1,2,4-Oxadiazole and thiadiazole compounds as immunomodulators

Patent metadata

Field	Value
Publication number	US-10781189-B2
Application number	US-201615556800-A
Country	US
Kind code	B2
Filing date	Mar 7, 2016
Priority date	Mar 10, 2015
Publication date	Sep 22, 2020
Grant date	Sep 22, 2020

Abstract

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.

First claim

We claim:

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

Assignees

• Aurigene Discovery Tech Ltd

Inventors

• Sasikumar Pottayil Govindan Nair
• Ramachandra Muralidhara
• Naremaddepalli Seetharamaiah Setty Sudarshan

Classifications

• C07D271/10

  1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles · CPC title

• C07K5/06078

  and aromatic or cycloaliphatic · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K5/0812

  and aromatic or cycloaliphatic · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title