Imidazolidin-2-one compounds as prmt5 modulators

Abstract

The present invention relates to the derivatives of compound of formula (I) and pharmaceutically acceptable salts thereof. The present invention further provides the methods of preparation of compound of formula (I) and use thereof as PRMT5 inhibitors. The compounds are useful as medicaments in the treatment of conditions where PRMT5 inhibition is desired, such as cancer, metabolic disorders, inflammation, autoimmune disease and hemoglobinopathies.

We claim: 
     
         1 . A method for the treatment or prevention of diseases or disorders mediated by PRMT5, comprising administering to a subject in need thereof a therapeutically effective amount of compound of formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
    represents a single bond or double bond; 
 A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; 
 Y is hydrogen, —SO 2 R a , —NR a R b , —C(O)R a , —C(O)NR a R b , —NHC(O)R a , —COOH, cyano, halogen, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl or oxo; wherein the said alkyl, alkenyl and alkynyl are optionally substituted with 1 to 3 groups selected from hydroxyl, halogen, acyl and heterocycloalkyl; 
 R is hydrogen, alkyl or halogen; 
 R a  is hydrogen, alkyl, halogen, alkoxy, heterocycloalkyl or cycloalkyl; wherein the heterocycloalkyl and cycloalkyl are optionally substituted with 1 to 3 groups selected from alkyl, hydroxyl, halogen and acyl; 
 R b  is hydrogen or alkyl; 
 R 1  is hydrogen or alkyl; R 2  is hydrogen, alkyl or absent; or R 1  and R 2  together represents an oxo group; 
 R 3  is hydrogen or alkyl; R 4  is hydrogen, alkyl, aryl or absent; or R 3  and R 4  together with the atoms to which they are attached form 3- to 8-membered cycloalkyl ring; 
 alternatively, R 1  and R 3  together with the atoms to which they are attached form, an optionally substituted aryl, heteroaryl or cycloalkyl, wherein the optional substituent is selected from 1 to 3 occurrences of R 5 ; 
 R 5  is alkyl, halogen or cyano; 
 ‘n’ is 1, 2 or 3; 
 ‘m’ is 0 or 1. 
 
     
     
         2 . The method of  claim 1 , wherein the diseases or disorders mediated by PRMT5 is cancer, a blood disorder, an inflammatory disorder, an autoimmune disease, proliferative disorder, metabolic disorder, a hereditary disorder, a hormone-related disease, immunodeficiency disorders, a condition associated with cell death, a destructive bone disorder, thrombin-induced platelet aggregation, liver disease or a cardiovascular disorder. 
     
     
         3 . The method of  claim 2 , wherein the cancer is solid tumor, benign or malignant tumor, carcinoma of the brain, kidney, lung, liver, stomach, vagina, ovaries, esophageal, gastric tumors, breast, bladder, colon, prostate, pancreas, lung, cervix, testis, skin, bone or thyroid; sarcoma, medulloblastoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, adenoma, adenocarcinoma, rectum adenocarcinoma, colon adenocarcinoma, lung adenocarcinoma keratoacanthoma, epidermoid carcinoma, hepatocellular carcinoma, large cell carcinoma, renal cell carcinoma, oligodendoglioma, ovarian clear cell carcinoma, ovarian serous crystadenocarcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematopoietic carcinoma, hematological malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell pro lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulnemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma. 
     
     
         4 . The method of  claim 2 , wherein blood disorder is sickle cell anemia or beta-thalessemia. 
     
     
         5 . The method of  claim 2 , wherein metabolic disorder is diabetes or obesity.