Cyclic Peptidomimetic Compounds as Immunomodulators

Abstract

The present invention relates to cyclic peptidomimetic compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signalling pathway. The invention also relates 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.

What is claimed is: 
     
         1 . A method of modulating an immune response mediated by PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of 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 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 method 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 method 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 method 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 method according to  claim 1 , wherein the compound of formula (I) is a compound in which
 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 0;   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 method according to  claim 1 , wherein the compound of formula (I) is a compound in which R 4  is C 1-5  alkyl; or R 4 ′ is C 1-5  alkyl. 
     
     
         7 . The method according to  claim 1 , wherein the compound of formula (I) has a structure selected from the group consisting of 
       
         
           
                 
                 
               
                     
                 
                   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 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   and 
                 
                     
                 
                   25 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt or a stereoisomer thereof. 
       
     
     
         8 . A method of inhibiting growth of tumour cells and/or metastasis in a subject, comprising administering to the subject a therapeutically effective amount of 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. 
       
     
     
         9 . The method of  claim 8 , wherein the tumour cells are from a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer and renal cancer. 
     
     
         10 . The method of  claim 8 , wherein the tumour cells are from a cancer selected from the group consisting of bone cancer, cancer of the head or neck, pancreatic cancer, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hogkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma cancer of the bladder, cancer of the kidney or reter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. 
     
     
         11 . A method of treating an infectious disease in a subject comprising administering to the subject a therapeutically effective amount of 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. 
       
     
     
         12 . The method according to  claim 11 , wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease. 
     
     
         13 . A method for treating a cancer or infectious disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one of the compounds according to  claim 7  and a pharmaceutically acceptable carrier or excipient. 
     
     
         14 . The method according to  claim 13 , wherein the cancer is breast cancer, colon cancer, lung cancer, melanoma, prostate cancer, or renal cancer. 
     
     
         15 . The method according to  claim 13 , wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease.