Cyclic peptidomimetic compounds as immunomodulators
Compounds of Formula (I) are provided: and pharmaceutically acceptable salts and stereoisomers thereof; wherein: R 1 is a side chain of amino acid Ala, Ser, Thr or Leu; R 2 is a side chain of amino acid Asp, Glu, Gln or Asn; [Aaa] is an amino acid residue selected from Ser, ASP, Ala, Ile, Phe, Trp, Lys, Glu or Thr; R 3 is hydrogen or alkyl; each of R 4 and R 4 ′ independently are hydrogen or alkyl; both R a and R a ′ are hydrogen; or together are an oxo (═O) group; both R b and R b ′ are hydrogen; or together are an oxo (═O) group; L is X is CH 2 , O or S; R 5 is hydrogen or alkyl; m is an integer from 1 to 3; and n is an integer from 2 to 20. The compounds are useful 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)
or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein,
R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn;
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr;
R 3 is hydrogen or alkyl;
each of R 4 and R 4 ′ independently are hydrogen or alkyl;
both R a and R a ′ are hydrogen; or together are an oxo (═O) group;
both R b and R b ′ are hydrogen; or together are an oxo (═O) group;
L is
X is CH 2 , O or S;
R 5 is hydrogen or alkyl;
m is an integer from 1 to 3; and
n is an integer from 2 to 20.
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 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn;
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr;
R 3 is hydrogen or alkyl;
each of R 4 and R 4 ′ independently are hydrogen or alkyl;
both R a and R a ′ are hydrogen; or together are an oxo (═O) group; and
both R b and R b ′ are hydrogen; or together are an oxo (═O) group.
3. 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 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn; and
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr.
4. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IC):
or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein,
R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn; and
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr.
5. The compound according to claim 1 , wherein,
R 1 is a side chain of amino acid Ser or Thr;
R 2 is aside chain of amino acid Asp, Asn or Glu;
[Aaa] is an amino acid residue Ser or Thr;
R 3 , R 4 and R 4 ′ independently are hydrogen;
both R a and R a ′ together represent an oxo (═O) group;
both R b and R b ′ together represent an oxo (═O) group;
L is —C(O)—(CH 2 ) m —(X—CH 2 —CH 2 ) n —NH—;
X is CH 2 or O;
m is an integer from 1 to 3; and
n is an integer from 2 to 20;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
6. The compound according to claim 1 , wherein R 4 is C 1-5 alkyl; or R 4 ′ is C 1-5 alkyl.
7. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
8. The pharmaceutical composition according to claim 7 further comprising at least one of an anticancer agent, chemotherapy agent, or antiproliferative compound.
9. A compound having a structural formula selected from the group consisting of
Com-
pound
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
or a pharmaceutically acceptable salt or a stereoisomer thereof.
10. A pharmaceutical composition comprising at least one of the compounds according to claim 9 and a pharmaceutically acceptable carrier or excipient.