino acid residues is an L amino acid residue.
19 . The compound of claim 1 , wherein the compound is:
Compound No.
Structure
97
98
99
100
101
102
103
104
119
120
121
122
123
124
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
20 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.